MD, Columbia University, College of Physicians and Surgeons, Medicine (2015)
BA, Harvard University, Molecular and Cellular Biology, Music (2011)
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Precision surgery: patient-specific bypass grafting and valve repair strategies
Autonomous robotic surgery
Photosynthetic therapies to circumvent myocardial ischemia
Collateral artery formation as protection against myocardial infarction
Angiogenesis and myocardial regeneration to prevent heart failure
Tissue engineering to limit ventricular remodeling
Understanding the biomechanics of injured and failing hearts
BACKGROUND: Early engagement in cardiothoracic (CT) surgery research may help attract trainees to academic CT surgery, but whether this early exposure boosts career-long academic achievement remains unknown.METHODS: A database of all CT surgery faculty at accredited, academic CT surgery training programs in the United States during the year 2018 was established. Excluding international medical graduates, surgeons who started general surgery residency in the United States prior to 2004 and who published at least one manuscript prior to traditional CT fellowship training were included (n=472). Each surgeon's educational background, work history, and research publications were recorded from publicly-available online sources.RESULTS: In total, 370 surgeons (78.4%) co-authored a CT surgery manuscript before fellowship training, while 102 (21.6%) published only on subjects unrelated to CT surgery. Regardless of whether surgeons pursued dedicated research training or not, those who co-authored a CT surgery manuscript prior to fellowship training published more papers per year as an attending (p<0.01), resulting in more total publications (p<0.01) and a higher H-index (p<0.01) over comparably long careers. Among CT surgeons who did not publish CT surgery research prior to fellowship training, those who co-authored a CT surgery manuscript during fellowship also exhibited enhanced future academic productivity.CONCLUSIONS: Academic CT surgeons who published CT surgery research prior to fellowship training ultimately exhibit more prolific and impactful research profiles compared to those who published only on subjects unrelated to CT surgery during training. Efforts to increase early engagement in CT surgery research among trainees should be fully endorsed.
View details for DOI 10.1016/j.athoracsur.2020.10.013
View details for PubMedID 33159869
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
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
OBJECTIVE: Endoscopic radial artery (RA) harvesting performed concurrently with internal mammary artery (IMA) takedown and endoscopic saphenous vein (SV) harvesting creates a crowded and inefficient operating room environment. We assessed the effect of a presternotomy RA harvest strategy on surgery time and costs.METHODS: A total of 41 patients underwent elective, first-time, isolated multivessel on-pump coronary artery bypass grafting including an IMA, RA, and SV graft. The first 20 patients (Phase I) underwent endoscopic RA harvesting concurrently with IMA takedown and endoscopic SV harvesting after sternotomy, requiring two sets of endoscopic harvesting equipment per case, each used by a separate individual. The final 21 patients (Phase II) underwent endoscopic RA harvesting during anesthesia line placement, completing the procedure before sternotomy, thus requiring only one set of endoscopic harvesting equipment reused by a single individual.RESULTS: There were no differences in baseline patient characteristics, number of bypasses, duration of SV or RA harvest time, or duration of cardiopulmonary bypass or cross-clamp time between the two groups. Total surgery time was reduced by 32 minutes in Phase II (P = 0.044). Relative to a total hospital direct cost of 100.00 units, total surgery costs were reduced from 29.33 units in Phase I to 25.62 units in Phase II (P = 0.001). No anesthesia- or RA harvest-related complications occurred in either group.CONCLUSIONS: Endoscopic RA harvesting can be safely performed during anesthesia line placement prior to sternotomy. Our simple but innovative strategy improves intraoperative workflow, reduces the time and cost of surgery, and advances the delivery of high-quality patient care.
View details for DOI 10.1177/1556984519882014
View details for PubMedID 31903868
Myocardial bridge (MB) of the left anterior descending (LAD) coronary artery occurs in approximately 25% of the population. For patients with a symptomatic, hemodynamically significant MB who fail medical therapy, MB unroofing represents the optimal surgical management. Here, we evaluated minimally invasive MB unroofing in selected patients compared with sternotomy.MB unroofing was performed in 141 adult patients via sternotomy on-pump (ST-on, n=40), sternotomy off-pump (ST-off, n=62), or mini thoracotomy off-pump (MT, n=39). Angina symptoms were assessed preoperatively and 6-months postoperatively using the Seattle Angina Questionnaire. Matching included all MT patients and 31 ST-off patients with similar MB characteristics, no previous cardiac surgery or coronary interventions, and no concomitant procedures.MT patients tended to have a shorter MB length than ST-on and ST-off patients (2.57 vs 2.93 vs 3.09 cm, p=0.166). ST-on patients had a longer hospital stay than ST-off and MT patients (5.0 vs 4.0 vs 3.0 days, p<0.001), and more blood transfusions (15.2% vs 0.0% vs 2.6%, p=0.002). After matching, MT patients had a shorter hospital stay than ST-off patients (3.0 vs 4.0 days, p=0.005). No deaths or major complications occurred in any group. In all groups, MB unroofing yielded significant symptomatic improvement regarding physical limitation, angina stability, angina frequency, treatment satisfaction, and quality of life.We report the largest experience of off-pump minimally invasive MB unroofing, which may be safely performed in carefully selected patients, yielding dramatic improvements in angina symptomatology at 6 months after surgery.
View details for DOI 10.1016/j.athoracsur.2020.11.023
View details for PubMedID 33333083
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
View details for PubMedID 30683833
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
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
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
Scimitar syndrome involves congenital anomalous pulmonary venous return to the inferior vena cava. Optimal management remains controversial. We describe the natural history of disease, nonsurgical and surgical outcomes, and risk factors for poor outcomes at our institution.Patients with anomalous pulmonary venous return to the inferior vena cava documented on echocardiography at our institution between January 1994 and January 2015 were reviewed retrospectively. The study protocol IRB-AAAO1805 was approved.Forty-seven patients were identified, including 20 infants with significant associated congenital heart defects (42.6%, including 7 with single ventricle physiology), and 10 infants (21.3%) and 16 noninfants (34.0%) with isolated scimitar syndrome. Median follow-up was 3.55 years. Noninfants exhibited lower incidences of right pulmonary artery hypoplasia (p < 0.001), aortopulmonary collaterals (p = 0.004), and scimitar vein obstruction at the caval confluence (p = 0.032). Eighteen patients (38.3%) underwent surgical repair for scimitar syndrome. Overall mortality after baffle repair or scimitar vein reimplantation was 37.5% (3 of 8) for infants and 0% (0 of 6) for noninfants (p = 0.209). Overall mortality for medically managed infants was 46.7% (7 of 15) compared with 0% (0 of 8) for noninfants (p = 0.052). Multivariable analyses identified infantile onset as an independent risk factor for stenosis or obstruction after repair (hazard ratio 9.34, p = 0.048), and single ventricle physiology as an independent risk factor for mortality among unrepaired patients (hazard ratio 29.8, p = 0.004).The severity of scimitar syndrome depends on presenting age and associated congenital heart disease. Nonsurgical and surgical outcomes are suboptimal for infantile disease, which is a risk factor for stenosis after repair. Single ventricle physiology is associated with poor prognosis.
View details for DOI 10.1016/j.athoracsur.2017.06.061
View details for PubMedID 29054305
OBJECTIVE: To test the hypothesis that factor eight inhibitor bypassing activity (FEIBA) can be used to control bleeding following left ventricular assist device (LVAD) implantation without increasing the 14-day composite thrombotic outcome of pump thrombus, ischemic cerebrovascular accidents, pulmonary embolism, and deep venous thrombosis.DESIGN: Retrospective cohort study.SETTING: Academic hospital.PARTICIPANTS: Three hundred nineteen consecutive patients who underwent LVAD implantation (December 1, 2009 to December 30, 2018).INTERVENTION: FEIBA administered to control perioperative hemorrhage.MEASUREMENTS AND MAIN RESULTS: The 82 patients (25.7%) in the FEIBA cohort had more risk factors for perioperative hemorrhage, such as lower preoperative platelet count (169 ± 66 v 194 ± 68?*?103/mL, p?=?0.004), prior cardiac surgery (36.6% v 21.9%, p?=?0.008), and longer cardiopulmonary bypass (CPB) time (100.3 v 75.2 minutes, p?=?0.001) than the 237 controls. After 16.6 units (95% CI: 14.3-18.9) of blood products were given, 992 units (95% CI: 821-1163) of FEIBA were required to control bleeding in the FEIBA cohort. Compared to the controls, there were no differences in the 14-day composite thrombotic outcome (11.0% v 7.6%, p?=?0.343) or mortality rate (3.7% v 1.3%, p?=?0.179). Multivariate logistical regression identified preoperative international normalized ratio (odds ratio [OR]: 1.30, 95% CI: 1.04-1.62) and CPB time (OR: 1.11, 95% CI: 1.02-1.20) as risk factors for 14-day thrombotic events, but FEIBA usage was not associated with an increased risk.CONCLUSIONS: In this retrospective cohort study, the use of FEIBA (1,000 units, 13 units/kg) to control perioperative hemorrhage following LVAD implantation was not associated with increases in mortality or composite thrombotic outcome.
View details for DOI 10.1053/j.jvca.2021.04.030
View details for PubMedID 34034934
BACKGROUND: The foundation for a successful academic surgical career begins in medical school. We examined whether attending a top-ranked medical school is correlated with enhanced research productivity and faster career advancement among academic cardiothoracic (CT) surgeons.MATERIALS AND METHODS: Research profiles and professional histories were obtained from publicly available sources for all CT surgery faculty at accredited US CT surgery teaching hospitals in 2018 (n=992). We focused on surgeons who completed medical school in the United States during or after 1990, the first-year US News & World Report released its annual medical school research rankings (n=451). Subanalyses focused on surgeons who completed a research fellowship (n=299) and those who did not (n=152).RESULTS: A total of 124 surgeons (27.5%) attended a US News & World Report top 10 medical school, whereas 327 (72.5%) did not. Surgeons who studied at a top 10 medical school published more articles per year as an attending surgeon (3.2 versus 1.9; P<0.0001), leading to more total publications (51.5 versus 27.0; P<0.0001) and a higher H-index (16.0 versus 11.0; P<0.0001) over a similar career duration (11.0 versus 10.0y; P=0.1294). These differences in career-long research productivity were statistically significant regardless of whether the surgeons completed a research fellowship or not. The surgeons in both groups, however, required a similar number of years to reach associate professor rank (P=0.6993) and full professor rank (P=0.7811) after starting their first attending job.CONCLUSIONS: Attending a top-ranked medical school is associated with enhanced future research productivity but not with faster career advancement in academic CT surgery.
View details for DOI 10.1016/j.jss.2021.01.008
View details for PubMedID 33794390
Pulmonary artery dissection is rare but highly lethal. Recent reports suggest that surgical repair of pulmonary artery dissection may yield good outcomes in selected patients, although postoperative right ventricular failure and death have been described. Currently, only one patient over age 60 years old has been reported to survive open surgical repair of pulmonary artery dissection. Here, we present the case of a sexagenarian with pulmonary artery hypertension complicated by a dissected pulmonary artery aneurysm which was successfully repaired using a composite valve-tube graft under a beating-heart strategy.
View details for DOI 10.1111/jocs.15459
View details for PubMedID 33651429
Cardiovascular disease remains the leading cause of death worldwide. While clinical trials of cell therapy have demonstrated largely neutral results, recent investigations into the mechanisms of natural myocardial regeneration have demonstrated promising new intersections between molecular, cellular, tissue, biomaterial, and biomechanical engineering solutions. New insight into the crucial role of inflammation in natural regenerative processes may explain why previous efforts have yielded only modest degrees of regeneration. Furthermore, the new understanding of the interdependent relationship of inflammation and myocardial regeneration have catalyzed the emergence of promising new areas of investigation at the intersection of many fields.
View details for DOI 10.3389/fbioe.2021.674172
View details for PubMedCentralID PMC8205517
Cardiovascular disease remains the leading cause of death worldwide despite significant advances in our understanding of the disease and its treatment. Consequently, the therapeutic potential of cell therapy and induction of natural myocardial regeneration have stimulated a recent surge of research and clinical trials aimed at addressing this challenge. Recent developments in the field have shed new light on the intricate relationship between inflammation and natural regeneration, an intersection that warrants further investigation.
View details for DOI 10.3389/fcell.2021.674180
View details for PubMedCentralID PMC8148343
National Institutes of Health (NIH) funding has declined among cardiothoracic surgeons. R01 grants are a well-known mechanism to support high-impact research, and we sought to clarify the association between NIH funding and academic achievement. We hypothesized that cardiothoracic surgeons who acquired R01 funding exhibit greater research output and faster career advancement. All cardiothoracic surgeons (n=992) working at accredited United States cardiothoracic surgery training hospitals in 2018 were included. Institutional webpages, Scopus, and Grantome were utilized to collect publicly-available data regarding each surgeon's training and career history, research publications, and NIH funding. 78 (7.9%) surgeons obtained R01 funding as a principal investigator, while 914 (92.1%) did not. R01-funded surgeons started their attending careers earlier (1998 vs 2005, p<0.0001) and were more likely to have pursued dedicated research training (p<0.0001). R01-funded surgeons authored 5.3 publications/year before their first R01 grant, 9.3 during the grant period, and 8.6 after the grant expired, all of which were greater than the publication rate of non-R01-funded surgeons at comparable career timepoints (2.0-3.0 publications/year, p<0.0001). Among time-matched surgeons who completed medical school in 1998 or earlier (n=73 R01-funded vs n=602 non-funded), R01-funded surgeons have published more total publications (178.0 vs 56.5 papers, p<0.0001) and exhibit a greater H-index (41.0 vs 19.0, p<0.0001). R01-funded surgeons have also advanced to higher academic ranks (p<0.0001) and are more likely to be chiefs of their departments or divisions (42.5% vs 25.7%, p=0.0035). Cardiothoracic surgeons who obtain R01 funding exhibit greater research productivity and faster career advancement.
View details for DOI 10.1053/j.semtcvs.2020.12.002
View details for PubMedID 33359763
BACKGROUND: A first attending job often sets the tone for academic surgeons' future careers, and many graduating trainees are faced with the decision to begin their career at their training institution or another institution. We hypothesized that surgeons hired as first-time faculty at their cardiothoracic surgery fellowship (CSF) institution exhibit greater research productivity and career advancement than those hired as first-time faculty at a different institution.METHODS: Cardiothoracic surgeons who were listed as clinical faculty at all 77 accredited U.S. cardiothoracic surgery training programs and who trained via the general surgery residency and CSF pathway in 2018 were included (n=904). Surgeon-specific data regarding professional history, publications, and grant funding were obtained from publicly available sources.RESULTS: 294/904 (32.5%) surgeons were hired as first-time faculty at their CSF institution while 610/904 (67.5%) surgeons were hired at a different institution (start year 2005 vs 2006, p=0.3424). Both groups exhibited similar research productivity upon starting their first job (total papers: 7.0 vs 7.0, p=0.5913). Following them to the present, surgeons hired at their CSF institution produced more total papers (64.5 vs 39.0, p<0.0001) and exhibited a higher H-index (20.0 vs 14.0, p<0.0001). Surgeons in both groups required a similar amount of time to achieve associate (p=0.2079) and full professor (p=0.5925) ranks.CONCLUSIONS: Surgeons hired as first-time faculty at their CSF institution may experience benefits to research productivity but not career advancement. Trainees may find it advantageous to begin their careers in a familiar environment where they have already formed a robust specialty-specific network.
View details for DOI 10.1016/j.athoracsur.2020.09.026
View details for PubMedID 33152331
BACKGROUND: Advanced clinical fellowships are important for training surgeons with a niche expertise. Whether this additional training impacts future academic achievement, however, remains unknown. Here, we investigated the impact of advanced fellowship training on research productivity and career advancement among active, academic cardiac surgeons. We hypothesized that advanced fellowships do not significantly boost future academic achievement.METHODS: Using online sources (eg, department webpages, CTSNet, Scopus, Grantome), we studied adult cardiac surgeons who are current faculty at accredited United States cardiothoracic surgery training programs, and who have practiced only at United States academic centers since 1986 (n= 227). Publicly available data regarding career advancement, research productivity, and grant funding were collected. Data are expressed as counts or medians.RESULTS: In our study, 78 (34.4%) surgeons completed an advanced clinical fellowship, and 149 (65.6%) did not. Surgeons who pursued an advanced fellowship spent more time focused on surgical training (P < .0001), and those who did not were more likely to have completed a dedicated research fellowship (P= .0482). Both groups exhibited similar cumulative total publications (P= .6862), H-index (P= .6232), frequency of National Institutes of Health grant funding (P= .8708), and time to achieve full professor rank (P= .7099). After stratification by current academic rank, or by whether surgeons pursued a dedicated research fellowship, completion of an advanced clinical fellowship was not associated with increased research productivity or accelerated career advancement.CONCLUSION: Academic adult cardiac surgeons who pursue advanced clinical fellowships exhibit similar research productivity and similar career advancement as those who do not pursue additional clinical training.
View details for DOI 10.1016/j.surg.2020.06.016
View details for PubMedID 32747139
Cell sheet technology using UpCell plates is a modern tool that enables the rapid creation of a single-layered cells without using extracellular matrix enzymatic digestion. Although this technique has the advantage of maintaining a sheet of cells without needing artificial scaffolds, these cell sheets remain extremely fragile. Collagen, the most abundant extracellular matrix component, is an attractive candidate for modulating tissue mechanical properties given its tunable property. In this study, we demonstrated rapid mechanical property augmentation of human dermal fibroblast cell sheets after incubation with bovine type I collagen for 24 hours on UpCell plates. We showed that treatment with collagen resulted in increased collagen I incorporation within the cell sheet without affecting cell morphology, cell type, or cell sheet quality. Atomic force microscopy measurements for controls, and cell sheets that received 50g/mL and 100g/mL collagen I treatments revealed an average Young's modulus of their respective intercellular regions: 6.6±1.0, 14.4±6.6, and 19.8±3.8 kPa during the loading condition, and 10.3±4.7, 11.7±2.2, and 18.1±3.4 kPa during the unloading condition. This methodology of rapid mechanical property augmentation of a cell sheet has a potential impact on cell sheet technology by improving the ease of construct manipulation, enabling new translational tissue engineering applications.
View details for DOI 10.1089/ten.TEA.2020.0128
View details for PubMedID 32703108
The genetic mechanisms underlying aortic stenosis (AS) and aortic insufficiency (AI) disease progression remain unclear. We hypothesized that normal aortic valves and those with AS or AI all exhibit unique transcriptional profiles. Normal control (NC) aortic valves were collected from non-matched donor hearts that were otherwise acceptable for transplantation (n = 5). Valves with AS or AI (n = 5, each) were collected from patients undergoing surgical aortic valve replacement. High-throughput sequencing of total RNA revealed 6438 differentially expressed genes (DEGs) for AS vs. NC, 4994 DEGs for AI vs. NC, and 2771 DEGs for AS vs. AI. Among 21 DEGs of interest, APCDD1L, CDH6, COL10A1, HBB, IBSP, KRT14, PLEKHS1, PRSS35, and TDO2 were upregulated in both AS and AI compared to NC, whereas ALDH1L1, EPHB1, GPX3, HIF3A, and KCNT1 were downregulated in both AS and AI (p < 0.05). COL11A1, H19, HIF1A, KCNJ6, PRND, and SPP1 were upregulated only in AS, and NPY was downregulated only in AS (p < 0.05). The functional network for AS clustered around ion regulation, immune regulation, and lipid homeostasis, and that for AI clustered around ERK1/2 regulation. Overall, we report transcriptional profiling data for normal human aortic valves from non-matched donor hearts that were acceptable for transplantation and demonstrated that valves with AS and AI possess unique genetic signatures. These data create a roadmap for the development of novel therapeutics to treat AS and AI.
View details for DOI 10.3390/genes11070789
View details for PubMedID 32674273
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
OBJECTIVE: The objective was to design and evaluate a clinically relevant, novel exvivo bicuspid aortic valve model that mimics the most common human phenotype with associated aortic regurgitation.METHODS: Three bovine aortic valves were mounted asymmetrically in a previously validated 3-dimensional-printed left heart simulator. The non-right commissure and the non-left commissure were both shifted slightly toward the left-right commissure, and the left and right coronary cusps were sewn together. The left-right commissure was then detached and reimplanted 10mm lower than its native height. Free margin shortening was used for valve repair. Hemodynamic status, high-speed videography, and echocardiography data were collected before and after the repair.RESULTS: The bicuspid aortic valve model was successfully produced and repaired. High-speed videography confirmed prolapse of the fused cusp of the baseline bicuspid aortic valve models in diastole. Hemodynamic and pressure data confirmed accurate simulation of diseased conditions with aortic regurgitation and the subsequent repair. Regurgitant fraction postrepair was significantly reduced compared with that at baseline (14.5 ± 4.4% vs 28.6%±3.4%; P=.037). There was no change in peak velocity, peak gradient, or mean gradient across the valve pre- versus postrepair: 293.3±18.3cm/sec versus 325.3±58.2cm/sec (P=.29), 34.3±4.2mm Hg versus 43.3±15.4mm Hg (P=.30), and 11±1mm Hg versus 9.3±2.5mm Hg (P=.34), respectively.CONCLUSIONS: An exvivo bicuspid aortic valve model was designed that recapitulated the most common human phenotype with aortic regurgitation. These valves were successfully repaired, validating its potential for evaluating valve hemodynamics and optimizing surgical repair for bicuspid aortic valves.
View details for DOI 10.1016/j.jtcvs.2020.06.028
View details for PubMedID 32747120
BACKGROUND: The use of bilateral internal mammary arteries (BIMA) in coronary artery bypass grafting remains controversial. The objective of this study was to investigate the long-term outcomes using BIMA versus single internal mammary artery (SIMA) in the United States.METHODS: Medicare beneficiaries who underwent primary isolated coronary artery bypass surgery using SIMA or BIMA from 1999 to 2010 were included in this retrospective study, with follow up through 2014. Greedy matching algorithms were used for 1:4 matching on propensity score based on age, gender, year of surgery, and comorbidities. Kaplan-Meier survival analyses were performed. The primary outcome was death from any cause.RESULTS: A total of 1,156,339 and 25,005 patients aged 72±7.6 and 70.3±7.9 years-old underwent primary isolated coronary artery bypass surgery using SIMA and BIMA, respectively. Matching created comparable groups with 95,780 SIMA and 24,160 BIMA patients. Matched median survival using SIMA was 11.8 versus 12.4 years using BIMA (p<.0001). At ten years of follow up, the respective survival rates of using SIMA versus BIMA were 58.3% versus 61.1%, respectively. The stratified matched median survival using SIMA versus BIMA with one, two, three, and four or more aortocoronary bypasses were 11.8 versus 12.3 years (p=.005), 11.7 versus 12.5 years (p<.0001), 11.9 versus 12.3 years (p=.01), and 11.4 versus 12 years (p=.02), respectively.CONCLUSIONS: Primary isolated coronary artery bypass surgery using BIMA rather than SIMA was associated with improved long-term survival. This survival advantage was independent of aortocoronary bypass grafts or patient diabetes status.
View details for DOI 10.1016/j.athoracsur.2020.05.049
View details for PubMedID 32599051
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
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
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
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
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
The clinical efficacy of neuregulin (NRG) in the treatment of heart failure is hindered by off-target exposure due to systemic delivery. We previously encapsulated neuregulin in a hydrogel (HG) for targeted and sustained myocardial delivery, demonstrating significant induction of cardiomyocyte proliferation and preservation of post-infarct cardiac function in a murine myocardial infarction (MI) model. Here, we performed a focused evaluation of our hydrogel-encapsulated neuregulin (NRG-HG) therapy's potential to enhance cardiac function in an ovine large animal MI model. Adult male Dorset sheep (n = 21) underwent surgical induction of MI by coronary artery ligation. The sheep were randomized to receive an intramyocardial injection of saline, HG only, NRG only, or NRG-HG circumferentially around the infarct borderzone. Eight weeks after MI, closed-chest intracardiac pressure-volume hemodynamics were assessed, followed by heart explant for infarct size analysis. Compared to each of the control groups, NRG-HG significantly augmented left ventricular ejection fraction (p = 0.006) and contractility based on the slope of the end-systolic pressure-volume relationship (p = 0.006). NRG-HG also significantly reduced infarct scar size (p = 0.002). Overall, using a bioengineered hydrogel delivery system, a one-time dose of NRG delivered intramyocardially to the infarct borderzone at the time of MI in adult sheep significantly reduces scar size and enhances ventricular contractility at 8 weeks after MI.
View details for DOI 10.3390/jcdd7040053
View details for PubMedID 33212844
The need for personal protective equipment during the COVID-19 pandemic is far outstripping our ability to manufacture and distribute these supplies to hospitals. In particular, the medical N95 mask shortage is resulting in healthcare providers reusing masks or utilizing masks with filtration properties that do not meet medical N95 standards. We developed a solution for immediate use: a mask adaptor, outfitted with a quarter section of an N95 respirator that maintains the N95 seal standard, thereby quadrupling the N95 supply. A variety of designs were 3D-printed and optimized based on the following criteria: seal efficacy, filter surface area and N95 respirator multiplicity. The final design is reusable and features a 3D-printed soft silicone base as well as a rigid 3D-printed cartridge to seal one-quarter of a 3M 1860 N95 mask. Our mask passed the computerized N95 fit test for six individuals. All files are publicly available with this publication. Our design can provide immediate support for healthcare professionals in dire need of medical N95 masks by extending the current supply by a factor of four.
View details for DOI 10.3390/healthcare8030225
View details for PubMedID 32717841
Papillary muscles serve as attachment points for chordae tendineae which anchor and position mitral valve leaflets for proper coaptation. As the ventricle contracts, the papillary muscles translate and rotate, impacting chordae and leaflet kinematics; this motion can be significantly affected in a diseased heart. In ex vivo heart simulation, an explanted valve is subjected to physiologic conditions and can be adapted to mimic a disease state, thus providing a valuable tool to quantitatively analyse biomechanics and optimize surgical valve repair. However, without the inclusion of papillary muscle motion, current simulators are limited in their ability to accurately replicate cardiac biomechanics. We developed and implemented image-guided papillary muscle (IPM) robots to mimic the precise motion of papillary muscles. The IPM robotic system was designed with six degrees of freedom to fully capture the native motion. Mathematical analysis was used to avoid singularity conditions, and a supercomputing cluster enabled the calculation of the system's reachable workspace. The IPM robots were implemented in our heart simulator with motion prescribed by high-resolution human computed tomography images, revealing that papillary muscle motion significantly impacts the chordae force profile. Our IPM robotic system represents a significant advancement for ex vivo simulation, enabling more reliable cardiac simulations and repair optimizations.
View details for DOI 10.1098/rsif.2020.0614
View details for PubMedID 33259750
Women remain underrepresented in Cardiothoracic Surgery (CTS). In 2005, Women in Thoracic Surgery (WTS) began offering scholarships to promote engagement of women in CTS careers. This study explores the effect of WTS scholarships on CTS career milestones.We assessed career development using the number of awardees matching into CTS residency/fellowship, American Board of Thoracic Surgery (ABTS) certification, and academic CTS appointment. Scholarship awardee data were obtained from our WTS database. Comparison data were gathered from the National Residency Match Program and ABTS. Details of the current roles of ABTS certified women were determined from public resources. Qualitative results were gathered from post-scholarship surveys.106 WTS scholarships have been awarded to 38 medical students (MS, 36%), 41 General Surgery residents (GR, 39%), and 27 CTS residents/fellows (CR, 25%). Among MS, 26% of awardees entered integrated CTS residency (vs. <0.1% for medical students, p<0.0001), while 37% entered general surgery residency (vs. 4.8% for medical students, p<0.0001). Of GR awardees, 59% entered CTS fellowships (vs. 7.7% for general surgery residents, p<0.0001), and of CR awardees, 100% earned ABTS certification (vs. 73% ABTS pass rate, p=.01). Of ABTS certified awardees, 44% are practicing CT surgeons at U.S. academic training institutions (vs. 33% of non-awardee ABTS certified women, p=0.419). All awardees reported that their scholarship was valuable in their development.Receipt of a WTS scholarship is associated with successful pursuit of CTS career milestones at significantly higher rates than contemporaries. These scholarships foster a supportive community for women trainees in CTS.
View details for DOI 10.1016/j.athoracsur.2020.07.020
View details for PubMedID 32961134
New transapical minimally invasive artificial chordae implantation devices are a promising alternative to traditional open-heart repair, with the potential for decreased postoperative morbidity and reduced recovery time. However, these devices can place increased stress on the artificial chordae. We designed an artificial papillary muscle to alleviate artificial chordae stresses and thus increase repair durability.The artificial papillary muscle device is a narrow elastic column with an inner core that can be implanted during the minimally invasive transapical procedure via the same ventricular incision site. The device was 3-dimensionally printed in biocompatible silicone for this study. To test efficacy, porcine mitral valves (n = 6) were mounted in a heart simulator, and isolated regurgitation was induced. Each valve was repaired with a polytetrafluoroethylene suture with apical anchoring followed by artificial papillary muscle anchoring. In each case, a high-resolution Fiber Bragg Grating sensor recorded forces on the suture.Hemodynamic data confirmed that both repairs-with and without the artificial papillary muscle device-were successful in eliminating mitral regurgitation. Both the peak artificial chordae force and the rate of change of force at the onset of systole were significantly lower with the device compared with apical anchoring without the device (P < .001 and P < .001, respectively).Our novel artificial papillary muscle could integrate with minimally invasive repairs to shorten the artificial chordae and behave as an elastic damper, thus reducing sharp increases in force. With our device, we have the potential to improve the durability of off-pump transapical mitral valve repair procedures.
View details for DOI 10.1016/j.jtcvs.2020.11.105
View details for PubMedID 33451843
Many graft configurations are clinically used for valve-sparing aortic root replacement, some specifically focused on recapitulating neosinus geometry. However, the specific impact of such neosinuses on valvular and root biomechanics and the potential influence on long-term durability are unknown.Using a custom 3-dimenstional-printed heart simulator with porcine aortic roots (n=5), the anticommissural plication, Stanford modification, straight graft (SG), Uni-Graft, and Valsalva graft configurations were tested in series using an incomplete counterbalanced measures design, with the native root as a control, to mitigate ordering effects. Hemodynamic and videometric data were analyzed using linear models with conduit as the fixed effect of interest and valve as a fixed nuisance effect with post hoc pairwise testing using Tukey's correction.Hemodynamics were clinically similar between grafts and control aortic roots. Regurgitant fraction varied between grafts, with SG and Uni-Graft groups having the lowest regurgitant fractions and anticommissural plication having the highest. Root distensibility was significantly lower in SG versus both control roots and all other grafts aside from the Stanford modification (P?0.01 for each). All grafts except SG had significantly higher cusp opening velocities versus native roots (P<0.01 for each). Relative cusp opening forces were similar between SG, Uni-Graft, and control groups, whereas anticommissural plication, Stanford modification, and Valsalva grafts had significantly higher opening forces versus controls (P<0.01). Cusp closing velocities were similar between native roots and the SG group, and were significantly lower than observed in the other conduits (P?0.01 for each). Only SG and Uni-Graft groups experienced relative cusp closing forces approaching that of the native root, whereas relative forces were >5-fold higher in the anticommissural plication, Stanford modification, and Valsalva graft groups.In this ex vivo modeling system, clinically used valve-sparing aortic root replacement conduit configurations have comparable hemodynamics but differ in biomechanical performance, with the straight graft most closely recapitulating native aortic root biomechanics.
View details for DOI 10.1161/CIRCULATIONAHA.120.046612
View details for PubMedID 33017215
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
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
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
Orthotopic heart transplantation with concomitant aortic surgery is rarely performed. Herein, we describe the successful management of a patient with an otherwise inoperable, ruptured aortic root pseudoaneurysm using combined cardioaortic replacement under hypothermic circulatory arrest.
View details for PubMedID 30608529
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
Tissue engineering approaches to regenerate myocardial tissue after disease or injury is promising. Integration with the host vasculature is critical to the survival and therapeutic efficacy of engineered myocardial tissues. To create more physiologically oriented engineered myocardial tissue with organized cellular arrangements and endothelial interactions, randomly oriented or parallel-aligned microfibrous polycaprolactone scaffolds were seeded with human pluripotent stem cell-derived cardiomyocytes (iCMs) and/or endothelial cells (iECs). The resultant engineered myocardial tissues were assessed in a subcutaneous transplantation model and in a myocardial injury model to evaluate the effect of scaffold anisotropy and endothelial interactions on vascular integration of the engineered myocardial tissue. Here we demonstrated that engineered myocardial tissue composed of randomly oriented scaffolds seeded with iECs promoted the survival of iECs for up to 14 days. However, engineered myocardial tissue composed of aligned scaffolds preferentially guided the organization of host capillaries along the direction of the microfibers. In a myocardial injury model, epicardially transplanted engineered myocardial tissues composed of randomly oriented scaffolds seeded with iCMs augmented microvessel formation leading to a significantly higher arteriole density after 4 weeks, compared to engineered tissues derived from aligned scaffolds. These findings that the scaffold microtopography imparts differential effect on revascularization, in which randomly oriented scaffolds promote pro-survival and pro-angiogenic effects, and aligned scaffolds direct the formation of anisotropic vessels. These findings suggest a dominant role of scaffold topography over endothelial co-culture in modulating cellular survival, vascularization, and microvessel architecture.
View details for DOI 10.3389/fbioe.2019.00208
View details for PubMedID 31552234
View details for PubMedCentralID PMC6733921
Heart-lung transplantation (HLTx) is an effective treatment for patients with advanced cardiopulmonary failure. However, no large multicenter study has focused on the relationship between donor and recipient risk factors and post-HLTx outcomes. Thus, we investigated this issue using data from the United Network for Organ Sharing database.All adult patients (age ?18 years) registered in the United Network for Organ Sharing database who underwent HLTx between 1987 and 2017 were included (n=997). We stratified the cohort by patients who were alive without retransplant at 1 year (n=664) and patients who died or underwent retransplant within 1 year of HLTx (n=333). The primary outcome was the influence of donor and recipient characteristics on 1-year post-HLTx recipient death or retransplant. Kaplan-Meier curves were created to assess overall freedom from death or retransplant. To obtain a better effect estimation on hazard and survival time, the parametric Accelerated Failure Time model was chosen to perform time-to-event modeling analyses.Overall graft survival at 1-year post-HLTx was 66.6%. Of donors, 53% were male, and the mean age was 28.2 years. Univariable analysis showed advanced donor age, recipient male sex, recipient creatinine, recipient history of prior cardiac or lung surgery, recipient extracorporeal membrane oxygenation support, transplant year, and transplant center volume were associated with 1-year post-HLTx death or retransplant. On multivariable analysis, advanced donor age (hazard ratio [HR], 1.017; P=0.0007), recipient male sex (HR, 1.701; P=0.0002), recipient extracorporeal membrane oxygenation support (HR, 4.854; P<0.0001), transplant year (HR, 0.962; P<0.0001), and transplantation at low-volume (HR, 1.694) and medium-volume centers (HR, 1.455) in comparison with high-volume centers (P=0.0007) remained as significant predictors of death or retransplant. These predictors were incorporated into an equation capable of estimating the preliminary probability of graft survival at 1-year post-HLTx on the basis of preoperative factors alone.HLTx outcomes may be improved by considering the strong influence of donor age, recipient sex, recipient hemodynamic status, and transplant center volume. Marginal donors and recipients without significant factors contributing to poor post-HLTx outcomes may still be considered for transplantation, potentially with less impact on the risk of early postoperative death or retransplant.
View details for DOI 10.1161/CIRCULATIONAHA.119.040682
View details for PubMedID 31589491
BACKGROUND: Studies assessing the safety and effectiveness of Del Nido cardioplegia for adult cardiac surgery remain limited. We investigated early outcomes after coronary artery bypass grafting (CABG) using single-dose Del Nido cardioplegia vs. conventional multi-dose blood cardioplegia. Methods?and?Results: The 81 consecutive patients underwent isolated CABG performed by a single surgeon. The initial 27 patients received anterograde blood cardioplegia, while the subsequent 54 patients received anterograde Del Nido cardioplegia. There were no differences in the baseline characteristics of each group nor any differences in the 30-day incidences of myocardial infarction, all-cause death, and readmission following surgery. The use of Del Nido cardioplegia was associated with shorter cardiopulmonary bypass time (98 vs. 115 min, P=0.011), shorter cross-clamp time (74 vs. 87 min, P=0.006), and decreased need for intraoperative defibrillation (13.0% vs. 33.3%, P=0.030) compared with blood cardioplegia. To control for the difference in cross-clamp time, we performed propensity score matching with a logistical treatment model and confirmed that Del Nido cardioplegia provided similar outcomes as blood cardioplegia and also reduced the need for defibrillation independent of cross-clamp time.CONCLUSIONS: Compared with conventional blood cardioplegia, Del Nido cardioplegia provided excellent myocardial protection with reduced need for intraoperative defibrillation, shorter bypass and cross-clamp times, and comparable early clinical outcomes for adult patients undergoing CABG.
View details for PubMedID 30531128
View details for PubMedID 29317089
View details for PubMedID 29576264
Whether a second arterial conduit improves outcomes after multivessel coronary artery bypass grafting remains unclear. Consequently, arterial conduits other than the left internal thoracic artery are seldom used in the United States.Using a state-maintained clinical registry including all 126 nonfederal hospitals in California, we compared all-cause mortality and rates of stroke, myocardial infarction, repeat revascularization, and sternal wound infection between propensity score-matched cohorts who underwent primary, isolated multivessel coronary artery bypass grafting with the left internal thoracic artery, and who received a second arterial conduit (right internal thoracic artery or radial artery, n=5866) or a venous conduit (n=53?566) between 2006 and 2011. Propensity score matching using 34 preoperative characteristics yielded 5813 matched sets. A subgroup analysis compared outcomes between propensity score-matched recipients of a right internal thoracic artery (n=1576) or a radial artery (n=4290).Second arterial conduit use decreased from 10.7% in 2006 to 9.1% in 2011 (P<0.0001). However, receipt of a second arterial conduit was associated with significantly lower mortality (13.1% versus 10.6% at 7 years; hazard ratio, 0.79; 95% confidence interval [CI], 0.72-0.87), and lower risks of myocardial infarction (hazard ratio, 0.78; 95% CI, 0.70-0.87) and repeat revascularization (hazard ratio, 0.82; 95% CI, 0.76-0.88). In comparison with radial artery grafts, right internal thoracic artery grafts were associated with similar mortality rates (right internal thoracic artery 10.3% versus radial artery 10.7% at 7 years; hazard ratio, 1.10; 95% CI, 0.89-1.37) and individual risks of cardiovascular events, but the risk of sternal wound infection was increased (risk difference, 1.07%; 95% CI, 0.15-2.07).Second arterial conduit use in California is low and declining, but arterial grafts were associated with significantly lower mortality and fewer cardiovascular events. A right internal thoracic artery graft offered no benefit over that of a radial artery, but did increase risk of sternal wound infection. These findings suggest surgeons should consider lowering their threshold for using arterial grafts, and the radial artery may be the preferred second conduit.
View details for PubMedID 29242351
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
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
High-sensitivity C-reactive protein (hs-CRP) is independently associated with cardiovascular events in coronary artery disease (CAD) patients and reducing the hs-CRP level may further benefit this population. We conduct this parallel design, randomized-controlled trial to assess the effectiveness of adjunct sodium tanshinone IIA sulfate (STS) therapy on circulating inflammation markers in CAD patients. Unstable angina or non-ST-elevation myocardial infarction patients with increased hs-CRP level were randomly assigned to atorvastatin-based standard medical therapy or standard therapy plus STS injection (80?mg, once daily for 14 consecutive days). The primary outcome was hs-CRP level. After the 14-day treatment, the experimental group (n?=?35) exhibited significantly lower levels of hs-CRP than the control group (n?=?35) (1.72 vs 3.20?mg/L, p?=?0.0191). Lower levels of interleukin-6, monocyte chemotactic protein-1 (MCP-1), and soluble CD40 ligand were also observed in the experimental group. Angina symptoms were also better controlled in the experimental group. At 30 days after treatment completion, MCP-1 levels remained lower in the experimental group than in the control group (313.88 vs 337.91?pg/mL, p?=?0.0078). No serious adverse events occurred. Our study demonstrates that on the basis of standard medical therapy, STS further reduce elevated hs-CRP and other circulating inflammation markers in CAD patients. (Chictr.org number: ChiCTR-TRC-12002361).
View details for PubMedID 29234038
Prolonged allograft ischaemic time in heart transplantation adversely impacts the performance of the donor heart in the immediate postoperative period and ultimately results in decreased post-transplant survival. Therefore, optimal surgical technique for heart transplantation should aim to minimize allograft ischaemic time. Here, we report a case of successful orthotopic heart transplantation using a modified technique to reduce allograft ischaemic time and warm ischaemic time.
View details for PubMedID 29186382
Pediatric cardiac surgery, especially for small neonates, typically requires blood products to counter hemodilution during cardiopulmonary bypass. Children with congenital heart defects whose families adhere to faith-based proscriptions against blood transfusion therefore represent a challenging surgical population. Here, we report the case of a ten-day-old, 3.6-kg patient of Jehovah's Witness faith, who was diagnosed with unilateral pulmonary artery discontinuity, bilateral patent ductus arteriosus, and an otherwise structurally normal heart. Pulmonary artery reimplantation was successfully performed without giving blood products. This case adds to previous reports of successful bloodless cardiac surgery in neonates and describes the specific strategies that contributed to successful pulmonary artery reimplantation.
View details for DOI 10.1177/2150135115582071
View details for PubMedID 26715005
Delayed gastric emptying is a significant postoperative complication of living donor hepatectomy for liver transplantation and may require endoscopic or surgical intervention in severe cases. Although the mechanism of posthepatectomy delayed gastric emptying remains unknown, vagal nerve injury during intraoperative dissection and adhesion formation postoperatively between the stomach and cut liver surface are possible explanations. Here, we present the first reported case of delayed gastric emptying following fully laparoscopic hepatectomy for living donor liver transplantation. Additionally, we also present a case in which symptoms developed after open right hepatectomy, but for which dissection for left hepatectomy was first performed. Through our experience and these two specific cases, we favor a neurovascular etiology for delayed gastric emptying after hepatectomy.
View details for DOI 10.1155/2014/582183
View details for PubMedID 25610698
View details for PubMedCentralID PMC4291134
Background. Coronary heart disease (CHD) due to atherosclerotic inflammation remains a significant threat to global health despite the success of the lipid-lowering, anti-inflammatory statins. Tanshinone IIA, a potent anti-inflammatory compound derived from Traditional Chinese Medicine (TCM), may be able to supplement statins by further reducing levels of circulating inflammatory markers correlated to cardiovascular risk. Here, we present the protocol of a randomized controlled trial (RCT) that will investigate the synergistic effect of sodium tanshinone IIA sulfate and simvastatin on reducing elevated inflammatory markers in patients with CHD.Seventy-two inpatients with confirmed CHD, elevated serum high-sensitivity C-reactive protein (Hs-CRP) level, and a TCM diagnosis of blood stasis syndrome will be enrolled and randomized 1?:?1 into the control or experimental group. Intervention. All subjects will receive a standard Western therapy including 20?mg simvastatin orally once per evening. Patients in the experimental group will additionally receive a daily 80?mg dose of sodium tanshinone IIA sulfate intravenously, diluted into 250?mL 0.9% NaCl solution. The treatment period will be 14 days. Outcomes. Primary outcome parameter: serum Hs-CRP level. Secondary outcome parameters: other circulating inflammatory markers (including IL-6, TNF ? , VCAM-1, CD40, sCD40L, MCP-1, and MMP-9), improvement in symptoms of angina and blood stasis syndrome, and safety. This trial is registered with ChiCTR-TRC-12002361.
View details for DOI 10.1155/2013/756519
View details for Web of Science ID 000323265300001
View details for PubMedID 23983803
View details for PubMedCentralID PMC3747599