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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 mm 2 (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., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

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., Competing Interests: MP reports stock ownership, board directorship and employment in Nyra Medical Inc. MP also received personal consulting fees from Heart Repair Technologies, and research grants from Heart Repair Technologies. MP led this work when he was at Emory University. DO received personal consulting fees from Nyra Medical Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Kikuchi, Onohara, Silverman, King, Tom, Govin, Guyton and Padala.)

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 mm 2 . 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., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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., (© 2023. The Author(s) under exclusive licence to Biomedical Engineering Society.)

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: R 2 = 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: R 2 = 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.

Many heart diseases can change the elasticity of myocardial tissues, making elastography a potential medical imaging strategy for heart disease diagnosis and cardiovascular risk assessment. Among the existing elastography methods, ultrasound elastography is an appealing choice because of ultrasound's inherent advantages of low cost, high safety, wide availability, and deep penetration. The existing investigations of cardiac ultrasound elastography were implemented based on a bulk model of heart tissue, treating the waves generated in the myocardial tissues as shear waves. In this pilot study, we considered the distinct geometric characteristics of heart tissue, i.e., being a layered structure and its dispersive nature as biological tissue. Based on these considerations, we modeled heart tissues as a layered-dispersive structure and developed a new ultrasound elastography method, ultrasonic guided wave elastography, to characterize the myocardial elasticity. The validity of this layered-dispersive model and the reliability of the developed guided wave elastography were first verified on tissue-mimicking phantoms. Then, the guided wave elastography was applied to an ex vivo imaging of a rat heart tissue specimen in real-time during the biaxial planar mechanical testing. The comparison of the real-time myocardial elasticity obtained from guided wave elastography and mechanical testing demonstrated strong matching, verifying the reliability of the developed cardiac guided wave elastography as a potential method for characterizing myocardial elasticity., Competing Interests: Conflict of Interest The authors declare that the research was conducted without any commercial or financial relationships that could potentially create a conflict of interest.

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., Competing Interests: M.P. reports stock ownership, board directorship, and employment in Nyra Medical Inc; receives personal consulting fees from Heart Repair Technologies and research grants from Heart Reparit Technologies; received Single Ventricle Blue Sky grant from Additional Ventures; and led this work when he was at Emory University. D.O. received personal consulting fees from Nyra Medical Inc. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (© 2023 The Author(s).)

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., (© 2023. The Author(s) under exclusive licence to Biomedical Engineering Society.)

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., Competing Interests: Funding Support and Author Disclosures Dr Delling is supported by the UCSF Resource Allocation Program 7501268 and by National Institutes of Health (NIH) research grant R01HL153447. Dr Noseworthy has received research funding from the NIH, including the National Heart, Lung, and Blood Institute (R21AG 62580-1, R01HL 131535-4, R01HL 143070-2), the National Institute on Aging (R01AG 062436-1), Agency for Healthcare Research and Quality (R01HS 25402-3), Food and Drug Administration (FD 06292), and the American Heart Association (18SFRN34230146; has filed patents related to the application of artificial intelligence to the ECG for diagnosis and risk stratification and has licensed several A-ECG algorithms to Anumana; is involved in potential equity/royalty relationship with AliveCor; is a study investigator in an ablation trial sponsored by Medtronic; and has served on an expert advisory panel for OptumLabs. Dr Adams’s institution, the Icahn School of Medicine at Mount Sinai, receives royalties for mitral and tricuspid valve repair prostheses related to his intellectual property from Edwards Lifesciences and Medtronic. Dr Borger’s institution receives speakers’ honoraria and/or consulting fees on his behalf from Edwards Lifesciences, Medtronic, Abbott, and CryoLife. Dr Elmariah has received research funding from the NIH (R01HL 151838) and the American Heart Association (19TPA34910170); has received research grants from Edwards Lifesciences, Medtronic, and Abbott Vascular; and is a consultant for Edwards Lifesciences. Dr Gerstenfeld has received lecture honoraria from Medtronic, Boston Scientific, and Abbott; has received research funding from, is on the scientific advisory board, and has received compensation from Biosense Webster; is on the scientific advisory board for and is PI of a clinical ablation trial sponsored by Farapulse; and is on the Data and Safety Monitoring Board for trials sponsored by Thermedical Inc and Abbott. Dr Norris has received research funding from the NIH (HL131546, GM103444, HL149696, HL122906), and the American Heart Association (19TPA34850095, 20SRG35540029, 19TPA34900016, 17CSA33590067). Dr Padala is supported by the National Heart, Lung, and Blood Institute (R01HL135145, R01HL140325, R01HL133667, R01HL144714, R01HL135505) and by the National Institute of Biomedical Imaging and Bioengineering (R01EB031101); has significant stock ownership and a role as a director in Nyra Medical; and has received consulting fees from Heart Repair Technologies Inc in the last 12 months. Dr Weinsaft is supported by NIH research grants R01HL128278 and R01HL151686. Dr Enriquez-Sarano has served as a consultant for Edwards, Cryolife, ChemImage, and HighLife. Dr Levine is supported by NIH research grants R01HL128099 and R01HL141917, American Heart Association 963793/Levine/2022, and funding of the Ellison Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2021 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jahnavi Mudigonda reports financial support was provided by American Heart Association. Muralidhar Padala reports financial support was provided by Carlyle Fraser Heart Center at Emory University Hospital Midtown. Muralidhar Padala reports a relationship with Nyra Medical, Inc and Heart Repair Technologies that includes: consulting or advisory and equity or stocks. Muralidhar Padala and Jahnavi Mudigonda has patent #PCT/US21/58 ​063 pending to PCT., (© 2022 The Authors.)

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., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Surgical annuloplasty for functional tricuspid regurgitation (FTR) is on the rise and can be performed in several ways with varied outcomes. In this study, we sought to compare the hemodynamic outcomes of tricuspid annuloplasty performed with a commercially available annuloplasty ring (tricuspid valve annuloplasty [TVA]) compared with focal suture annuloplasty (Hetzer) in an experimental FTR model., Methods: An ex vivo FTR model was developed by inducing right ventricular dilatation by acute afterload elevation, causing severe tricuspid valve tethering and annular dilatation, leading to regurgitation. Ten porcine hearts in which FTR was induced underwent TVA with a 26-mm Edwards MC3 ring and Hetzer annuloplasty with a pledgeted suture cinching the anteroposterior and septal annulus. FTR was measured before after each repair, and tenting geometry, valve kinematics, and subvalvular geometry were measured with echocardiography., Results: At baseline, none of the hearts had FTR, but upon afterload elevation an FTR volume of 17.7 ± 9.2 mL (26.38 ± 17.47% regurgitant fraction) was measured (P < .0001). TVA reduced regurgitation by 50% and Hetzer annuloplasty by 56% , respectively, but both left persistent FTR. Anteroseptal tenting area was 279.0 ± 158.9 mm 2 before repair and decreased significantly to 147.2 ± 134.8 mm 2  (P = .0195) with Hetzer but not with TVA. Posteroseptal tenting area was 425.1 ± 169.2 mm 2 before repair and was significantly reduced by both techniques (TVA: 200.3 ± 102.9 mm 2 [P = .0012]; Hetzer: 237.6 ± 127.6 mm 2 [P = .0270])., Conclusions: Tricuspid annuloplasty with a ring or a focal suture can reduce FTR but not eliminate it. Annular approaches did not relieve tricuspid valve tethering and reduced leaflet mobility persisted. Either subannular repairs or judicious use of valve replacement may be necessary., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

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., (© 2022 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

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., (© 2022. The Author(s) under exclusive licence to Biomedical Engineering Society.)

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., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: The left ventricle remodels from an ellipsoidal/conical shape to a spherical shape after a myocardial infarction. The spherical ventricle is inefficient as a pumping chamber, has higher wall stresses, and can lead to congestive heart failure. We sought to investigate if restoring physiological ventricular shape with a beating heart implant improves pump function., Methods: Rats were induced with a myocardial infarction, developing left ventricular dilatation and dysfunction, and becoming spherical over 3 weeks. Thereafter, they were randomized to undergo left ventricular reshaping with a beating heart implant (n = 19) or continue follow-up without an implant (n = 19). Biweekly echocardiography was performed until 12 weeks, with half the rats euthanized at 6 weeks and remaining at 12 weeks. At termination, invasive hemodynamic parameters and histopathology were performed., Results: At 3 weeks after the infarction, rats had a 22% fall in ejection fraction, 31% rise in end diastolic volume, and 23% rise in sphericity. Transventricular implant reshaping reduced the volume by 12.6% and sphericity by 21%, restoring physiologic ventricular shape and wall stress. Over the 12-week follow-up, pump function improved significantly with better ventricular-vascular coupling in the reshaped hearts. In this group, cardiomyocyte cross-section area was higher and the cells were less elongated., Conclusions: Reshaping a postinfarction, failing left ventricle to restore its physiological conical shape significantly improves long-term pump function., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

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/mm 2 was measured, that is sufficient to withstand a high shear of 15 dynes/cm 2 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., Competing Interests: JM and MP are co-inventors of a patent application relevant to this technology, whose rights are assigned to Emory University. MP owns stock in Nyra Medical, and is an officer of this company. This entity did not have any role in this study, nor did it sponsor or review it. MP has received personal consulting fees from Heart Repair Technologies, which again did not have any role in this work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mudigonda, Xu, Amedi, Lane, Corporan, Wang and Padala.)

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.

Introduction: Mitral regurgitation (MR) imposes volume overload on the left ventricle (LV) and elevates wall stress, triggering its adverse remodeling. Pronounced LV dilation, minimal wall thinning, and a gradual decline in cardiac ejection fraction (EF) are observed. The structural changes in the myocardium that define these gross, organ level remodeling are not known. Cardiomyocyte elongation and slippage have both been hypothesized, but neither are confirmed, nor are the changes to the cardiomyocyte structure known. Using a rodent model of MR, we used immunohistochemistry and transmission electron microscopy (TEM) to describe the ultrastructural remodeling of the cardiomyocyte. Methods: Twenty-four male Sprague-Dawley rats (350-400 g) were assigned to two groups: group (1) rats induced with severe MR ( n = 18) and group (2) control rats that were healthy and age and weight matched ( n = 6). MR was induced in the beating heart using a 23-G ultrasound-guided, transapical needle to perforate the anterior mitral leaflet, and the rats were followed to 2, 10, and 20 weeks ( n = 6/time-point). Echocardiography was performed to quantify MR severity and to measure LV volume and function at each time-point. Explanted myocardial tissue were examined with TEM and immunohistochemistry to investigate the ultrastructural changes. Results: MR induced rapid and significant increase in end-diastolic volume (EDV), with a 50% increase by 2 weeks, compared with control. Rise in end-systolic volume (ESV) was more gradual; however, by 20 weeks, both EDV and ESV in MR rats were increased by 126% compared with control. A significant decline in EF was measured at 10 weeks of MR. At the ultrastructural level, as early as 2 weeks after MR, cardiomyocyte elongation and increase in cross-sectional area were observed. TEM depicted sarcomere shortening, with loss of Z-line and I-band. Desmin, a cytoskeletal protein that is uniformly distributed along the length of the cardiomyocyte, was disorganized and localized to the intercalated disc, in the rats induced with MR and not in the controls. In the rats with MR, the linear registry of the mitochondrial arrangement along the sarcomeres was lost, with mitochondrial fragmentation, aggregation around the nucleus, and irregularities in the cristae. Discussion: In the setting of chronic mitral regurgitation, LV dilatation occured by cardiomyocyte elongation, which manifests at the subcellular level as distinct ultrastructural alterations of the sarcomere, cytoskeleton, and mitochondria. Since the cytoskeleton not only provides tensegrity but has functional consequences on myocyte function, further investigation into the impact of cytoskeletal remodeling on progressive heart failure or recovery of function upon correcting the valve lesion are needed., Competing Interests: MP is a consultant to Heart Repair Technologies Inc and Boston Scientific, and receives consulting fees. MP also discloses a significant stock ownership in Nyra Medical Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Corporan, Segura and Padala.)

Background: Undersizing mitral annuloplasty (UMA) to repair functional mitral regurgitation lacks durability, as it forces leaflet coaptation without relieving the sub-leaflet tethering forces. In this biomechanical study, we demonstrate that papillary muscle approximation (PMA) prior to UMA can drastically relieve tethering forces and improve valve function, without the need for significant annular downsizing., Methods: An ex vivo model of functional mitral regurgitation (FMR) was used, in which pig mitral valves were geometrically perturbed to induce FMR, and the repairs were performed. Nine pig mitral valves were studied as follows: normal(baseline), functional mitral regurgitation (FMR), true-sized annuloplasty to 30mm (TSR), and undersized annuloplasty to 26mm (DSR); and concomitant papillary muscle approximation (PMA) at both ring sizes. Mitral regurgitation, valve kinematics, and chordal forces were measured and compared between groups., Results: FMR geometry induced a 16.31±7.33% regurgitant fraction, compared to none at baseline. 30mm/TSR reduced regurgitation to 6.05±5.63% and a 26mm/DSR to 5.06±6.76%. Addition of papillary muscle approximation prior to either rings, reduced regurgitation to 3.87±6.79% with the true sized ring (TSR+PMA), and 3.71±6.25% with the downsized ring (DSR+PMA). Peak anterior and posterior marginal chordal forces were elevated to 0.09±0.1N and 0.12±0.1N respectively with FMR, which were not reduced by annuloplasty of either sizes. Addition of PMA, reduced the forces significantly to 0.23±0.02N and 0.51±0.04N., Conclusion: This biomechanical study, demonstrates that papillary muscle approximation relieves tethering forces and when added to annuloplasty, and mobilizes the leaflets to achieve a good valve closure. Such a result could be achieved without the need for extensive annular downsizing., Competing Interests: Conflict of interest: There are no direct conflicts of interest in this work. MP reports consulting fees from Heart Repair Technologies. MP, KSS, ELS report stock ownership in Nyra Medical. Neither of these entities sponsored or had any role in this work.

Objective: Primary mitral regurgitation is a valvular lesion in which the left ventricular ejection fraction remains preserved for long periods, delaying a clinical trigger for mitral valve intervention. In this study, we sought to investigate whether adverse left ventricular remodeling occurs before a significant fall in ejection fraction and characterize these changes., Methods: Sixty-five rats were induced with severe mitral regurgitation by puncturing the mitral valve leaflet with a 23-G needle using ultrasound guidance. Rats underwent longitudinal cardiac echocardiography at biweekly intervals and hearts explanted at 2 weeks (n = 15), 10 weeks (n = 15), 20 weeks (n = 15), and 40 weeks (n = 15). Sixty age- and weight-matched healthy rats were used as controls. Unbiased RNA-sequencing was performed at each terminal point., Results: Regurgitant fraction was 40.99 ± 9.40%, with pulmonary flow reversal in the experimental group, and none in the control group. Significant fall in ejection fraction occurred at 14 weeks after mitral regurgitation induction. However, before 14 weeks, end-diastolic volume increased by 93.69 ± 52.38% (P < .0001 compared with baseline), end-systolic volume increased by 118.33 ± 47.54% (P < .0001 compared with baseline), and several load-independent pump function indices were reduced. Transcriptomic data at 2 and 10 weeks before fall in ejection fraction indicated up-regulation of myocyte remodeling and oxidative stress pathways, whereas those at 20 and 40 weeks indicated extracellular matrix remodeling., Conclusions: In this rodent model of mitral regurgitation, left ventricular ejection fraction was preserved for a long duration, yet rapid and severe left ventricular dilatation, and biological remodeling occurred before a clinically significant fall in ejection fraction., (Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Calcific aortic valve disease (CAVD) pathophysiology is a complex, multistage process, usually diagnosed at advanced stages after significant anatomical and hemodynamic changes in the valve. Early detection of disease progression is thus pivotal in the development of prevention and mitigation strategies. In this study, we developed a diet-based, non-genetically modified mouse model for early CAVD progression, and explored the utility of two-photon excited fluorescence (TPEF) microscopy for early detection of CAVD progression. TPEF imaging provides label-free, non-invasive, quantitative metrics with the potential to correlate with multiple stages of CAVD pathophysiology including calcium deposition, collagen remodeling and osteogenic differentiation., Methods: Twenty-week old C57BL/6J mice were fed either a control or pro-calcific diet for 16 weeks and monitored via echocardiography, histology, immunohistochemistry, and quantitative polarized light imaging. Additionally, TPEF imaging was used to quantify tissue autofluorescence (A) at 755 nm, 810 nm and 860 nm excitation, to calculate TPEF 755-860 ratio (A 860/525 /(A 755/460  + A 860/525 )) and TPEF Collagen-Calcium ratio (A 810/525 /(A 810/460  + A 810/525 )) in the murine valves. In a separate experiment, animals were fed the above diets till 28 weeks to assess for later-stage calcification., Results: Pro-calcific mice showed evidence of lipid deposition at 4 weeks and calcification at 16 weeks at the valve commissures. The valves of pro-calcific mice also showed positive expression for markers of osteogenic differentiation, myofibroblast activation, proliferation, inflammatory cytokines and collagen remodeling. Pro-calcific mice exhibited lower TPEF autofluorescence ratios, at locations coincident with calcification, that correlated with increased collagen disorganization and positive expression of osteogenic markers. Additionally, locations with lower TPEF autofluorescence ratios at 4 and 16 weeks exhibited increased calcification at later 28-week timepoints., Conclusions: This study suggests the potential of TPEF autofluorescence metrics to serve as a label-free tool for early detection and monitoring of CAVD pathophysiology.

Objective: Mitral regurgitation (MR) developing concomitant with ischemic cardiomyopathy is a frequently diagnosed valvular lesion, for which an optimal therapeutic strategy is unknown. The contribution of MR to the ongoing cardiac remodeling from myocardial infarction (MI) remains controversial. We have developed a novel experimental model in which MI and severe MR can be independently introduced, to study the role of MR in chronic remodeling of the ischemic heart., Methods: A total of 98 rats were induced with MI+MR (group 1), MI (group 2), MR (group 3), or sham surgery (group 4). MR was induced by inserting a needle into the anterior mitral leaflet via the ventricular apex in a beating heart. MI was induced by ligating the left coronary artery. Biweekly ultrasound examinations were performed after surgery, and invasive hemodynamic assessments were performed in some rats at 2, 10, and 20 weeks., Results: At 2 weeks postsurgery, the mean end-diastolic volume was 432 ± 103 μL in ischemic hearts with MR, compared with 390 ± 76.3 μL in ischemic hearts without MR (a 10.76% difference). By 20 weeks, the mean volume was significantly greater in the former group (767 ± 246 μL vs 580 ± 85 μL; a 32.24% difference). At 2 weeks, mean end-systolic volume was 147 ± 46.8 μL in the ischemic hearts with MR and 147 ± 45.7 μL in those without MR. By 20 weeks, the mean volumes had increased to 357 ± 136.4 μL and 271 ± 82.3 μL, respectively (a 31.73% difference)., Conclusions: MR in ischemic hearts significantly increased end-diastolic and end-systolic volumes of the left ventricle, indicating adverse cardiac remodeling and worse systolic function., (Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Functional mitral regurgitation in the setting of an enlarged heart is challenging to repair surgically with an annular approach, and the need to develop subannular and ventricular approaches is recognized yet unrealized because of the lack of models for investigations. In this study, we report a novel model of functional mitral regurgitation induced by left ventricular thinning and distension in pig hearts. Seven pig hearts were explanted at a local slaughterhouse, and left ventricular distension induced by thinning the ventricular myocardium by 60-65% of its original thickness. Distension of the thinned hearts with a 120 mmHg column confirmed significant left ventricular dilatation and mitral valve tethering. These hearts were then mounted into a pulsatile flow model and animated at 120 mmHg left ventricular pressure, 5 L/min cardiac output at 70 beats/min. Echocardiography was used to assess valvular kinematics and hemodynamics. Left ventricular wall thickness reduced by 60.5% ± 10.1% at the basal plane, 64.8% ± 11.3% at the equatorial plane, and 64.0% ± 11.4% at the apical plane after thinning. Upon distension, ventricular volumes increased by 852.4% ± 639.8% after left ventricular thinning, with an 89.5% ± 33.9% increase in sphericity index. Mitral valve systolic tenting height increased from 7.92 ± 2.06 to 15.02 ± 3.89 mm, systolic tethering area increased from 130.7 ± 38.2 to 409.9 ± 124.6 mm and an average mitral regurgitation fraction of 24.4% ± 16.6% was measured. In a case study, use of multimodality imaging to test the efficacy of transcatheter mitral devices was confirmed. Ventricular wall thinning leading to passive left ventricular distension and dilatation is a reproducible ex vivo model of mitral valve tethering and functional mitral regurgitation, which in combination with multimodality imaging provides a good simulation model.

Risk stratification in coronary artery disease is an ongoing challenge for which few tools are available for quantifying physiology within coronary arteries. Recently, anatomy-driven computational fluid dynamic modeling has enabled the mapping of local flow dynamics in coronary stenoses, with derived parameters such as WSS exhibiting a strong capability for predicting adverse clinical events on a patient-specific basis. As cardiac catheterization is common in patients with coronary artery disease, minimally invasive technologies capable of identifying pathologic flow in situ in real time could have a significant impact on clinical decision- making. As a step toward in vivo quantification of slow flow near the arterial wall, proof-of-concept for 3-D intravascular imaging of blood flow dynamics is provided using a 118-element forward-viewing ring array transducer and a research ultrasound system. Blood flow velocity components are estimated in the direction of primary flow using an unfocused wave Doppler approach, and in the lateral and elevation directions, using a transverse oscillation approach. This intravascular 3-D vector velocity system is illustrated by acquiring real-time 3-D data sets in phantom experiments and in vivo in the femoral artery of a pig. The effect of the catheter on blood flow dynamics is also experimentally assessed in flow phantoms with both straight and stenotic vessels. Results indicate that 3-D flow dynamics can be measured using a small form factor device and that a hollow catheter design may provide minimal disturbance to flow measurements in a stenosis (peak velocity: 54.97 ± 2.13 cm/s without catheter vs. 51.37 ± 1.08 cm/s with hollow catheter, 6.5% error). In the future, such technologies could enable estimation of 3-D flow dynamics near the wall in patients already undergoing catheterization., (Copyright © 2020 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Mitral regurgitation (MR) is a widely prevalent heart valve lesion, which causes cardiac remodeling and leads to congestive heart failure. Though the risks of uncorrected MR and its poor prognosis are known, the longitudinal changes in cardiac function, structure and remodeling are incompletely understood. This knowledge gap has limited our understanding of the optimal timing for MR correction, and the benefit that early versus late MR correction may have on the left ventricle. To investigate the molecular mechanisms that underlie left ventricular remodeling in the setting of MR, animal models are necessary. Traditionally, the aorto-caval fistula model has been used to induce volume overload, which differs from clinically relevant lesions such as MR. MR represents a low-pressure volume overload hemodynamic stressor, which requires animal models that mimic this condition. Herein, we describe a rodent model of severe MR in which the anterior leaflet of the rat mitral valve is perforated with a 23G needle, in a beating heart, with echocardiographic image guidance. The severity of MR is assessed and confirmed with echocardiography, and the reproducibility of the model is reported.