A three-dimensional valve-on-chip microphysiological system implicates cell cycle progression, cholesterol metabolism and protein homeostasis in early calcific aortic valve disease progression.

BACKGROUND: Calcific aortic valve disease (CAVD) is one of the most common forms of valvulopathy, with a 50 % elevated risk of a fatal cardiovascular event, and greater than 15,000 annual deaths in North America alone. The treatment standard is valve replacement as early diagnostic, mitigation, and drug strategies remain underdeveloped. The development of early diagnostic and therapeutic strategies requires the fabrication of effective in vitro valve mimetic models to elucidate early CAVD mechanisms. METHODS: In this study, we developed a multilayered physiologically relevant 3D valve-on-chip (VOC) system that incorporated aortic valve mimetic extracellular matrix (ECM), porcine aortic valve interstitial cell (VIC) and endothelial cell (VEC) co-culture and dynamic mechanical stimuli. Collagen and glycosaminoglycan (GAG) based hydrogels were assembled in a bilayer to mimic healthy or diseased compositions of the native fibrosa and spongiosa. Multiphoton imaging and proteomic analysis of healthy and diseased VOCs were performed. RESULTS: Collagen-based bilayered hydrogel maintained the phenotype of the VICs. Proteins related to cellular processes like cell cycle progression, cholesterol biosynthesis, and protein homeostasis were found to be significantly altered and correlated with changes in cell metabolism in diseased VOCs. This study suggested that diseased VOCs may represent an early, adaptive disease initiation stage, which was corroborated by human aortic valve proteomic assessment. CONCLUSIONS: In this study, we developed a collagen-based bilayered hydrogel to mimic healthy or diseased compositions of the native fibrosa and spongiosa layers. When the gels were assembled in a VOC with VECs and VICs, the diseased VOCs revealed key insights about the CAVD initiation process. STATEMENT OF SIGNIFICANCE: Calcific aortic valve disease (CAVD) elevates the risk of death due to cardiovascular pathophysiology by 50 %, however, prevention and mitigation strategies are lacking, clinically. Developing tools to assess early disease would significantly aid in the prevention of disease and in the development of therapeutics. Previously, studies have utilized collagen and glycosaminoglycan-based hydrogels for valve cell co-cultures, valve cell co-cultures in dynamic environments, and inorganic polymer-based multilayered hydrogels; however, these approaches have not been combined to make a physiologically relevant model for CAVD studies. We fabricated a bi-layered hydrogel that closely mimics the aortic valve and used it for valve cell co-culture in a dynamic platform to gain mechanistic insights into the CAVD initiation process using proteomic and multiphoton imaging assessment.

Mitral regurgitation increases systolic strains in remote zone and worsens left ventricular dyssynchrony in a swine model of ischemic cardiomyopathy.

Background: Ischemic mitral regurgitation (IMR) imposes volume overload on the left ventricle (LV), accelerating adverse LV remodeling. In this study, we sought to investigate the impact of volume overload due to IMR on regional myocardial contractile mechanics. Methods: Ten Yorkshire swine were induced with myocardial infarction (MI) by occluding the left circumflex coronary artery (LCx). Cardiac MRI was performed at baseline (BL) and 2.5 months (2.5M) post-MI. IMR was quantified with epicardial echocardiography 3 months post-MI. The animals were then assigned to 2 groups: no/mild MR (nmMR, n = 4) and moderate/severe MR (msMR, n = 6). MRI images were analyzed to assess infarction size, end-diastolic and end-systolic volume (EDV and ESV, respectively), ejection fraction (EF), longitudinal strain (LS), circumferential strain (CS), and systolic dyssynchrony index (SDI). The myocardial region was divided into infarction, border, and remote zones based on the LCx-supplied region. Results: There was no difference in the infarction size. Group-wise comparison of LS and CS between BL and 2.5M demonstrated that LS and CS in the infarction zone and the border zone decreased at 2.5M in both groups. However, LS and CS in the remote zone were elevated only in the msMR group (LS: -9.81 ± 3.96 vs. -12.58 ± 5.07, p < 0.01; CS; -12.78 ± 3.81 vs. -16.09 ± 3.33, p < 0.01) at 2.5M compared to BL. The SDI of CS was significantly elevated in the msMR group (0.1255 vs. 0.0974, p = 0.015) at 2.5M compared to BL. Conclusions: Elevated LS and CS in the remote zone were observed in moderate/severe MR and ventricular dyssynchrony. These elevated cardiac strains, coupled with ventricular dyssynchrony, may contribute to the progression of MR, thereby accelerating heart failure.

A Comparison of Normalization Techniques for Individual Baseline-Free Estimation of Absolute Hypovolemic Status Using a Porcine Model.

Hypovolemic shock is one of the leading causes of death in the military. The current methods of assessing hypovolemia in field settings rely on a clinician assessment of vital signs, which is an unreliable assessment of hypovolemia severity. These methods often detect hypovolemia when interventional methods are ineffective. Therefore, there is a need to develop real-time sensing methods for the early detection of hypovolemia. Previously, our group developed a random-forest model that successfully estimated absolute blood-volume status (ABVS) from noninvasive wearable sensor data for a porcine model (n = 6). However, this model required normalizing ABVS data using individual baseline data, which may not be present in crisis situations where a wearable sensor might be placed on a patient by the attending clinician. We address this barrier by examining seven individual baseline-free normalization techniques. Using a feature-specific global mean from the ABVS and an external dataset for normalization demonstrated similar performance metrics compared to no normalization (normalization: R2 = 0.82 ± 0.025|0.80 ± 0.032, AUC = 0.86 ± 5.5 × 10-3|0.86 ± 0.013, RMSE = 28.30 ± 0.63%|27.68 ± 0.80%; no normalization: R2 = 0.81 ± 0.045, AUC = 0.86 ± 8.9 × 10-3, RMSE = 28.89 ± 0.84%). This demonstrates that normalization may not be required and develops a foundation for individual baseline-free ABVS prediction.

Dynamic Coronary Blood Flow Velocity and Wall Shear Stress Estimation Using Ultrasound in an Ex Vivo Porcine Heart.

PURPOSE: Wall shear stress (WSS) is a critically important physical factor contributing to atherosclerosis. Mapping the spatial distribution of local, oscillatory WSS can identify important mechanisms underlying the progression of coronary artery disease. METHODS: In this study, blood flow velocity and time-varying WSS were estimated in the left anterior descending (LAD) coronary artery of an ex vivo beating porcine heart using ultrasound with an 18 MHz linear array transducer aligned with the LAD in a forward-viewing orientation. A pulsatile heart loop with physiologically-accurate flow was created using a pulsatile pump. The coronary artery wall motion was compensated using a local block matching technique. Next, 2D and 3D velocity magnitude and WSS maps in the LAD coronary artery were estimated at different time points in the cardiac cycle using an ultrafast Doppler approach. The blood flow velocity estimated using the presented approach was compared with a commercially-available, calibrated single element blood flow velocity measurement system. RESULTS: The resulting root mean square error (RMSE) of 2D velocity magnitude acquired from a high frequency, linear array transducer was less than 8% of the maximum velocity estimated by the commercial system. CONCLUSION: When implemented in a forward-viewing intravascular ultrasound device, the presented approach will enable dynamic estimation of WSS, an indicator of plaque vulnerability in coronary arteries.

An Animal Model of Functional Tricuspid Regurgitation by Leaflet Tethering Using Image-Guided Chordal Encircling Snares.

Several interventional therapies are in development to treat functional tricuspid regurgitation. Most have failed to achieve adequate efficacy, as animal models of this lesion are lacking. We developed a new image-guided technique in swine, by tethering the tricuspid valve chordae using echo-guided chordal encircling snares. Five swine underwent baseline echocardiographic assessment of tricuspid valve function, followed by echo-guided placement of snares that encircle the chordae inserting into the anterior and posterior tricuspid valve leaflets. Tethering these snares and stabilizing them on the right ventricle caused the regurgitant fraction to increase from 8.48±5.38% to 48.76±12.5%, and the valve tenting area to increase from 60.26±52.19 to 160.9±86.92 mm2. Image-guided chordal encircling snares could reproducibly induce clinically significant levels of functional tricuspid regurgitation and create a valve geometry like that seen in patients, providing a new animal model for use to study novel interventional devices.

Transapical ventricular reshaping reduces functional mitral regurgitation and improves ventricular function in a preclinical model of ischemic cardiomyopathy.

OBJECTIVE: A significant proportion of patients with advanced heart failure present with dilated left ventricles and functional mitral regurgitation. These patients currently have limited treatment options. The MitraClip device (Abbott) has benefited only patients with smaller left ventricles (end-diastolic dimension <70 mm), whereas those with larger left ventricles did not benefit. A possible explanation is correcting functional mitral regurgitation alone may not adequately reduce the wall stresses of a dilated left ventricle. We have developed a beating-heart device that not only approximates the papillary muscles to reduce functional mitral regurgitation but also modifies the left ventricle size and shape to reduce wall stress. METHODS: Yorkshire swine (n = 16) had a myocardial infarction induced by permanent occlusion of the left circumflex with intracoronary ethanol. Three months later, the animals developed heart failure and moderate or greater functional mitral regurgitation. Through a transapical approach, the new device was implanted under echocardiography guidance to reshape the left ventricle and correct functional mitral regurgitation. The acute impact of this approach on the mitral valve and left ventricle was assessed with echocardiography and invasive hemodynamics. RESULTS: After reshaping, echocardiography showed a decrease in end-diastolic volume by 36.3 ± 30.5 mL (P < .001), a decrease in sphericity index by 0.143 ± 0.087 (P < .001), and an increase in ejection fraction of 5.90% ± 6.38% (P < .01). Mitral valve tenting area was reduced by 39.29 ± 33.66 mm2 (P < .001), coaptation length was increased by 2.12 ± 1.02 mm (P < .001), and posterior excursion angle was improved by 9.07° ± 9.14° (P < .01), resulting in functional mitral regurgitation reduction. CONCLUSIONS: Correction of functional mitral regurgitation with favorable changes in mitral valve geometry and reduction in left ventricle geometry is possible with the proposed device.

Computational Modeling of the Subject-Specific Effects of Annuloplasty Ring Sizing on the Mitral Valve to Repair Functional Mitral Regurgitation.

Surgical repair of functional mitral regurgitation (FMR) that occurs in nearly 60% of heart failure (HF) patients is currently performed with undersizing mitral annuloplasty (UMA), which lacks short- and long-term durability. Heterogeneity in valve geometry makes tailoring this repair to each patient challenging, and predictive models that can help with planning this surgery are lacking. In this study, we present a 3D echo-derived computational model, to enable subject-specific, pre-surgical planning of the repair. Three computational models of the mitral valve were created from 3D echo data obtained in three pigs with HF and FMR. An annuloplasty ring model in seven sizes was created, each ring was deployed, and post-repair valve closure was simulated. The results indicate that large annuloplasty rings (> 32 mm) were not effective in eliminating regurgitant gaps nor in restoring leaflet coaptation or reducing leaflet stresses and chordal tension. Smaller rings (≤ 32 mm) restored better systolic valve closure in all investigated cases,but excessive valve tethering and restricted motion of the leaflets were still present. This computational study demonstrates that for effective correction of FMR, the extent of annular reduction differs between subjects, and overly reducing the annulus has deleterious effects on the valve.

Chronic in utero mitral inflow obstruction unloads left ventricular volume in a novel late gestation fetal lamb model.

Objective: The in utero no flow/no grow hypothesis postulates that reduced inflow of blood into the left ventricle due to a stenotic mitral valve could lead to ventricular hypoplasia and hypoplastic left heart syndrome. This has been demonstrated in chick embryos, but less so in large animals. We investigated the impact of mitral obstruction on left and right ventricular growth in fetal lambs. Methods: Twelve pregnant ewes, most bearing twins, were instrumented at 119 ± 1 days gestational age. Carotid artery and jugular vein catheters, an ascending aorta flow probe, and a left atrial deflated balloon catheter were implanted into 1 fetus (left atrial balloon group), and the twin remained an uninstrumented control. The balloon was inflated gradually over 8 days until net antegrade aortic flow was eliminated. Fetal transesophageal echocardiography was performed at the time of surgery and just before termination in both groups. Results: Terminal fetal body weights were comparable between groups. Terminal heart/body weight ratio was higher in left atrial balloon group fetuses (6.9 ± 0.8 g/kg) compared with controls (5.9 ± 0.6 g, P = .0126). The left ventricular/right ventricular weight ratio was 24% (P = .0077) lower in left atrial balloon group fetuses than in controls. Left ventricular/heart weight (0.24 ± 0.04 g/g vs 0.30 ± 0.04 g/g, P = .0009), left ventricular end-diastolic volume (2.3 ± 0.7 mL vs 7.1 ± 0.8 mL; P = .0012), and left ventricular end-systolic volume (1.01 mL [0.95-1.95 mL] vs 3.38 mL [3.28-3.57 mL], P = .0042) were lower in left atrial balloon group fetuses compared with controls. Right ventricular weight (g/kg), right ventricular end-diastolic volume, and right ventricular end-systolic volume were similar between groups. Conclusions: In this late-gestation fetal lamb model, in utero obstruction of mitral inflow slowed left ventricular growth and caused right ventricular remodeling.

Research Opportunities in the Treatment of Mitral Valve Prolapse: JACC Expert Panel.

In light of the adverse prognosis related to severe mitral regurgitation, heart failure, or sudden cardiac death in a subset of patients with mitral valve prolapse (MVP), identifying those at higher risk is key. For the first time in decades, researchers have the means to rapidly advance discovery in the field of MVP thanks to state-of-the-art imaging techniques, novel omics methodologies, and the potential for large-scale collaborations using web-based platforms. The National Heart, Lung, and Blood Institute recently initiated a webinar-based workshop to identify contemporary research opportunities in the treatment of MVP. This report summarizes 3 specific areas in the treatment of MVP that were the focus of the workshop: 1) improving management of degenerative mitral regurgitation and associated left ventricular systolic dysfunction; 2) preventing sudden cardiac death in MVP; and 3) understanding the mechanisms and progression of MVP through genetic studies and small and large animal models, with the potential of developing medical therapies.

In vivo efficacy of a polymer layered decellularized matrix composite as a cell honing cardiovascular tissue substitute.

Cardiovascular surgery involves reconstruction of tissues that are under cyclical mechanical loading, and in constant contact with pulsatile blood flow. Durable biomaterials for such tissue reconstruction are scarce, as they need to be mechanically strong, hemocompatible, and resist structural deterioration from calcification. While homografts are ideal, they are scarce; xenografts are immunogenic and rendered inactive from glutaraldehyde fixation, causing them to calficy and structurally deteriorate over time; decellularized xenografts are devoid of cells, mechanically weak; and synthetic polymeric scaffolds are thrombogenic or too dense to enable host cell infiltration. In this work, we report the in vivo feasibility of a new polymer-decellularized matrix composite material (decellularized bovine pericardium-polycaprolactone: chitosan) fabricated by electrospinning, which is designed to be mechanically strong and achieve programmed host cell honing to integrate into the host. In a rodent and sheep model, this new material was found to be hemocompatible, and enabled host cell infiltration into the polymer and the decellularized matrix core underlying the polymer. Presence of M2 macrophages and several vascular cell types, with matrix remodeling in the vicinity of the cells was observed in the explanted tissues. In summary, the proposed composite material is a novel approach to create in-situ host integrating tissue substitutes, with better non-thrombogenicity, reduced infections and endocarditis, and potentially the ability to grow with the patient and remodeling into a native tissue structure.

Passive mechanical properties of the left ventricular myocardium and extracellular matrix in hearts with chronic volume overload from mitral regurgitation.

Cardiac volume overload from mitral regurgitation (MR) is a trigger for left ventricular dilatation, remodeling, and ultimate failure. While the functional and structural adaptations to this overload are known, the adaptation of myocardial mechanical properties remains unknown. Using a rodent model of MR, in this study, we discern changes in the passive material properties of the intact and decellularized myocardium. Eighty Sprague-Dawley rats (350-400 g) were assigned to two groups: (1) MR (n = 40) and (2) control (n = 40). MR was induced in the beating heart by perforating the mitral leaflet with a 23G needle, and rats were terminated at 2, 10, 20, or 40 weeks (n = 10/time-point). Echocardiography was performed at baseline and termination, and explanted hearts were used for equibiaxial mechanical testing of the intact myocardium and after decellularization. Two weeks after inducing severe MR, the myocardium was more extensible compared to control, however, stiffness and extensibility of the extracellular matrix did not differ from control at this timepoint. By 20 weeks, the myocardium was stiffer with a higher elastic modulus of 1920 ± 246 kPa, and a parallel rise in extracellular matrix stiffness. Despite some matrix stiffening, it only contributed to 31% and 36% of the elastic modulus of the intact tissue in the circumferential and longitudinal directions. At 40 weeks, similar trends of increasing stiffness were observed, but the contribution of extracellular matrix remained relatively low. Chronic MR induces ventricular myocardial stiffening, which seems to be driven by the myocyte compartment of the muscle, and not the extracellular matrix.

A Biohybrid Material With Extracellular Matrix Core and Polymeric Coating as a Cell Honing Cardiovascular Tissue Substitute.

Objective: To investigate the feasibility of a hybrid material in which decellularized pericardial extracellular matrix is functionalized with polymeric nanofibers, for use as a cardiovascular tissue substitute. Background: A cardiovascular tissue substitute, which is gradually resorbed and is replaced by host's native tissue, has several advantages. Especially in children and young adults, a resorbable material can be useful in accommodating growth, but also enable rapid endothelialization that is necessary to avoid thrombotic complications. In this study, we report a hybrid material, wherein decellularized pericardial matrix is functionalized with a layer of polymeric nanofibers, to achieve the mechanical strength for implantation in the cardiovascular system, but also have enhanced cell honing capacity. Methods: Pericardial sacs were decellularized with sodium deoxycholate, and polycaprolactone-chitosan fibers were electrospun onto the matrix. Tissue-polymer interaction was evaluated using spectroscopic methods, and the mechanical properties of the individual components and the hybrid material were quantified. In-vitro blood flow loop studies were conducted to assess hemocompatibility and cell culture methods were used to assess biocompatibility. Results: Encapsulation of the decellularized matrix with 70 µm thick matrix of polycaprolactone-chitosan nanofibers, was feasible and reproducible. Spectroscopy of the cross-section depicted new amide bond formation and C-O-C stretch at the interface. An average peel strength of 56.13 ± 11.87 mN/mm2 was measured, that is sufficient to withstand a high shear of 15 dynes/cm2 without delamination. Mechanical strength and extensibility ratio of the decellularized matrix alone were 18,000 ± 4,200 KPa and 0.18 ± 0.03% whereas that of the hybrid was higher at 20,000 ± 6,600 KPa and 0.35 ± 0.20%. Anisotropy index and stiffness of the biohybrid were increased as well. Neither thrombus formation, nor platelet adhesion or hemolysis was measured in the in-vitro blood flow loop studies. Cellular adhesion and survival were adequate in the material. Conclusion: Encapsulating a decellularized matrix with a polymeric nanofiber coating, has favorable attributes for use as a cardiovascular tissue substitute.

Patient-Specific Three-Dimensional Ultrasound Derived Computational Modeling of the Mitral Valve.

Several new techniques to repair the mitral valve affected by functional mitral regurgitation are in development. However, due to the heterogeneity of valve lesions between patients, predicting the outcomes of novel treatment approaches is challenging. We present a patient-specific, 3D ultrasound-derived computational model of the mitral valve for procedure planning, that faithfully mimics the pathological valve dynamics. 3D ultrasound images were obtained in three pigs induced with heart failure and which developed functional mitral regurgitation. For each case, images were segmented, and finite element model of mitral valve was constructed. Annular and papillary muscle dynamics were extracted and imposed as kinematic boundary conditions, and the chordae were pre-strained to induce valve tethering. Valve closure was simulated by applying physiologic transvalvular pressure on the leaflets. Agreement between simulation results and truth datasets was confirmed, with accurate location of regurgitation jets and coaptation defects. Inclusion of kinematic patient-specific boundary conditions was necessary to achieve these results, whereas use of idealized boundary conditions deviated from the truth dataset. Due to the impact of boundary conditions on the model, the effect of repair strategies on valve closure varied as well, indicating that our approach of using patient-specific boundary conditions for mitral valve modeling is valid.

In vivo safety study using radiation at wavelengths and dosages relevant to intravascular imaging.

SIGNIFICANCE: Intravascular photoacoustic (IVPA) imaging can identify native lipid in atherosclerotic plaques in vivo. However, the large number of laser pulses required to produce 3D images is a safety concern that has not been fully addressed. AIM: We aim to evaluate if irradiation at wavelengths and dosages relevant to IVPA imaging causes target vessel damage. APPROACH: We irradiate the carotid artery of swine at one of several energy dosages using radiation at 1064 or 1720 nm and use histological evaluation by a pathologist to identify dose-dependent damage. RESULTS: Media necrosis was the only dose-dependent form of injury. Damage was present at a cumulative fluence of 50 J / cm2 when using 1720 nm light. Damage was more equivocally identified at 700 J / cm2 using 1064 nm. CONCLUSIONS: In prior work, IVPA imaging of native lipid in swine has been successfully conducted below the damage thresholds identified. This indicates that it will be possible to use IVPA imaging in a clinical setting without damaging vessel tissue. Future work should determine if irradiation causes an increase in blood thrombogenicity and confirm whether damaged tissue will heal over longer time points.

Effect of early versus late onset mitral regurgitation on left ventricular remodeling in ischemic cardiomyopathy in an animal model.

BACKGROUND: Patients who survive a myocardial infarction have progressive cardiac dysfunction and ventricular remodeling. Mitral regurgitation is often diagnosed in these patients, and is a risk factor that portends poor prognosis. Whether such postinfarction mitral regurgitation magnifies adverse left ventricular remodeling is unclear, which was studied in an animal model. METHODS: Forty-one adult rats were induced with myocardial infarction using left coronary artery ligation and assigned to 3 groups: group 1, myocardial infarction only; group 2, myocardial infarction with severe mitral regurgitation introduced after 4 weeks; and group 3, myocardial infarction with severe mitral regurgitation introduced after 10 weeks. Valve regurgitation was introduced by advancing a transapical ultrasound-guided needle into the mitral valve anterior leaflet. Animals were survived to 20 weeks from the index procedure, with biweekly cardiac ultrasound, and invasive hemodynamics and histology at termination. RESULTS: At 20 weeks, end diastolic volume was largest in the groups with mitral regurgitation, compared with the group without the valve lesion (group 1, 760.9 ± 124.6 µL; group 2, 958.0 ± 115.1 µL; group 3, 968.3 ± 214.9 µL). Similarly, end systolic volume was larger in groups with regurgitation (group 1, 431.2 ± 152.6 µL; group 2, 533.2 ± 130.8 µL; group 3, 533.1 ± 177.5 µL). In the infarction-only group, left ventricular remodeling was maximal until 6 weeks and plateaued thereafter. In groups with mitral regurgitation, left ventricular remodeling was significantly elevated at the onset of regurgitation and persisted. CONCLUSIONS: Mitral regurgitation is a potent driver of adverse cardiac remodeling after a myocardial infarction, irrespective of the timing of its onset.

Undersizing mitral annuloplasty alters left ventricular mechanics in a swine model of ischemic mitral regurgitation.

OBJECTIVE: Undersizing mitral annuloplasty (UMA) is a frequently used surgical repair technique to correct ischemic mitral regurgitation in patients with heart failure. In this study, we sought to test the hypothesis that downsizing the mitral annulus can adversely affect the shape and mechanics of the left ventricle inhibiting its functional recovery. METHODS: Eighteen farm swine that underwent an inferolateral myocardial infarction and developed ischemic mitral regurgitation of >2+ severity after 2 months were assigned as follows: 9 swine received an undersized mitral annuloplasty, 6 received papillary muscle approximation (PMA), and 3 animals did not receive any other intervention. Animals lived another 3 months and cardiac magnetic resonance imaging was performed before termination to assess ventricle mechanics and function. RESULTS: Ejection fraction was comparable between the 2 repair groups before surgery, but was significantly lower in UMA at 38.89% ± 7.91% versus 50.83% ± 9.04% in the PMA group (P = .0397). Animals receiving UMA had lower regional peak fractional shortening and reduced systolic and diastolic radial velocities compared with PMA and in some regions were lower than sham. Animals that underwent UMA had higher circumferential strain than sham, but lower than PMA. UMA animals have lower longitudinal strain compared to sham group and lower LV torsion than PMA. CONCLUSIONS: Undersizing the mitral annulus with an annuloplasty ring can restore valvular competence, but unphysiologically impair ventricle mechanics. Mitral valve repair strategies should focus not only on restoring valve competence, but preserving ventricle mechanics.

Image-Guided Targeted Mitral Valve Tethering with Chordal Encircling Snares as a Preclinical Model of Secondary Mitral Regurgitation.

Development of transcatheter mitral valve interventions has ushered a significant need for large animal models of secondary mitral regurgitation. Though currently used heart failure models that chronically develop secondary mitral regurgitation are viable, the severity is lower than patients, the incubation time is long, and mortality is high. We sought to develop a swine model of acute secondary mitral regurgitation that uses image-guided placement of snares around the mitral chordae. Twenty-seven adult swine (n = 27) were assigned to secondary mitral regurgitation induced by valve tethering with image-guided chordal encircling snares (group 1, n = 7, tether MR (tMR)); secondary mitral regurgitation by percutaneous posterolateral myocardial infarction causing ventricular dysfunction and regurgitation (group 2, n = 6, functional MR (fMR)); and control animals (group 3, n = 14). Regurgitant fraction in tMR was 42.1 ± 14.2%, in fMR was 22 ± 9.6%, and in controls was 5.3 ± 3.8%. Mitral tenting height was 9.6 ± 1.3 mm in tMR, 10.1 ± 1.5 mm in fMR, and 5.8 ± 1.2 mm in controls. Chordal encircling tethers reproducibly induce clinically relevant levels of secondary mitral regurgitation, providing a new animal model for use in translational research.