Stromal cell-derived factor-1 alpha improves cardiac function in a novel diet-induced coronary atherosclerosis model, the SR-B1ΔCT/LDLR KO mouse.

BACKGROUND AND AIMS: There are a limited number of pharmacologic therapies for coronary artery disease, and few rodent models of occlusive coronary atherosclerosis and consequent myocardial infarction with which one can rapidly test new therapeutic approaches. Here, we characterize a novel, fertile, and easy-to-use HDL receptor (SR-B1)-based model of atherogenic diet-inducible, fatal coronary atherosclerosis, the SR-B1ΔCT/LDLR KO mouse. Additionally, we test intramyocardial injection of Stromal Cell-Derived Factor-1 alpha (SDF-1α), a potent angiogenic cytokine, as a possible therapy to rescue cardiac function in this mouse. METHODS: SR-B1ΔCT/LDLR KO mice were fed the Paigen diet or standard chow diet, and we determined the effects of the diets on cardiac function, histology, and survival. After two weeks of feeding either the Paigen diet (n = 24) or standard chow diet (n = 20), the mice received an intramyocardial injection of either SDF-1α or phosphate buffered saline (PBS). Cardiac function and angiogenesis were assessed two weeks later. RESULTS: When six-week-old mice were fed the Paigen diet, they began to die as early as 19 days later and 50% had died by 38 days. None of the mice maintained on the standard chow diet died by day 72. Hearts from mice on the Paigen diet showed evidence of cardiomegaly, myocardial infarction, and occlusive coronary artery disease. For the five mice that survived until day 28 that underwent an intramyocardial injection of PBS on day 15, the average ejection fraction (EF) decreased significantly from day 14 (the day before injection, 52.1 ± 4.3%) to day 28 (13 days after the injection, 30.6 ± 6.8%) (paired t-test, n = 5, p = 0.0008). Of the 11 mice fed the Paigen diet and injected with SDF-1α on day 15, 8 (72.7%) survived to day 28. The average EF for these 8 mice increased significantly from 48.2 ± 7.2% on day 14 to63.6 ± 6.9% on day 28 (Paired t-test, n = 8, p = 0.003). CONCLUSIONS: This new mouse model and treatment with the promising angiogenic cytokine SDF-1α may lead to new therapeutic approaches for ischemic heart disease.

Large Animal Translational Validation of 3 Mitral Valve Repair Operations for Mitral Regurgitation Using a Mitral Valve Prolapse Model: A Comprehensive In Vivo Biomechanical Engineering Analysis.

BACKGROUND: Various mitral repair techniques have been described. Though these repair techniques can be highly effective when performed correctly in suitable patients, limited quantitative biomechanical data are available. Validation and thorough biomechanical evaluation of these repair techniques from translational large animal in vivo studies in a standardized, translatable fashion are lacking. We sought to evaluate and validate biomechanical differences among different mitral repair techniques and further optimize repair operations using a large animal mitral valve prolapse model. METHODS: Male Dorset sheep (n=20) had P2 chordae severed to create the mitral valve prolapse model. Fiber Bragg grating force sensors were implanted to measure chordal forces. Ten sheep underwent 3 randomized, paired mitral valve repair operations: neochord repair, nonresectional leaflet remodeling, and triangular resection. The other 10 sheep underwent neochord repair with 2, 4, and 6 neochordae. Data were collected at baseline, mitral valve prolapse, and after each repair. RESULTS: All mitral repair techniques successfully eliminated regurgitation. Compared with mitral valve prolapse (0.54±0.18 N), repair using neochord (0.37±0.20 N; P=0.02) and remodeling techniques (0.30±0.15 N; P=0.001) reduced secondary chordae peak force. Neochord repair further decreased primary chordae peak force (0.21±0.14 N) to baseline levels (0.20±0.17 N; P=0.83), and was associated with lower primary chordae peak force compared with the remodeling (0.34±0.18 N; P=0.02) and triangular resectional techniques (0.36±0.27 N; P=0.03). Specifically, repair using 2 neochordae resulted in higher peak primary chordal forces (0.28±0.21 N) compared with those using 4 (0.22±0.16 N; P=0.02) or 6 neochordae (0.19±0.16 N; P=0.002). No difference in peak primary chordal forces was observed between 4 and 6 neochordae (P=0.05). Peak forces on the neochordae were the lowest using 6 neochordae (0.09±0.11 N) compared with those of 4 neochordae (0.15±0.14 N; P=0.01) and 2 neochordae (0.29±0.18 N; P=0.001). CONCLUSIONS: Significant biomechanical differences were observed underlying different mitral repair techniques in a translational large animal model. Neochord repair was associated with the lowest primary chordae peak force compared to the remodeling and triangular resectional techniques. Additionally, neochord repair using at least 4 neochordae was associated with lower chordal forces on the primary chordae and the neochordae. This study provided key insights about mitral valve repair optimization and may further improve repair durability.

Structural, angiogenic, and immune responses influencing myocardial regeneration: a glimpse into the crucible.

Complete cardiac regeneration remains an elusive therapeutic goal. Although much attention has been focused on cardiomyocyte proliferation, especially in neonatal mammals, recent investigations have unearthed mechanisms by which non-cardiomyocytes, such as endothelial cells, fibroblasts, macrophages, and other immune cells, play critical roles in modulating the regenerative capacity of the injured heart. The degree to which each of these cell types influence cardiac regeneration, however, remains incompletely understood. This review highlights the roles of these non-cardiomyocytes and their respective contributions to cardiac regeneration, with emphasis on natural heart regeneration after cardiac injury during the neonatal period.

Beating Heart Transplant Procedures Using Organs From Donors With Circulatory Death.

Importance: The use of ex vivo normothermic organ perfusion has enabled the use of deceased after circulatory death (DCD) donors for heart transplants. However, compared with conventional brain death donation, DCD heart transplantation performed with ex vivo organ perfusion involves an additional period of warm and cold ischemia, exposing the allograft to multiple bouts of ischemia reperfusion injury and may contribute to the high rates of extracorporeal membrane oxygenation usage after DCD heart transplantation. Objective: To assess whether the beating heart method of DCD heart transplantation is safe and whether it has an acceptable rate of extracorporeal membrane oxygenation use postoperatively. Design, Setting, and Participants: This case series includes 10 patients with end-stage heart failure undergoing DCD heart transplantation at a single academic medical center from October 1, 2022, to August 3, 2023. Data were analyzed from October 2022 to August 2023. Interventions: Using a beating heart method of implantation of the donor allograft. Main Outcomes and Measures: The main outcome was primary graft dysfunction necessitating postoperative initiation of mechanical circulatory support. Survival and initiation of mechanical circulatory support were secondary outcomes. Results: In this case series, 10 consecutive patients underwent DCD heart transplantation via the beating heart method. Ten of 10 recipients were male (100%), the mean (SD) age was 51.2 (13.8) years, and 7 (70%) had idiopathic dilated cardiomyopathy. Ten patients (100%) survived, and 0 patients had initiation of extracorporeal membrane oxygenation postoperatively. No other mechanical circulatory support, including intra-aortic balloon pump, was initiated postoperatively. Graft survival was 100% (10 of 10 patients), and, at the time of publication, no patients have been listed for retransplantation. Conclusions and Relevance: In this study of 10 patients undergoing heart transplantation, the beating heart implantation method for DCD heart transplantation was safe and may mitigate ischemia reperfusion injury, which may lead to lower rates of primary graft dysfunction necessitating extracorporeal membrane oxygenation. These results are relevant to institutions using DCD donors for heart transplantation.

Four decades of progress in heart-lung transplantation: Two hundred seventy-one cases at a single institution.

OBJECTIVE: The objective of this study is to evaluate survival for combined heart-lung transplant (HLTx) recipients across 4 decades at a single institution. We aim to summarize our contemporary practice based on more than 271 HLTx procedures over 40 years. METHODS: Data were collected from a departmental database and the United Network for Organ Sharing. Recipients younger than age 18 years, those undergoing redo HLTx, or triple-organ system transplantation were excluded, leaving 271 patients for analysis. The pioneering era was defined by date of transplant between 1981 and 2000 (n = 155), and the modern era between 2001 and 2022 (n = 116). Survival analysis was performed using cardinality matching of populations based on donor and recipient age, donor and recipient sex, ischemic time, and sex matching. RESULTS: Between 1981 and 2022, 271 HLTx were performed at a single institution. Recipients in the modern era were older (age 42 vs 34 y; P < .001) and had shorter waitlist times (78 vs 234 days; P < .001). Allografts from female donors were more common in the modern era (59% vs 39%; P = .002). In the matched survival analysis, 30-day survival (97% vs 84%; P = .005), 1-year survival (89% vs 77%; P = .041), and 10-year survival (53% vs 26%; P = .012) significantly improved in the modern era relative to the pioneering era, respectively. CONCLUSIONS: Long-term survival in HLTx is achievable with institutional experience and may continue to improve in the coming decades. Advances in mechanical circulatory support, improved maintenance immunosuppression, and early recognition and management of acute complications such as primary graft dysfunction and acute rejection have dramatically improved the prognosis for recipients of HLTx in our contemporary institutional experience.

Electrophysiological mapping of the epicardium via 3D-printed flexible arrays.

Cardiac electrophysiology mapping and ablation are widely used to treat heart rhythm disorders such as atrial fibrillation (AF) and ventricular tachycardia (VT). Here, we describe an approach for rapid production of three dimensional (3D)-printed mapping devices derived from magnetic resonance imaging. The mapping devices are equipped with flexible electronic arrays that are shaped to match the epicardial contours of the atria and ventricle and allow for epicardial electrical mapping procedures. We validate that these flexible arrays provide high-resolution mapping of epicardial signals in vivo using porcine models of AF and myocardial infarction. Specifically, global coverage of the epicardial surface allows for mapping and ablation of myocardial substrate and the capture of premature ventricular complexes with precise spatial-temporal resolution. We further show, as proof-of-concept, the localization of sites of VT by means of beat-to-beat whole-chamber ventricular mapping of ex vivo Langendorff-perfused human hearts.

Dedifferentiation and Proliferation of Artery Endothelial Cells Drive Coronary Collateral Development in Mice.

BACKGROUND: Collateral arteries act as natural bypasses which reroute blood flow to ischemic regions and facilitate tissue regeneration. In an injured heart, neonatal artery endothelial cells orchestrate a systematic series of cellular events, which includes their outward migration, proliferation, and coalescence into fully functional collateral arteries. This process, called artery reassembly, aids complete cardiac regeneration in neonatal hearts but is absent in adults. The reason for this age-dependent disparity in artery cell response is completely unknown. In this study, we investigated if regenerative potential of coronary arteries is dictated by their ability to dedifferentiate. METHODS: Single-cell RNA sequencing of coronary endothelial cells was performed to identify differences in molecular profiles of neonatal and adult endothelial cells in mice. Findings from this in silico analyses were confirmed with in vivo experiments using genetic lineage tracing, whole organ immunostaining, confocal imaging, and cardiac functional assays in mice. RESULTS: Upon coronary occlusion, neonates showed a significant increase in actively cycling artery cells and expressed prominent dedifferentiation markers. Data from in silico pathway analyses and in vivo experiments suggested that upon myocardial infarction, cell cycle reentry of preexisting neonatal artery cells, the subsequent collateral artery formation, and recovery of cardiac function are dependent on arterial VegfR2 (vascular endothelial growth factor receptor-2). This subpopulation of dedifferentiated and proliferating artery cells was absent in nonregenerative postnatal day 7 or adult hearts. CONCLUSIONS: These data indicate that adult artery endothelial cells fail to drive collateral artery development due to their limited ability to dedifferentiate and proliferate.

Microfluidic encapsulation of photosynthetic cyanobacteria in hydrogel microparticles augments oxygen delivery to rescue ischemic myocardium.

Cardiovascular disease, primarily caused by coronary artery disease, is the leading cause of death in the United States. While standard clinical interventions have improved patient outcomes, mortality rates associated with eventual heart failure still represent a clinical challenge. Macrorevascularization techniques inadequately address the microvascular perfusion deficits that persist beyond primary and secondary interventions. In this work, we investigate a photosynthetic oxygen delivery system that rescues the myocardium following acute ischemia. Using a simple microfluidic system, we encapsulated Synechococcus elongatus into alginate hydrogel microparticles (HMPs), which photosynthetically deliver oxygen to ischemic tissue in the absence of blood flow. We demonstrate that HMPs improve the viability of S. elongatus during the injection process and allow for simple oxygen diffusion. Adult male Wistar rats (n = 45) underwent sham surgery, acute ischemia reperfusion surgery, or a chronic ischemia reperfusion surgery, followed by injection of phosphate buffered saline (PBS), S. elongatus suspended in PBS, HMPs, or S. elongatus encapsulated in HMPs. Treatment with S. elongatus-HMPs mitigated cellular apoptosis and improved left ventricular function. Thus, delivery of S. elongatus encapsulated in HMPs improves clinical translation by utilizing a minimally invasive delivery platform that improves S. elongatus viability and enhances the therapeutic benefit of a novel photosynthetic system for the treatment of myocardial ischemia.

Trimmed central venous catheters do not increase endothelial injury in an ovine model.

INTRODUCTION: Central venous catheters (CVCs) are often trimmed during heart transplantation and pediatric cardiac surgery. However, the risk of endothelial injury caused by the cut tip of the CVC has not been evaluated. We hypothesized that there is no difference in the degree of endothelial injury associated with trimmed CVCs versus standard untrimmed CVCs. METHODS: In four adult male sheep, the left external jugular vein was exposed in three segments, one designated for an untouched control group, one for the trimmed CVC group, and one for the untrimmed CVC group. Trimmed and untrimmed CVC tips were rotated circumferentially within their respective segments to abrade the lumen of the vein. The vein samples were explanted, and two representative sections from each sample were analyzed using hematoxylin and eosin (H&E) staining, as well as with immunohistochemistry against CD31, von Willebrand factor (vWF), endothelial nitric oxide synthase (eNOS), and caveolin. Higher immunohistochemical stain distributions and intensities are associated with normal health and function of the venous endothelium. Data are presented as counts with percentages or as means with standard error. RESULTS: H&E staining revealed no evidence of endothelial injury in 6/8 (75%) samples from the untouched control group, and no injury in 4/8 (50%) samples from both the trimmed and untrimmed CVC groups (p = 0.504). In all remaining samples from each group, only mild endothelial injury was observed. Immunohistochemical analysis comparing trimmed CVCs versus untrimmed CVCs revealed no difference in the percentage of endothelial cells staining positive for CD31 (57.5% ± 7.2% vs 55.0% ± 9.2%, p = 0.982), vWF (73.8% ± 8.0% vs 62.5% ± 9.6%, p = 0.579), eNOS (66.3% ± 4.2% vs 63.8% ± 7.5%, p = 0.962), and caveolin (53.8% ± 5.0% vs 51.3% ± 4.4%, p = 0.922). There were no significant differences between the groups in the distributions of stain intensity for CD31, vWF, eNOS, and caveolin. CONCLUSION: Trimmed CVCs do not increase endothelial injury compared to standard untrimmed CVCs.

The Critical Biomechanics of Aortomitral Angle and Systolic Anterior Motion: Engineering Native Ex Vivo Simulation.

Systolic anterior motion (SAM) of the mitral valve (MV) is a complex pathological phenomenon often occurring as an iatrogenic effect of surgical and transcatheter intervention. While the aortomitral angle has long been linked to SAM, the mechanistic relationship is not well understood. We developed the first ex vivo heart simulator capable of recreating native aortomitral biomechanics, and to generate models of SAM, we performed anterior leaflet augmentation and sequential undersized annuloplasty procedures on porcine aortomitral junctions (n = 6). Hemodynamics and echocardiograms were recorded, and echocardiographic analysis revealed significantly reduced coaptation-septal distances confirming SAM (p = 0.003) and effective manipulation of the aortomitral angle (p < 0.001). Upon increasing the angle in our pathological models, we recorded significant increases (p < 0.05) in both coaptation-septal distance and multiple hemodynamic metrics, such as aortic peak flow and effective orifice area. These results indicate that an increased aortomitral angle is correlated with more efficient hemodynamic performance of the valvular system, presenting a potential, clinically translatable treatment opportunity for reducing the risk and adverse effects of SAM. As the standard of care shifts towards surgical and transcatheter interventions, it is increasingly important to better understand SAM biomechanics, and our advances represent a significant step towards that goal.

A Novel Rheumatic Mitral Valve Disease Model with Ex Vivo Hemodynamic and Biomechanical Validation.

PURPOSE: Rheumatic heart disease is a major cause of mitral valve (MV) dysfunction, particularly in disadvantaged areas and developing countries. There lacks a critical understanding of the disease biomechanics, and as such, the purpose of this study was to generate the first ex vivo porcine model of rheumatic MV disease by simulating the human pathophysiology and hemodynamics. METHODS: Healthy porcine valves were altered with heat treatment, commissural suturing, and cyanoacrylate tissue coating, all of which approximate the pathology of leaflet stiffening and thickening as well as commissural fusion. Hemodynamic data, echocardiography, and high-speed videography were collected in a paired manner for control and model valves (n = 4) in an ex vivo left heart simulator. Valve leaflets were characterized in an Instron tensile testing machine to understand the mechanical changes of the model (n = 18). RESULTS: The model showed significant differences indicative of rheumatic disease: increased regurgitant fractions (p < 0.001), reduced effective orifice areas (p < 0.001), augmented transmitral mean gradients (p < 0.001), and increased leaflet stiffness (p = 0.025). CONCLUSION: This work represents the creation of the first ex vivo model of rheumatic MV disease, bearing close similarity to the human pathophysiology and hemodynamics, and it will be used to extensively study both established and new treatment techniques, benefitting the millions of affected victims.

The impact of the American Association for Thoracic Surgery on National Institutes of Health grant funding for cardiothoracic surgeons.

OBJECTIVES: The American Association for Thoracic Surgery, through its annual meeting, pilot grant funding, Scientific Affairs and Government Relations Committee activity, and academic development programs (Grant Writing Workshop, Clinical Trials Course, Innovation Summit), has aimed to develop the research careers of cardiothoracic surgeons. We hypothesized that American Association for Thoracic Surgery activities have helped increase National Institutes of Health grants awarded to cardiothoracic surgeons. METHODS: A database of 1869 academic cardiothoracic surgeons in the United States was created in December 2020. National Institutes of Health grant records from 1985 to 2020 were obtained for each surgeon using National Institutes of Health Research Portfolio Online Reporting Tools Expenditures and Results. Analyses were normalized to the number of active surgeons per year, based on the year of each surgeon's earliest research publication on Scopus. RESULTS: A total of 346 cardiothoracic surgeons have received 696 National Institutes of Health grants totaling more than $1.5 billion in funding, with 48 surgeons actively serving as principal investigator of 66 R01 grants in 2020. The prevalence of research grants (7.4 vs 5.6 grants per 100 active surgeons, P < .0001), percentage of surgeons with a research grant (5.3% vs 4.7%, P = .0342), and number of research grants per funded surgeon (1.4 vs 1.2 grants, P < .0001) were significantly greater during the Scientific Affairs and Government Relations era (2003-2020) than the pre-Scientific Affairs and Government Relations era (1985-2002). The incidence of new research grants after surgeon participation in an American Association for Thoracic Surgery academic development program was significantly greater than that in the absence of participation (3.5 vs 1.1 new grants per 100 surgeons per year, P < .0001). CONCLUSIONS: Through dedicated efforts and programs, the American Association for Thoracic Surgery has provided effective support to help increase National Institutes of Health grant funding awarded to cardiothoracic surgeons.

Analysis of the revised heart allocation policy and the influence of increased mechanical circulatory support on survival.

OBJECTIVES: In 2018, the new United Network for Organ Sharing heart allocation policy took effect. This study evaluated waitlist mortality, mechanical circulatory support utilization, and its influence on posttransplant survival. METHODS: Two 12-month cohorts matched for time of year before and after the policy change were defined by inclusion criteria of first-time transplant recipients aged 18 years or older who were listed and underwent transplant during the same era. Student t test and Wilcoxon rank-sum test were used for mean and median differences, respectively. Categorical variables were compared using χ2 or Fisher exact test. Kaplan-Meier curves were used to characterize survival, including time-to-event analysis with the log-rank test. Fine-Gray modeling was used to characterize waitlist mortality. Cox proportional-hazard models were used for multivariate analysis. RESULTS: Waitlist mortality in the new era is significantly improved based on a competing-risks model (Gray test P = .0064). Unadjusted 180-day posttransplant mortality increased from 5.8% during the old era to 8.0% during the new (P = .0134). However, time-to-event analysis showed similar 180-day survival in both eras. After risk adjustment, the hazard ratio for posttransplant 180-day mortality during the new era was 1.18 (95% CI, 0.85-1.64; P = .333). The posttransplant 180-day mortality of the extracorporeal membrane oxygenation bridge-to-transplant subgroup improved from 28.6% in the old era to 8.4% in the new era (P = .0103; log-rank P = .0021). Patients with an intra-aortic balloon pump at the time of transplant had similar 180-day posttransplant mortality between eras (5.4% vs 7.0%; P = .4831). CONCLUSIONS: The United Network for Organ Sharing policy change is associated with reduced waitlist mortality and similar risk adjusted posttransplant 180-day mortality. The new era is also associated with improved 180-day survival in patients undergoing bridge to transplant with extracorporeal membrane oxygenation.

Integration of Reinforcement Learning in a Virtual Robotic Surgical Simulation.

Background. The revolutions in AI hold tremendous capacity to augment human achievements in surgery, but robust integration of deep learning algorithms with high-fidelity surgical simulation remains a challenge. We present a novel application of reinforcement learning (RL) for automating surgical maneuvers in a graphical simulation.Methods. In the Unity3D game engine, the Machine Learning-Agents package was integrated with the NVIDIA FleX particle simulator for developing autonomously behaving RL-trained scissors. Proximal Policy Optimization (PPO) was used to reward movements and desired behavior such as movement along desired trajectory and optimized cutting maneuvers along the deformable tissue-like object. Constant and proportional reward functions were tested, and TensorFlow analytics was used to informed hyperparameter tuning and evaluate performance.Results. RL-trained scissors reliably manipulated the rendered tissue that was simulated with soft-tissue properties. A desirable trajectory of the autonomously behaving scissors was achieved along 1 axis. Proportional rewards performed better compared to constant rewards. Cumulative reward and PPO metrics did not consistently improve across RL-trained scissors in the setting for movement across 2 axes (horizontal and depth).Conclusion. Game engines hold promising potential for the design and implementation of RL-based solutions to simulated surgical subtasks. Task completion was sufficiently achieved in one-dimensional movement in simulations with and without tissue-rendering. Further work is needed to optimize network architecture and parameter tuning for increasing complexity.

Career Progression and Research Productivity of Women in Academic Cardiothoracic Surgery.

BACKGROUND: The objective of this work was to delineate career progression and research productivity of women practicing cardiothoracic surgery in the academic setting. METHODS: Cardiothoracic surgeons at the 79 accredited US cardiothoracic surgery training programs in 2020 were included in this cross-sectional analysis. Data regarding subspecialization, training, practice history, and publications were gathered from public sources including department websites, CTSNet, and Scopus. RESULTS: A total of 1065 surgeons (51.3% cardiac, 32.1% thoracic, 16.6% congenital) were identified. Women accounted for 10.6% (113) of the population (7.9% of cardiac, 15.5% of thoracic, 9.6% of congenital surgeons). The median number of cardiothoracic surgeons per institution was 12 (interquartile range [IQR], 10-17), with a median of 1 woman (IQR, 0-2). Fifteen of 79 programs (19%) had no women. Among women faculty 5.3% were clinical instructors, 51.3% were assistant professors, 23.0% were associate professors, 16.8% were full professors, and 3.5% had unspecified titles (vs 2.0%, 32.9%, 23.0%, 37.5%, and 4.6% among men, respectively; P < .001). Women and men authored a comparable number of first-author (0.4 [IQR, 0.0-1.3] vs 0.5 [IQR, 0.0-1.1], P = .56) publications per year but fewer last-author (0.1 [IQR, 0.0-0.7] vs 0.4 [IQR, 0.0-1.3], P < .0001) and total publications per year (2.7 [IQR, 1.0-6.2] vs 3.7 [IQR, 1.3-7.8], P = .05) than men. The H-index was lower for women than for men overall (8.0 [IQR, 3.0-15.0] vs 15.0 [IQR, 7.0-28.0], P < .001) but was similar between men and women who had been practicing for 10 to 20 years. CONCLUSIONS: Gender disparities persist in academic cardiothoracic surgery. Efforts should be made to support women in achieving senior roles and academic productivity.

Native and Post-Repair Residual Mitral Valve Prolapse Increases Forces Exerted on the Papillary Muscles: A Possible Mechanism for Localized Fibrosis?

BACKGROUND: Recent studies have linked mitral valve prolapse to localized myocardial fibrosis, ventricular arrhythmia, and even sudden cardiac death independent of mitral regurgitation or hemodynamic dysfunction. The primary mechanistic theory is rooted in increased papillary muscle traction and forces due to prolapse, yet no biomechanical evidence exists showing increased forces. Our objective was to evaluate the biomechanical relationship between prolapse and papillary muscle forces, leveraging advances in ex vivo modeling and technologies. We hypothesized that mitral valve prolapse with limited hemodynamic dysfunction leads to significantly higher papillary muscle forces, which could be a possible trigger for cellular and electrophysiological changes in the papillary muscles and adjacent myocardium. METHODS: We developed an ex vivo papillary muscle force transduction and novel neochord length adjustment system capable of modeling targeted prolapse. Using 3 unique ovine models of mitral valve prolapse (bileaflet or posterior leaflet prolapse), we directly measured hemodynamics and forces, comparing physiologic and prolapsing valves. RESULTS: We found that bileaflet prolapse significantly increases papillary muscle forces by 5% to 15% compared with an optimally coapting valve, which are correlated with statistically significant decreases in coaptation length. Moreover, we observed significant changes in the force profiles for prolapsing valves when compared with normal controls. CONCLUSIONS: We discovered that bileaflet prolapse with the absence of hemodynamic dysfunction results in significantly elevated forces and altered dynamics on the papillary muscles. Our work suggests that the sole reduction of mitral regurgitation without addressing reduced coaptation lengths and thus increased leaflet surface area exposed to ventricular pressure gradients (ie, billowing leaflets) is insufficient for an optimal repair.