Ex Vivo Analysis of a Porcine Bicuspid Aortic Valve and Aneurysm Disease Model.
The Annals of thoracic surgery
Safety of photosynthetic Synechococcus elongatus for in vivo cyanobacteria-mammalian symbiotic therapeutics.
We identified an extremely rare congenital porcine type 0 lateral bicuspid aortic valve (BAV) from a fresh porcine heart. Using a 3D-printed ex vivo left heart simulator, we analyzed valvular hemodynamics at baseline, in an aortic aneurysm disease model, and after valve-sparing root replacement (VSRR). We showed that BAV regurgitation due to aortic aneurysm can be successfully repaired without significant hemodynamic impairment with the VSRR technique in an individualized approach. Our results provide direct hemodynamic evidence supporting the use of VSRR for patients with BAV regurgitation.
View details for DOI 10.1016/j.athoracsur.2020.05.086
View details for PubMedID 32663472
Multiaxial Lenticular Stress-Strain Relationship of Native Myocardium is Preserved by Infarct-Induced Natural Heart Regeneration in Neonatal Mice.
2020; 10 (1): 7319
The cyanobacterium Synechococcus elongatus (SE) has been shown to rescue ischaemic heart muscle after myocardial infarction by photosynthetic oxygen production. Here, we investigated SE toxicity and hypothesized that systemic SE exposure does not elicit a significant immune response in rats. Wistar rats intravenously received SE (n=12), sterile saline (n=12) or E. coli lipopolysaccharide (LPS, n=4), and a subset (8 SE, 8 saline) received a repeat injection 4weeks later. At baseline, 4h, 24h, 48h, 8days and 4weeks after injection, clinical assessments, blood cultures, blood counts, lymphocyte phenotypes, liver function tests, proinflammatory cytokines and immunoglobulins were assessed. Across all metrics, SE rats responded comparably to saline controls, displaying no clinically significant immune response. As expected, LPS rats exhibited severe immunological responses. Systemic SE administration does not induce sepsis or toxicity in rats, thereby supporting the safety of cyanobacteria-mammalian symbiotic therapeutics using this organism.
View details for DOI 10.1111/1751-7915.13596
View details for PubMedID 32476224
A novel cross-species model of Barlow's disease to biomechanically analyze repair techniques in an exvivo left heart simulator.
The Journal of thoracic and cardiovascular surgery
Neonatal mice exhibit natural heart regeneration after myocardial infarction (MI) on postnatal day 1 (P1), but this ability is lost by postnatal day 7 (P7). Cardiac biomechanics intricately affect long-term heart function, but whether regenerated cardiac muscle is biomechanically similar to native myocardium remains unknown. We hypothesized that neonatal heart regeneration preserves native left ventricular (LV) biomechanical properties after MI. C57BL/6J mice underwent sham surgery or left anterior descending coronary artery ligation at age P1 or P7. Echocardiography performed 4 weeks post-MI showed that P1 MI and sham mice (n=22, each) had similar LV wall thickness, diameter, and ejection fraction (59.6% vs 60.7%, p=0.6514). Compared to P7 shams (n=20), P7 MI mice (n=20) had significant LV wall thinning, chamber enlargement, and depressed ejection fraction (32.6% vs 61.8%, p<0.0001). Afterward, the LV was explanted and pressurized ex vivo, and the multiaxial lenticular stress-strain relationship was tracked. While LV tissue modulus for P1 MI and sham mice were similar (341.9 kPa vs 363.4 kPa, p=0.6140), the modulus for P7 MI mice was significantly greater than that for P7 shams (691.6 kPa vs 429.2 kPa, p=0.0194). We conclude that, in neonatal mice, regenerated LV muscle has similar biomechanical properties as native LV myocardium.
View details for DOI 10.1038/s41598-020-63324-w
View details for PubMedID 32355240
A novel 3D-Printed preferential posterior mitral annular dilation device delineates regurgitation onset threshold in an ex vivo heart simulator.
Medical engineering & physics
OBJECTIVE: Barlow's disease remains challenging to repair, given the complex valvular morphology and lack of quantitative data to compare techniques. Although there have been recent strides in exvivo evaluation of cardiac mechanics, to our knowledge, there is no disease model that accurately simulates the morphology and pathophysiology of Barlow's disease. The purpose of this study was to design such a model.METHODS: To simulate Barlow's disease, a cross-species exvivo model was developed. Bovine mitral valves (n=4) were sewn into a porcine annulus mount to create excess leaflet tissue and elongated chordae. A heart simulator generated physiologic conditions while hemodynamic data, high-speed videography, and chordal force measurements were collected. The regurgitant valves were repaired using nonresectional repair techniques such as neochord placement.RESULTS: The model successfully imitated the complexities of Barlow's disease, including redundant, billowing bileaflet tissues with notable regurgitation. After repair, hemodynamic data confirmed reduction of mitral leakage volume (25.9±2.9 vs 2.1±1.8mL, P<.001) and strain gauge analysis revealed lower primary chordae forces (0.51±0.17 vs 0.10±0.05N, P<.001). In addition, the maximum rate of change of force was significantly lower postrepair for both primary (30.80±11.38 vs 8.59±4.83N/s, P<.001) and secondary chordae (33.52±10.59 vs 19.07±7.00N/s, P=.006).CONCLUSIONS: This study provides insight into the biomechanics of Barlow's disease, including sharply fluctuating force profiles experienced by elongated chordae prerepair, as well as restoration of primary chordae forces postrepair. Our disease model facilitates further in-depth analyses to optimize the repair of Barlow's disease.
View details for DOI 10.1016/j.jtcvs.2020.01.086
View details for PubMedID 32249088
Natural Heart Regeneration in a Neonatal Rat Myocardial Infarction Model.
2020; 9 (1)
Mitral regurgitation (MR) due to annular dilation occurs in a variety of mitral valve diseases and is observed in many patients with heart failure due to mitral regurgitation. To understand the biomechanics of MR and ultimately design an optimized annuloplasty ring, a representative disease model with asymmetric dilation of the mitral annulus is needed. This work shows the design and implementation of a 3D-printed valve dilation device to preferentially dilate the posterior mitral valve annulus. Porcine mitral valves (n=3) were sewn into the device and mounted within a left heart simulator that generates physiologic pressures and flows through the valves, while chordal forces were measured. The valves were incrementally dilated, inducing MR, while hemodynamic and force data were collected. Flow analysis demonstrated that MR increased linearly with respect to percent annular dilation when dilation was greater than a 25.6% dilation threshold (p<0.01). Pre-threshold, dilation did not cause significant increases in regurgitant fraction. Forces on the chordae tendineae increased as dilation increased prior to the identified threshold (p < 0.01); post-threshold, the MR resulted in highly variable forces. Ultimately, this novel dilation device can be used to more accurately model a wide range of MR disease states and their corresponding repair techniques using ex vivo experimentation. In particular, this annular dilation device provides the means to investigate the design and optimization of novel annuloplasty rings.
View details for DOI 10.1016/j.medengphy.2020.01.005
View details for PubMedID 32008935
Multi-phase catheter-injectable hydrogel enables dual-stage protein-engineered cytokine release to mitigate adverse left ventricular remodeling following myocardial infarction in a small animal model and a large animal model.
2020; 127: 154974
Newborn mice and piglets exhibit natural heart regeneration after myocardial infarction (MI). Discovering other mammals with this ability would provide evidence that neonatal cardiac regeneration after MI may be a conserved phenotype, which if activated in adults could open new options for treating ischemic cardiomyopathy in humans. Here, we hypothesized that newborn rats undergo natural heart regeneration after MI. Using a neonatal rat MI model, we performed left anterior descending coronary artery ligation or sham surgery in one-day-old rats under hypothermic circulatory arrest (n = 74). Operative survival was 97.3%. At 1 day post-surgery, rats in the MI group exhibited significantly reduced ejection fraction (EF) compared to shams (87.1% vs. 53.0%, p < 0.0001). At 3 weeks post-surgery, rats in the sham and MI groups demonstrated no difference in EF (71.1% vs. 69.2%, respectively, p = 0.2511), left ventricular wall thickness (p = 0.9458), or chamber diameter (p = 0.7801). Masson's trichome and picrosirius red staining revealed minimal collagen scar after MI. Increased numbers of cardiomyocytes positive for 5-ethynyl-2'-deoxyuridine (p = 0.0072), Ki-67 (p = 0.0340), and aurora B kinase (p = 0.0430) were observed within the peri-infarct region after MI, indicating ischemia-induced cardiomyocyte proliferation. Overall, we present a neonatal rat MI model and demonstrate that newborn rats are capable of endogenous neocardiomyogenesis after MI.
View details for DOI 10.3390/cells9010229
View details for PubMedID 31963369
In Vivo Validation of Restored Chordal Biomechanics After Mitral Ring Annuloplasty in a Rare Ovine Case of Natural Chronic Functional Mitral Regurgitation.
Journal of cardiovascular development and disease
2020; 7 (2)
Although ischemic heart disease is the leading cause of death worldwide, mainstay treatments ultimately fail because they do not adequately address disease pathophysiology. Restoring the microvascular perfusion deficit remains a significant unmet need and may be addressed via delivery of pro-angiogenic cytokines. The therapeutic effect of cytokines can be enhanced by encapsulation within hydrogels, but current hydrogels do not offer sufficient clinical translatability due to unfavorable viscoelastic mechanical behavior which directly impacts the ability for minimally-invasive catheter delivery. In this report, we examine the therapeutic implications of dual-stage cytokine release from a novel, highly shear-thinning biocompatible catheter-deliverable hydrogel. We chose to encapsulate two protein-engineered cytokines, namely dimeric fragment of hepatocyte growth factor (HGFdf) and engineered stromal cell-derived factor 1? (ESA), which target distinct disease pathways. The controlled release of HGFdf and ESA from separate phases of the hyaluronic acid-based hydrogel allows extended and pronounced beneficial effects due to the precise timing of release. We evaluated the therapeutic efficacy of this treatment strategy in a small animal model of myocardial ischemia and observed a significant benefit in biological and functional parameters. Given the encouraging results from the small animal experiment, we translated this treatment to a large animal preclinical model and observed a reduction in scar size, indicating this strategy could serve as a potential adjunct therapy for the millions of people suffering from ischemic heart disease.
View details for DOI 10.1016/j.cyto.2019.154974
View details for PubMedID 31978642
A Novel Aortic Regurgitation Model from Cusp Prolapse with Hemodynamic Validation Using an Ex Vivo Left Heart Simulator.
Journal of cardiovascular translational research
Mitral valve chordae tendineae forces are elevated in the setting of mitral regurgitation (MR). Ring annuloplasty is an essential component of surgical repair for MR, but whether chordal forces are reduced after mitral annuloplasty has never been validated in vivo. Here, we present an extremely rare ovine case of natural, severe chronic functional MR, in which we used force-sensing fiber Bragg grating neochordae to directly measure chordal forces in the baseline setting of severe MR, as well as after successful mitral ring annuloplasty repair. Overall, our report is the first to confirm in vivo that mitral ring annuloplasty reduces elevated chordae tendineae forces associated with chronic functional MR.
View details for DOI 10.3390/jcdd7020017
View details for PubMedID 32429298
Mitral chordae tendineae force profile characterization using a posterior ventricular anchoring neochordal repair model for mitral regurgitation in a three-dimensional-printed ex vivo left heart simulator.
European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery
Although ex vivo simulation is a valuable tool for surgical optimization, a disease model that mimics human aortic regurgitation (AR) from cusp prolapse is needed to accurately examine valve biomechanics. To simulate AR, four porcine aortic valves were explanted, and the commissure between the two largest leaflets was detached and re-implanted 5 mm lower to induce cusp prolapse. Four additional valves were tested in their native state as controls. All valves were tested in a heart simulator while hemodynamics, high-speed videography, and echocardiography data were collected. Our AR model successfully reproduced cusp prolapse with significant increase in regurgitant volume compared with that of the controls (23.2?±?8.9 versus 2.8?±?1.6 ml, p?=?0.017). Hemodynamics data confirmed the simulation of physiologic disease conditions. Echocardiography and color flow mapping demonstrated the presence of mild to moderate eccentric regurgitation in our AR model. This novel AR model has enormous potential in the evaluation of valve biomechanics and surgical repair techniques. Graphical Abstract.
View details for DOI 10.1007/s12265-020-10038-z
View details for PubMedID 32495264
Custom Patient-Specific Three-Dimensional Printed Mitral Valve Models for Pre-Operative Patient Education Enhance Patient Satisfaction and Understanding
JOURNAL OF MEDICAL DEVICES-TRANSACTIONS OF THE ASME
2019; 13 (3)
Modeling conduit choice for valve-sparing aortic root replacement on biomechanics with a 3-dimensional-printed heart simulator
JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY
2019; 158 (2): 392?403
Bioengineered analog of stromal cell-derived factor 1 alpha preserves the biaxial mechanical properties of native myocardium after infarction
JOURNAL OF THE MECHANICAL BEHAVIOR OF BIOMEDICAL MATERIALS
2019; 96: 165?71
A Biocompatible Therapeutic Catheter-Deliverable Hydrogel for In Situ Tissue Engineering
ADVANCED HEALTHCARE MATERIALS
2019; 8 (5)
Ex vivo biomechanical study of apical versus papillary neochord anchoring for mitral regurgitation.
The Annals of thoracic surgery
OBJECTIVES: Posterior ventricular anchoring neochordal (PVAN) repair is a non-resectional technique for correcting mitral regurgitation (MR) due to posterior leaflet prolapse, utilizing a single suture anchored in the myocardium behind the leaflet. This technique has demonstrated clinical efficacy, although a theoretical limitation is stability of the anchoring suture. We hypothesize that the PVAN suture positions the leaflet for coaptation, after which forces are distributed evenly with low repair suture forces.METHODS: Porcine mitral valves were mounted in a 3-dimensional-printed heart simulator and chordal forces, haemodynamics and echocardiography were collected at baseline, after inducing MR by severing chordae, and after PVAN repair. Repair suture forces were measured with a force-sensing post positioned to mimic in vivo suture placement. Forces required to pull the myocardial suture free were also determined.RESULTS: Relative primary and secondary chordae forces on both leaflets were elevated during prolapse (P<0.05). PVAN repair eliminated MR in all valves and normalized chordae forces to baseline levels on anterior primary (0.37±0.23 to 0.22±0.09 N, P<0.05), posterior primary (0.62±0.37 to 0.14±0.05 N, P=0.001), anterior secondary (1.48±0.52 to 0.85±0.43 N, P<0.001) and posterior secondary chordae (1.42±0.69 to 0.59±0.17 N, P=0.005). Repair suture forces were minimal, even compared to normal primary chordae forces (0.08±0.04 vs 0.19±0.08 N, P=0.002), and were 90 times smaller than maximum forces tolerated by the myocardium (0.08±0.04 vs 6.9±1.3 N, P<0.001).DISCUSSION: PVAN repair eliminates MR by positioning the posterior leaflet for coaptation, distributing forces throughout the valve. Given extremely low measured forces, the strength of the repair suture and the myocardium is not a limitation.
View details for DOI 10.1093/ejcts/ezz258
View details for PubMedID 31638697
A Biocompatible Therapeutic Catheter-Deliverable Hydrogel for In Situ Tissue Engineering.
Advanced healthcare materials
BACKGROUND: Neochordoplasty is an important repair technique, though optimal anchoring position is unknown. While typically anchored at papillary muscles, new percutaneous devices anchor the chordae at or near the ventricular apex, which may have an effect on chordal forces and the long-term durability of the repair.METHODS: Porcine mitral valves (n=6) were mounted in a left heart simulator that generates physiological pressure and flow through the valves while chordal forces were measured using Fiber Bragg Grating strain gauge sensors. Isolated mitral regurgitation was induced by cutting P2 primary chordae and the regurgitant valve was repaired using PTFE neochord with apical anchoring, followed by papillary muscle fixation for comparison. In both cases, the neochord was anchored to a customized force-sensing post positioned to mimic the relevant in vivo placement.RESULTS: Echocardiographic and hemodynamic data confirmed that the repairs restored physiologic hemodynamics. Forces on the chordae and neochord were lower for papillary fixation than the apical (p=0.003). Additionally, the maximum rate of change of force was higher for the chordae and neochord for apical fixation when compared to papillary (p=0.028).CONCLUSIONS: Apical point of anchoring results in higher forces on the chordae and neochord stitch as well as an increased rate of loading on the neochord when compared to the papillary muscle fixation. These results suggest the papillary fixation repair may have superior durability.
View details for PubMedID 30836099
A Unique Collateral Artery Development Program Promotes Neonatal Heart Regeneration.
Hydrogels have emerged as a diverse class of biomaterials offering a broad range of biomedical applications. Specifically, injectable hydrogels are advantageous for minimally invasive delivery of various therapeutics and have great potential to treat a number of diseases. However, most current injectable hydrogels are limited by difficult and time-consuming fabrication techniques and are unable to be delivered through long, narrow catheters, preventing extensive clinical translation. Here, the development of an easily-scaled, catheter-injectable hydrogel utilizing a polymer-nanoparticle crosslinking mechanism is reported, which exhibits notable shear-thinning and self-healing behavior. Gelation of the hydrogel occurs immediately upon mixing the biochemically modified hyaluronic acid polymer with biodegradable nanoparticles and can be easily injected through a high-gauge syringe due to the dynamic nature of the strong, yet reversible crosslinks. Furthermore, the ability to deliver this novel hydrogel through a long, narrow, physiologically-relevant catheter affixed with a 28-G needle is highlighted, with hydrogel mechanics unchanged after delivery. Due to the composition of the gel, it is demonstrated that therapeutics can be differentially released with distinct elution profiles, allowing precise control over drug delivery. Finally, the cell-signaling and biocompatibility properties of this innovative hydrogel are demonstrated, revealing its wide range of therapeutic applications.
View details for PubMedID 30714355
Development and ex vivo validation of novel force-sensing neochordae for measuring chordae tendineae tension in the mitral valve apparatus using optical fibers with embedded Bragg gratings.
Journal of biomechanical engineering
Collateral arteries are an uncommon vessel subtype that can provide alternate blood flow to preserve tissue following vascular occlusion. Some patients with heart disease develop collateral coronary arteries, and this correlates with increased survival. However, it is not known how these collaterals develop or how to stimulate them. We demonstrate that neonatal mouse hearts use a novel mechanism to build collateral arteries in response to injury. Arterial endothelial cells (ECs) migrated away from arteries along existing capillaries and reassembled into collateral arteries, which we termed "artery reassembly". Artery ECs expressed CXCR4, and following injury, capillary ECs induced its ligand, CXCL12. CXCL12 or CXCR4 deletion impaired collateral artery formation and neonatal heart regeneration. Artery reassembly was nearly absent in adults but was induced by exogenous CXCL12. Thus, understanding neonatal regenerative mechanisms can identify pathways that restore these processes in adults and identify potentially translatable therapeutic strategies for ischemic heart disease.
View details for PubMedID 30686582
Use of a supramolecular polymeric hydrogel as an effective post-operative pericardial adhesion barrier.
Nature biomedical engineering
2019; 3 (8): 611?20
Few technologies exist that can provide quantitative data on forces within the mitral valve apparatus. Marker-based strain measurements can be performed, but chordal geometry and restricted optical access are limitations. Foil-based strain sensors have been described and work well, but the sensor footprint limits the number of chordae that can be measured. We instead utilized Fiber Bragg Grating (FBG) sensors-optical strain gauges made of 125µm diameter silica fibers- to overcome some limitations of previous methods of measuring chordae tendineae forces. Using FBG sensors, we created a force-sensing neochord that mimics the natural shape and movement of native chordae. FBG sensors reflect a specific wavelength of light depending on the spatial period of gratings. When force is applied, the gratings move relative to one another, shifting the wavelength of reflected light. This shift is directly proportional to force applied. The FBG sensors were housed in a protective sheath fashioned from a 0.025" flat coil, and attached to the chordae using polytetrafluoroethylene suture. The function of the force-sensing neochordae was validated in a 3D-printed left heart simulator, which demonstrated that FBG sensors provide highly sensitive force measurements of mitral valve chordae at a temporal resolution of 1000 Hz. As ventricular pressures increased, such as in hypertension, chordae forces also increased. Overall, FBG sensors are a viable, durable, and high-fidelity sensing technology that can be effectively used to measure mitral valve chordae forces and overcome some limitations of other such technologies.
View details for DOI 10.1115/1.4044142
View details for PubMedID 31253992
Bioengineered analog of stromal cell-derived factor 1? preserves the biaxial mechanical properties of native myocardium after infarction.
Journal of the mechanical behavior of biomedical materials
2019; 96: 165?71
Post-operative adhesions form as a result of normal wound healing processes following any type of surgery. In cardiac surgery, pericardial adhesions are particularly problematic during reoperations, as surgeons must release the adhesions from the surface of the heart before the intended procedure can begin, thereby substantially lengthening operation times and introducing risks of haemorrhage and injury to the heart and lungs during sternal re-entry and cardiac dissection. Here we show that a dynamically crosslinked supramolecular polymer-nanoparticle hydrogel, with viscoelastic and flow properties that enable spraying onto tissue as well as robust tissue adherence and local retention in vivo for two weeks, reduces the formation of pericardial adhesions. In a rat model of severe pericardial adhesions, the hydrogel markedly reduced the severity of the adhesions, whereas commercial adhesion barriers (including Seprafilm and Interceed) did not. The hydrogels also reduced the severity of cardiac adhesions (relative to untreated animals) in a clinically relevant cardiopulmonary-bypass model in sheep. This viscoelastic supramolecular polymeric hydrogel represents a promising clinical solution for the prevention of post-operative pericardial adhesions.
View details for DOI 10.1038/s41551-019-0442-z
View details for PubMedID 31391596
Modeling conduit choice for valve-sparing aortic root replacement on biomechanics with a 3-dimensional-printed heart simulator.
The Journal of thoracic and cardiovascular surgery
Adverse remodeling of the left ventricle (LV) after myocardial infarction (MI) results in abnormal tissue biomechanics and impaired cardiac function, often leading to heart failure. We hypothesized that intramyocardial delivery of engineered stromal cell-derived factor 1? analog (ESA), our previously-developed supra-efficient pro-angiogenic chemokine, preserves biaxial LV mechanical properties after MI. Male Wistar rats (n?=?45) underwent sham surgery (n?=?15) or permanent left anterior descending coronary artery ligation. Rats sustaining MI were randomized for intramyocardial injections of either saline (100??L, n?=?15) or ESA (6??g/kg, n?=?15), delivered at four standardized borderzone sites. After 4 weeks, echocardiography was performed, and the hearts were explanted. Tensile testing of the anterolateral LV wall was performed using a displacement-controlled biaxial load frame, and modulus was determined after constitutive modeling. At 4 weeks post-MI, compared to saline controls, ESA-treated hearts had greater wall thickness (1.68?±?0.05?mm vs 1.42?±?0.08?mm, p?=?0.008), smaller end-diastolic LV internal dimension (6.88?±?0.29?mm vs 7.69?±?0.22?mm, p?=?0.044), and improved ejection fraction (62.8?±?3.0% vs 49.4?±?4.5%, p?=?0.014). Histologic analysis revealed significantly reduced infarct size for ESA-treated hearts compared to saline controls (29.4?±?2.9% vs 41.6?±?3.1%, p?=?0.021). Infarcted hearts treated with ESA exhibited decreased modulus compared to those treated with saline in both the circumferential (211.5?±?6.9?kPa vs 264.3?±?12.5?kPa, p?=?0.001) and longitudinal axes (194.5?±?6.5?kPa vs 258.1?±?14.4?kPa, p?0.001). In both principal directions, ESA-treated infarcted hearts possessed similar tissue compliance as sham non-infarcted hearts. Overall, intramyocardial ESA therapy improves post-MI ventricular remodeling and function, reduces infarct size, and preserves native LV biaxial mechanical properties.
View details for PubMedID 31035067
Rapid Self-Assembly of Bioengineered Cardiovascular Bypass Grafts From Scaffold-Stabilized, Tubular Bilevel Cell Sheets
2018; 138 (19): 2130?44
Angiogenesis precedes cardiomyocyte migration in regenerating mammalian hearts
JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY
2018; 155 (3): 1118-+
OBJECTIVE: The optimal conduit for valve-sparing aortic root replacement is still debated, with several conduit variations available, ranging from straight tubular grafts to Valsalva grafts. Benefits of neosinus reconstruction include enhanced flow profiles and improved hemodynamics. Curiously, however, some clinical data suggest that straight grafts may have greater long-term durability. In this study, we hypothesized that straight tubular grafts may help maintain the native cylindrical position of the aortic valve commissures radially, resulting in preserved leaflet coaptation, reduced stresses, and potentially improved valve performance.METHODS: Using 3D printing, a left heart simulator with a valve-sparing root replacement model and a physiologic coronary circulation was constructed. Aortic valves were dissected from fresh porcine hearts and reimplanted into either straight tubular grafts (n=6) or Valsalva grafts (n=6). Conduits were mounted into the heart simulator and hemodynamic, echocardiographic, and high-speed videometric data were collected.RESULTS: Hemodynamic parameters and coronary blood flow were similar between straight and Valsalva grafts, although the former were associated with lower regurgitant fractions, less peak intercommissural radial separation, preserved leaflet coaptation, decreased leaflet velocities, and lower relative leaflet forces compared with Valsalva grafts.CONCLUSIONS: Valsalva grafts and straight grafts perform equally well in terms of gross hemodyanics and coronary blood flow. Interestingly, however, the biomechanics of these 2 conduits differ considerably, with straight grafts providing increased radial commissural stability and leaflet coaptation. Further investigation into how these parameters influence clinical outcomes is warranted.
View details for PubMedID 30745047
SDF 1-alpha Attenuates Myocardial Injury Without Altering the Direct Contribution of Circulating Cells.
Journal of cardiovascular translational research
Although the mammalian heart's ability to fully regenerate is debated, its potential to extensively repair itself is gaining support. We hypothesized that heart regeneration relies on rapid angiogenesis to support myocardial regrowth and sought to characterize the timeline for angiogenesis and cell proliferation in regeneration.One-day-old CD-1 mice (P1, N = 60) underwent apical resection or sham surgery. Hearts were explanted at serial time points from 0 to 30 days postresection and analyzed with immunohistochemistry to visualize vessel ingrowth and cardiomyocyte migration into the resected region. Proliferating cells were labeled with 5-ethynyl-2'-deoxyuridine injections 12 hours before explant. 5-Ethynyl-2'-deoxyuridine-positive cells were counted in both the apex and remote areas of the heart. Masson's trichrome was used to assess fibrosis.By 30 days postresection, hearts regenerated with minimal fibrosis. Compared with sham surgery, apical resection stimulated a significant increase in proliferation of preexisting cardiomyocytes between 3 and 11 days after injury. Capillary migration into the apical thrombus was detected as early as 2 days postresection, with development of mature arteries by 5 days postresection. New vessels became perfused by 5 days postresection as evidenced by lectin injection. Vessel density and diameter significantly increased within the resected area over 21 days, and vessel ingrowth always preceded cardiomyocyte migration, with coalignment of most migrating cardiomyocytes with ingrowing vessels.Endothelial cells migrate into the apical thrombus early after resection, develop into functional arteries, and precede cardiomyocyte ingrowth during mammalian heart regeneration. This endogenous neonatal response emphasizes the importance of expeditious angiogenesis required for neomyogenesis.
View details for PubMedID 29452461
Rapid Self-Assembly of Bioengineered Cardiovascular Bypass Grafts From Scaffold-Stabilized, Tubular Bilevel Cell Sheets.
2018; 138 (19): 2130?44
Stromal cell-derived factor 1-alpha (SDF) is a potent bone marrow chemokine capable of recruiting circulating progenitor populations to injured tissue. SDF has known angiogenic capabilities, but bone marrow-derived cellular contributions to tissue regeneration remain controversial. Bone marrow from DsRed-transgenic donors was transplanted into recipients to lineage-trace circulating cells after myocardial infarction (MI). SDF was delivered post-MI, and hearts were evaluated for recruitment and plasticity of bone marrow-derived populations. SDF treatment improved ventricular function, border zone vessel density, and CD31+ cell frequency post-MI. Bone marrow-derived endothelial cells were observed; these cells arose through both cell fusion and transdifferentiation. Circulating cells also adopted cardiomyocyte fates, but such events were exceedingly rare and almost exclusively resulted from cell fusion. SDF did not significantly alter the proportion of circulating cells that adopted non-hematopoietic fates. Mechanistic insight into the governance of circulating cells is essential to realizing the full potential of cytokine therapies.
View details for PubMedID 29468554
Tissue-engineered smooth muscle cell and endothelial progenitor cell bi-level cell sheets prevent progression of cardiac dysfunction, microvascular dysfunction, and interstitial fibrosis in a rodent model of type 1 diabetes-induced cardiomyopathy.
2017; 16 (1): 142
Cardiovascular bypass grafting is an essential treatment for complex cases of atherosclerotic disease. Because the availability of autologous arterial and venous conduits is patient-limited, self-assembled cell-only grafts have been developed to serve as functional conduits with off-the-shelf availability. The unacceptably long production time required to generate these conduits, however, currently limits their clinical utility. Here, we introduce a novel technique to significantly accelerate the production process of self-assembled engineered vascular conduits.Human aortic smooth muscle cells and skin fibroblasts were used to construct bilevel cell sheets. Cell sheets were wrapped around a 22.5-gauge Angiocath needle to form tubular vessel constructs. A thin, flexible membrane of clinically approved biodegradable tissue glue (Dermabond Advanced) served as a temporary, external scaffold, allowing immediate perfusion and endothelialization of the vessel construct in a bioreactor. Subsequently, the matured vascular conduits were used as femoral artery interposition grafts in rats (n=20). Burst pressure, vasoreactivity, flow dynamics, perfusion, graft patency, and histological structure were assessed.Compared with engineered vascular conduits formed without external stabilization, glue membrane-stabilized conduits reached maturity in the bioreactor in one-fifth the time. After only 2 weeks of perfusion, the matured conduits exhibited flow dynamics similar to that of control arteries, as well as physiological responses to vasoconstricting and vasodilating drugs. The matured conduits had burst pressures exceeding 500 mm?Hg and had sufficient mechanical stability for surgical anastomoses. The patency rate of implanted conduits at 8 weeks was 100%, with flow rate and hind-limb perfusion similar to those of sham controls. Grafts explanted after 8 weeks showed a histological structure resembling that of typical arteries, including intima, media, adventitia, and internal and external elastic membrane layers.Our technique reduces the production time of self-assembled, cell sheet-derived engineered vascular conduits to 2 weeks, thereby permitting their use as bypass grafts within the clinical time window for elective cardiovascular surgery. Furthermore, our method uses only clinically approved materials and can be adapted to various cell sources, simplifying the path toward future clinical translation.
View details for PubMedID 30474423
An innovative biologic system for photon-powered myocardium in the ischemic heart.
2017; 3 (6): e1603078
Diabetes mellitus is a risk factor for coronary artery disease and diabetic cardiomyopathy, and adversely impacts outcomes following coronary artery bypass grafting. Current treatments focus on macro-revascularization and neglect the microvascular disease typical of diabetes mellitus-induced cardiomyopathy (DMCM). We hypothesized that engineered smooth muscle cell (SMC)-endothelial progenitor cell (EPC) bi-level cell sheets could improve ventricular dysfunction in DMCM.Primary mesenchymal stem cells (MSCs) and EPCs were isolated from the bone marrow of Wistar rats, and MSCs were differentiated into SMCs by culturing on a fibronectin-coated dish. SMCs topped with EPCs were detached from a temperature-responsive culture dish to create an SMC-EPC bi-level cell sheet. A DMCM model was induced by intraperitoneal streptozotocin injection. Four weeks after induction, rats were randomized into 3 groups: control (no DMCM induction), untreated DMCM, and treated DMCM (cell sheet transplant covering the anterior surface of the left ventricle).SMC-EPC cell sheet therapy preserved cardiac function and halted adverse ventricular remodeling, as demonstrated by echocardiography and cardiac magnetic resonance imaging at 8 weeks after DMCM induction. Myocardial contrast echocardiography demonstrated that myocardial perfusion and microvascular function were preserved in the treatment group compared with untreated animals. Histological analysis demonstrated decreased interstitial fibrosis and increased microvascular density in the SMC-EPC cell sheet-treated group.Treatment of DMCM with tissue-engineered SMC-EPC bi-level cell sheets prevented cardiac dysfunction and microvascular disease associated with DMCM. This multi-lineage cellular therapy is a novel, translatable approach to improve microvascular disease and prevent heart failure in diabetic patients.
View details for PubMedID 29096622
A Simple, Standard Method to Characterize Pressure/Flow Performance of Vascular Access Cannulas
2013; 59 (1): 24-29
Coronary artery disease is one of the most common causes of death and disability, afflicting more than 15 million Americans. Although pharmacological advances and revascularization techniques have decreased mortality, many survivors will eventually succumb to heart failure secondary to the residual microvascular perfusion deficit that remains after revascularization. We present a novel system that rescues the myocardium from acute ischemia, using photosynthesis through intramyocardial delivery of the cyanobacterium Synechococcus elongatus. By using light rather than blood flow as a source of energy, photosynthetic therapy increases tissue oxygenation, maintains myocardial metabolism, and yields durable improvements in cardiac function during and after induction of ischemia. By circumventing blood flow entirely to provide tissue with oxygen and nutrients, this system has the potential to create a paradigm shift in the way ischemic heart disease is treated.
View details for PubMedID 28630913
Empirical Hospital and Professional Charges for Patient Care Associated with Out of Hospital Cardiac Arrest Before and After Implementation of Therapeutic Hypothermia for Comatose Survivors
2012; 83 (10): 1265-1270
Vascular access cannulas for extracorporeal life support are characterized by French (Fr) size alone, which affords limited information on pressure (P) and flow (Q) performance, making their selection difficult. Previously, we developed an accurate metric of cannula performance, the M number, but its complexity and the need of a nomogram hindered its utility. We propose adoption of an easier and clinically useful metric to assess cannula performance: Q at 100 mm Hg P, the updated M number, or the "UM number." A circuit was created using a centrifugal pump, Tygon tubing, and a reservoir. A total of 74 cannulas (arterial, venous, and double lumen) ranging from 6 to 50 Fr size were studied. Glycerol solution with a viscosity of 3 cP was used to mimic blood. A Biopac system and ultrasonic flow probe was used to collect P/Q data across a cannula's performance range. The UM number describes the pressure-flow characteristics of any given cannula. It can be used to select access cannulas based on performance and to determine if flow matches expected flow during use.
View details for DOI 10.1097/MAT.0b013e3182746401
View details for Web of Science ID 000312900900005
View details for PubMedID 23183160
Hospitalist Time Usage and Cyclicality: Opportunities to Improve Efficiency
JOURNAL OF HOSPITAL MEDICINE
2010; 5 (6): 329-334
The objectives of this study are to characterize the total hospital and professional charges for patients with out of hospital cardiac arrest both with and without therapeutic hypothermia treatment.Retrospective cohort study of all adult patients with non-traumatic out of hospital cardiac arrest brought to the ED of a single tertiary care hospital over 20 months preceding and 20 months following implementation of therapeutic hypothermia for comatose survivors. Billing and clinical data were obtained from administrative databases and the electronic medical record using explicit audited abstraction. Demographic, payer characteristics, median charges and reimbursements with interquartile ranges are described before and after implementation, stratified by patient outcome.Two hundred and twenty-three patients met study criteria. The median charge was $3,112 among the 135 patients (60.5%) that did not survive to admission and $94,916 among the 88 (39.5%) that did. Median charges before and after implementation of therapeutic hypothermia were $6,324 and $15,537 respectively. Medicare was the most frequent payer. Good neurological outcome occurred in 11/115 patients (9.6%) prior to implementation and 22/108 patients (20.4%) after. Among 23 patients treated with hypothermia, good neurological outcome occurred in 11 patients (47.8%). Good neurological outcome and treatment with hypothermia were associated with increased procedure utilization and higher charges.Empirical patient level data confirm that charges for patients with out of hospital cardiac arrest are substantial, even among patients that do not survive to hospital admission. Treatment with therapeutic hypothermia is associated with better outcomes, more procedures, and higher charges.
View details for DOI 10.1016/j.resuscitation.2012.03.001
View details for Web of Science ID 000309050600028
View details for PubMedID 22410427
Academic medical centers (AMCs) have a constrained resident work force. Many AMCs have increased the use of nonresident service hospitalists to manage continued growth in clinical volume. To optimize their time in the hospital, it is important to understand hospitalists' work flow.We performed a time-motion study of hospitalists carrying the admission pager throughout the 3 types of shifts we have at our hospital (day shift, swing shift, and night shift).Tertiary academic medical center in the Midwest.Hospitalists spend about 15% of their time on direct patient care, and two-thirds of their time on indirect patient care. Of the indirect activities, communication and documentation dominate. Travel demands make up over 7% of a hospitalists' time. There are spikes in indirect patient care, followed closely by spikes in direct patient care, at shift changes.At our AMC, indirect patient care activities accounted for the majority of the admitting hospitalists' time spent in the hospital, with documentation and communication dominating this time. Travel takes a significant fraction of hospitalists' time. There is also a cyclical nature to activities performed throughout the day, which can cause patient delays and impose variability on support services. There is a need for both service-specific and systemic improvements for AMCs to efficiently manage further growth in their inpatient volume.
View details for DOI 10.1002/jhm.613
View details for Web of Science ID 000281290600004
View details for PubMedID 20803670