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OBJECTIVE: Minimally invasive mitral valve surgery (mini-MVS) is typically reserved for patients who have not undergone open cardiac surgery. In the reoperative setting, using intrapericardial dissection for crossclamping the aorta through a minimally invasive approach can be difficult and, at times, risky. Cold fibrillatory cardiac arrest (CFCA) with systemic cardiopulmonary bypass without cross-clamping is a well-described technique; however, data about its safety for patients who undergo reoperative mini-MVS are limited. METHODS: Data for 34 patients who underwent reoperative mini-MVS with CFCA from March 2017 to March 2022 were reviewed retrospectively. A mini right thoracotomy (n = 30) or robotic (n = 4) approach was used. Systemic hypothermia was induced to a target temperature of 25 °C. RESULTS: Patient mean (SD) age was 64.5 (9.6) years, and 15 of 34 (44.1%) patients were women. Of those 34 patients, 23 (67.6%) had severe regurgitation, and 11 (32.4%) had severe stenosis. Before mini-MVS, 28 patients had undergone valve surgery, and 8 had undergone coronary artery bypass graft surgery. The mitral valve was repaired in 5 of 34 (14.7%) and replaced in 29 of 34 (85.3%) patients. No difference was observed in preoperative and postoperative left ventricular function (P = .82). In 1 patient, kidney failure developed that necessitated dialysis. No postoperative stroke or mortality at 30 days occurred. CONCLUSION: Mini-MVS with CFCA is well tolerated in patients with prior cardiac surgery. Myocardial function was not impaired, nor was the risk of stroke increased in this cohort, indicating that CFCA is a safe alternative in this high-risk population.
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Procedimientos Quirúrgicos Mínimamente Invasivos , Válvula Mitral , Humanos , Femenino , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Válvula Mitral/cirugía , Válvula Mitral/fisiopatología , Válvula Mitral/diagnóstico por imagen , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Resultado del Tratamiento , Procedimientos Quirúrgicos Cardíacos/métodos , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Anciano , Insuficiencia de la Válvula Mitral/cirugía , Insuficiencia de la Válvula Mitral/fisiopatología , Insuficiencia de la Válvula Mitral/diagnóstico , Implantación de Prótesis de Válvulas Cardíacas/métodos , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Paro Cardíaco Inducido/métodos , Reoperación , Hipotermia Inducida/métodos , Estudios de SeguimientoRESUMEN
Purpose: The number of ischemic heart failure (HF) patients is growing dramatically worldwide. However, there are at present no preventive treatments for HF. Our previous study showed that Gata4 overexpression improved cardiac function after myocardial infarction in the rat heart. We also found that Gata4 overexpression significantly increased a Pnoc gene expression, an endogenous ligand for cell membrane receptor, ORL1. We hypothesized that an activation of ORL1 receptor would suppress HF in a rat ischemic heart model. Method: Adult Sprague Dawley rats (8 weeks old, 6 males and 6 females) underwent left anterior descending coronary artery ligation. Three weeks later, normal saline or MCOPPB (ORL1 activator, 2.5mg/kg/day) intraperitoneal injection was started, and continued 5 days a week, for 3 months. Echocardiography was performed six times, pre-operative, 3 days after coronary artery ligation, pre-MCOPPB or saline injection, and 1, 2, and 3 months after saline or MCOPPB injection started. Animals were euthanized after 3 months follow up and the heart was harvested for histological analysis. Results: ORL1 activator, MCOPPB, significantly improved cardiac function after myocardial infarction in rat (Ejection fraction, MCOPPB vs saline at euthanasia, 67 ± 3 vs 43 ± 2, p < 0.001). MCOPPB also decreased fibrosis and induced angiogenesis. Conclusion: ORL1 activator, MCOPPB, may be a novel treatment for preventing HF progression.
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BACKGROUND: We determined the safety of early discharge after coronary artery bypass grafting (CABG) in patients with uncomplicated postoperative courses and compared outcomes with routine discharge in a national cohort. We identified preoperative factors associated with readmission after early discharge after CABG. METHODS: The Nationwide Readmissions Database was queried to identify patients undergoing CABG from January 2016 to December 2018. Patients were stratified based on length of stay (LOS) as early (≤4 days) vs routine (5-10 days) discharge. Patients were excluded with hospital courses indicative of complicated stays (emergent procedures, LOS >10 days, discharge to extended care facility or with home health, index hospitalization mortality). Propensity score matching was performed to compare outcomes between cohorts. Multivariable logistic regression models were used to identify factors associated with readmission after early discharge. RESULTS: During the study period, 91,861 patients underwent CABG with an uncomplicated postoperative course (â¼20% of CABG population). Of these, 31% (28,790 of 91,861) were discharged early, and 69% (63,071 of 91,861) were routinely discharged. After propensity score matching, patients discharged early had lower readmission rates at 30 days, 90 days, and up to 1 year (P < .001 for all). The index hospitalization cost was lower with early discharge ($26,676 vs $32,859; P < .001). Early discharge was associated with a lower incidence of nosocomial infection at the index hospitalization (0.17% vs 0.81%, P < .001) and readmission from infection (14.5% vs 18%, P = .016). CONCLUSIONS: Early discharge after uncomplicated CABG can be considered in a highly selective patient population. Early-discharge patients are readmitted less frequently than matched routine-discharge patients, with a lower incidence of readmission from infection. Appropriate postdischarge processes to facilitate early discharge after CABG should be further pursued.
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Puente de Arteria Coronaria , Tiempo de Internación , Alta del Paciente , Readmisión del Paciente , Humanos , Puente de Arteria Coronaria/efectos adversos , Puente de Arteria Coronaria/métodos , Masculino , Readmisión del Paciente/estadística & datos numéricos , Femenino , Alta del Paciente/estadística & datos numéricos , Anciano , Persona de Mediana Edad , Estados Unidos/epidemiología , Tiempo de Internación/estadística & datos numéricos , Estudios Retrospectivos , Complicaciones Posoperatorias/epidemiología , Factores de Tiempo , Puntaje de Propensión , Enfermedad de la Arteria Coronaria/cirugíaRESUMEN
BACKGROUND: XC001 is a novel adenoviral-5 vector designed to express multiple isoforms of VEGF (vascular endothelial growth factor) and more safely and potently induce angiogenesis. The EXACT trial (Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment) assessed the safety and preliminary efficacy of XC001 in patients with no option refractory angina. METHODS: In this single-arm, multicenter, open-label trial, 32 patients with no option refractory angina received a single treatment of XC001 (1×1011 viral particles) via transepicardial delivery. RESULTS: There were no severe adverse events attributed to the study drug. Twenty expected severe adverse events in 13 patients were related to the surgical procedure. Total exercise duration increased from a mean±SD of 359.9±105.55 seconds at baseline to 448.2±168.45 (3 months), 449.2±175.9 (6 months), and 477.6±174.7 (12 months; +88.3 [95% CI, 37.1-139.5], +84.5 [95% CI, 34.1-134.9], and +115.5 [95% CI, 59.1-171.9]). Total myocardial perfusion deficit on positron emission tomography imaging decreased by 10.2% (95% CI, -3.1% to 23.5%), 14.3% (95% CI, 2.8%-25.7%), and 10.2% (95% CI, -0.8% to -21.2%). Angina frequency decreased from a mean±SD 12.2±12.5 episodes to 5.2±7.2 (3 months), 5.1±7.8 (6 months), and 2.7±4.8 (12 months), with an average decrease of 7.7 (95% CI, 4.1-11.3), 6.6 (95% CI, 3.5-9.7), and 8.8 (4.6-13.0) episodes at 3, 6, and 12 months. Angina class improved in 81% of participants at 6 months. CONCLUSIONS: XC001 administered via transepicardial delivery is safe and generally well tolerated. Exploratory improvements in total exercise duration, ischemic burden, and subjective measures support a biologic effect sustained to 12 months, warranting further investigation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04125732.
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Angina de Pecho , Terapia Genética , Vectores Genéticos , Neovascularización Fisiológica , Factor A de Crecimiento Endotelial Vascular , Humanos , Masculino , Femenino , Persona de Mediana Edad , Angina de Pecho/terapia , Angina de Pecho/fisiopatología , Terapia Genética/efectos adversos , Anciano , Resultado del Tratamiento , Factor A de Crecimiento Endotelial Vascular/genética , Factores de Tiempo , Tolerancia al Ejercicio , Adenoviridae/genética , Recuperación de la FunciónRESUMEN
Academic global surgery consists of collaborative partnerships that address surgical inequities through research, training, education, advocacy, and diplomacy. It has been characterized by increased scholastic production through global surgery publications, dedicated global surgery sessions within scientific conferences, global surgery-specific research grants, database development to support global surgery research, global surgery research fellowships, and global surgery-based academic promotion paradigms. The increased emphasis on global surgery research has been accompanied by multiple ethical challenges. This article reviews critical ethical dilemmas presented by global surgery research efforts and proposes interventions on the partnership, infrastructural, and policy levels to enhance fidelity within research partnerships.
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Competencia Clínica , Empoderamiento , Cirujanos , Humanos , Cirujanos/psicología , Cirugía General/educaciónRESUMEN
Objective: In patients who underwent mitral valve replacement for infectious endocarditis, we evaluated the association of prosthesis choice with readmission rates and causes (the primary outcomes), as well as with in-hospital mortality, cost, and length of stay (the secondary outcomes). Methods: Patients with infectious endocarditis who underwent isolated mitral valve replacement from January 2016 to December 2018 were identified in the United States Nationwide Readmissions Database and stratified by valve type. Propensity score matching was used to compare adjusted outcomes. Results: A weighted total of 4206 patients with infectious endocarditis underwent bioprosthetic mitral valve replacement (n = 3132) and mechanical mitral valve replacement (n = 1074) during the study period. Patients in the bioprosthetic mitral valve replacement group were older than those in the mechanical mitral valve replacement group (median 57 vs 46 y, P < .001). After propensity matching, the bioprosthetic mitral valve replacement group (n = 1068) had similar in-hospital mortality, length of stay, and costs compared with the mechanical mitral valve replacement group (n = 1056). Overall, 90-day readmission rates were high (28.9%) and comparable for bioprosthetic mitral valve replacement (30.5%) and mechanical mitral valve replacement (27.5%, P = .4). Likewise, there was no difference in readmissions over a calendar year by prosthesis type. Readmissions for infection and bleeding were common for both bioprosthetic mitral valve replacement and mechanical mitral valve replacement groups. Conclusions: Outcomes and readmission rates were similar for mechanical mitral valve replacement and bioprosthetic mitral valve replacement in infectious endocarditis, suggesting that valve choice should not be determined by endocarditis status. Additionally, strategies to mitigate readmission for infection and bleeding are needed for both groups.
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This study investigated cardiac stress and mitochondrial oxidative phosphorylation (OxPhos) in human donation after circulatory death (DCD) hearts regarding warm ischemic time (WIT) and subsequent cold storage and compared them with that of human brain death donor (DBD) hearts. A total of 24 human hearts were procured for the research study-6 in the DBD group and 18 in the DCD group. DCD group was divided into three groups (n = 6) based on different WITs (20, 40, and 60 min). All hearts received del Nido cardioplegia before being placed in normal saline cold storage for 6 h. Left ventricular biopsies were performed at hours 0, 2, 4, and 6. Cardiac stress [nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits: 47-kDa protein of phagocyte oxidase (p47phox), 91-kDa glycoprotein of phagocyte oxidase (gp91phox)] and mitochondrial oxidative phosphorylation [OxPhos, complex I (NADH dehydrogenase) subunit of ETC (CI)-complex V (ATP synthase) subunit of ETC (CV)] proteins were measured in cardiac tissue and mitochondria respectively. Modulation of cardiac stress and mitochondrial dysfunction were observed in both DCD and DBD hearts. However, DCD hearts suffered more cardiac stress (overexpressed NADPH oxidase subunits) and diminished mitochondrial OxPhos than DBD hearts. The severity of cardiac stress and impaired oxidative phosphorylation in DCD hearts correlated with the longer WIT and subsequent cold storage time. More drastic changes were evident in DCD hearts with a WIT of 60 min or more. Activation of NADPH oxidase via overproduction of p47phox and gp91phox proteins in cardiac tissue may be responsible for cardiac stress leading to diminished mitochondrial oxidative phosphorylation. These protein changes can be used as biomarkers for myocardium damage and might help assess DCD and DBD heart transplant suitability.NEW & NOTEWORTHY First human DCD heart research studied cardiac stress and mitochondrial dysfunction concerning WIT and the efficacy of del Nido cardioplegia as an organ procurement solution and subsequent cold storage. Mild to moderate cardiac stress and mitochondrial dysfunction were noticed in DCD hearts with WIT 20 and 40 min and cold storage for 4 and 2 h, respectively. These changes can serve as biomarkers, allowing interventions to preserve mitochondria and extend WIT in DCD hearts.
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Trasplante de Corazón , Enfermedades Mitocondriales , Humanos , Muerte Encefálica , Fosforilación Oxidativa , Donantes de Tejidos , NADPH Oxidasas , Biomarcadores , Oxidorreductasas , Muerte , Estudios RetrospectivosRESUMEN
BACKGROUND: Single-dose del Nido solution was recently used in human donation after circulatory death (DCD) heart procurement. We compared the effect of del Nido cardioplegia on myocardial edema, inflammatory response, and injury in human DCD hearts and human donation after brain death (DBD) hearts with different warm ischemic times (WIT) and subsequent cold saline storage times (CST). METHODS: A total of 24 human hearts, including 6 in the DBD group and 18 in the DCD group-were procured for the research study. The DCD group was divided into 3 subgroups based on WIT: 20, 40, and ≥60 minutes. All hearts received 1 L of del Nido cardioplegia before being placed in cold saline for 6 hours. Left ventricular biopsies were performed at 0, 2, 4, and 6 hours. Temporal changes in myocardial edema, inflammatory cytokines (TNF-α, IL-6, and IL-1ß), and histopathology injury scores were compared between the DBD and DCD groups. RESULTS: DCD hearts showed more profound changes in myocardial edema, inflammation, and injury than DBD hearts at baseline and subsequent CST. The DCD heart with WIT of 20 and 40 minutes with CST of 4 and 2 hours, respectively, appeared to have limited myocardial edema, inflammation, and injury. DCD hearts with WIT ≥60 minutes showed severe myocardial edema, inflammation, and injury at baseline and subsequent CST. CONCLUSIONS: Single-dose cold del Nido cardioplegia and subsequent cold normal saline storage can preserve both DCD and DBD hearts. DCD hearts have been shown to be able to tolerate a WIT of 20 minutes and subsequent CST of 4 hours without experiencing significant myocardial edema, inflammation, and injury.
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Trasplante de Corazón , Isquemia Tibia , Humanos , Trasplante de Corazón/efectos adversos , Corazón/fisiología , Edema/etiología , Inflamación , Donantes de TejidosRESUMEN
BACKGROUND: Technical skill is essential for good outcomes in cardiac surgery. However, no objective methods exist to measure dexterity while performing surgery. The purpose of this study was to validate sensor-based hand motion analysis (HMA) of technical dexterity while performing a graft anastomosis within a validated simulator. METHODS: Surgeons at various training levels performed an anastomosis while wearing flexible sensors (BioStamp nPoint, MC10 Inc) with integrated accelerometers and gyroscopes on each hand to quantify HMA kinematics. Groups were stratified as experts (n = 8) or novices (n = 18). The quality of the completed anastomosis was scored using the 10 Point Microsurgical Anastomosis Rating Scale (MARS10). HMA parameters were compared between groups and correlated with quality. Logistic regression was used to develop a predictive model from HMA parameters to distinguish experts from novices. RESULTS: Experts were faster (11 ± 6 minutes vs 21 ± 9 minutes; P = .012) and used fewer movements in both dominant (340 ± 166 moves vs 699 ± 284 moves; P = .003) and nondominant (359 ± 188 moves vs 567 ± 201 moves; P = .02) hands compared with novices. Experts' anastomoses were of higher quality compared with novices (9.0 ± 1.2 MARS10 vs 4.9 ± 3.2 MARS10; P = .002). Higher anastomosis quality correlated with 9 of 10 HMA parameters, including fewer and shorter movements of both hands (dominant, r = -0.65, r = -0.46; nondominant, r = -0.58, r = -0.39, respectively). CONCLUSIONS: Sensor-based HMA can distinguish technical dexterity differences between experts and novices, and correlates with quality. Objective quantification of hand dexterity may be a valuable adjunct to training and education in cardiac surgery training programs.
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Procedimientos Quirúrgicos Cardíacos , Cirujanos , Humanos , Mano , Anastomosis Quirúrgica , Movimiento (Física) , Competencia ClínicaRESUMEN
BACKGROUND: New therapies are needed for patients with refractory angina. Encoberminogene rezmadenovec (XC001), a novel adenoviral-5 vector coding for all 3 major isoforms of VEGF (vascular endothelial growth factor), demonstrated enhanced local angiogenesis in preclinical models; however, the maximal tolerated dose and safety of direct epicardial administration remain unknown. METHODS: In the phase 1 portion of this multicenter, open-label, single-arm, dose-escalation study, patients with refractory angina received increasing doses of encoberminogene rezmadenovec (1×109, 1×1010, 4×1010, and 1×1011 viral particles) to evaluate its safety, tolerability, and preliminary efficacy. Patients had class II to IV angina on maximally tolerated medical therapy, demonstrable ischemia on stress testing, and were angina-limited on exercise treadmill testing. Patients underwent minithoracotomy with epicardial delivery of 15 0.1-mL injections of encoberminogene rezmadenovec. The primary outcome was safety via adverse event monitoring over 6 months. Efficacy assessments included difference from baseline to months 3, 6 (primary), and 12 in total exercise duration, myocardial perfusion deficit using positron emission tomography, angina class, angina frequency, and quality of life. RESULTS: From June 2, 2020 to June 25, 2021, 12 patients were enrolled into 4 dosing cohorts with 1×1011 viral particle as the highest planned dose. Seventeen serious adverse events were reported in 7 patients; none were related to study drug. Six serious adverse events in 4 patients were related to the thoracotomy, 3 non-serious adverse events were possibly related to study drug. The 2 lowest doses did not demonstrate improvements in total exercise duration, myocardial perfusion deficit, or angina frequency; however, there appeared to be improvements in all parameters with the 2 higher doses. CONCLUSIONS: Epicardial delivery of encoberminogene rezmadenovec via minithoracotomy is feasible, and up to 1×1011 viral particle appears well tolerated. A dose response was observed across 4 dosing cohorts in total exercise duration, myocardial perfusion deficit, and angina class. The highest dose (1×1011 viral particle) was carried forward into phase 2. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04125732.
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Calidad de Vida , Factor A de Crecimiento Endotelial Vascular , Humanos , Resultado del Tratamiento , Angina de Pecho/terapia , Prueba de EsfuerzoRESUMEN
Objectives: Safety-net hospitals (SNHs) provide essential services to predominantly underserved patients regardless of their ability to pay. We hypothesized that patients who underwent coronary artery bypass grafting (CABG) would have inferior observed outcomes at SNHs compared with non-SNHs but that matched cohorts would have comparable outcomes. Methods: We queried the Nationwide Readmissions Database for patients who underwent isolated CABG from 2016 to 2018. We ranked hospitals by the percentage of all admissions in which the patient was uninsured or insured with Medicaid; hospitals in the top quartile were designated as SNHs. We used propensity-score matching to mitigate the effect of confounding factors and compare outcomes between SNHs and non-SNHs. Results: A total of 525,179 patients underwent CABG, including 96,133 (18.3%) at SNHs, who had a greater burden of baseline comorbidities (median Elixhauser score 8 vs 7; P = .04) and more frequently required urgent surgery (57.1% vs 52.8%; P < .001). Observed in-hospital mortality (2.1% vs 1.8%; P = .004) and major morbidity, length of stay (9 vs 8 days; P < .001), cost ($46,999 vs $38,417; P < .001), and readmission rate at 30 (12.4% vs 11.3%) and 90 days (19.0% vs 17.7%) were greater at SNHs (both P < .001). After matching, none of these differences persisted except length of stay (9 vs 8 days) and cost ($46,977 vs $39,343) (both P < .001). Conclusions: After matching, early outcomes after CABG were comparable at SNHs and non-SNHs. Improved discharge resources could reduce length of stay and curtail cost, improving the value of CABG at SNHs.
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INTRODUCTION: NIH funding to departments of surgery reported as benchmark Blue Ridge Institute for Medical Research (BRIMR) rankings are unclear. METHODS: We analyzed inflation-adjusted BRIMR-reported NIH funding to departments of surgery and medicine between 2011 and 2021. RESULTS: NIH funding to departments of surgery and medicine both increased 40% from 2011 to 2021 ($325 million to $454 million; $3.8 billion to $5.3 billion, P < 0.001 for both). The number of BRIMR-ranked departments of surgery decreased 14% during this period while departments of medicine increased 5% (88 to 76 versus 111 to 116; P < 0.001). There was a greater increase in the total number of medicine PIs versus surgery PIs during this period (4377 to 5224 versus 557 to 649; P < 0.001). These trends translated to further concentration of NIH-funded PIs in medicine versus surgery departments (45 PIs/program versus 8.5 PIs/program; P < 0.001). NIH funding and PIs/program in 2021 were respectively 32 and 20 times greater for the top versus lowest 15 BRIMR-ranked surgery departments ($244 million versus $7.5 million [P < 0.01]; 20.5 versus 1.3 [P < 0.001]). Twelve (80%) of the top 15 surgery departments maintained this ranking over the 10-year study period. CONCLUSIONS: Although NIH funding to departments of surgery and medicine is growing at a similar rate, departments of medicine and top-funded surgery departments have greater funding and concentration of PIs/program versus surgery departments overall and lowest-funded surgery departments. Strategies used by top-performing departments to obtain and maintain funding may assist less well-funded departments in obtaining extramural research funding, thus broadening the access of surgeon-scientists to perform NIH-supported research.
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Investigación Biomédica , Medicina , Cirujanos , Humanos , Facultades de Medicina , Departamentos de HospitalesRESUMEN
INTRODUCTION: Prosthesis choice during aortic valve replacement (AVR) weighs lifelong anticoagulation with mechanical valves (M-AVR) against structural valve degeneration in bioprosthetic valves (B-AVR). METHODS: The Nationwide Readmissions Database was queried to identify patients who underwent isolated surgical AVR between January 1, 2016 and December 31, 2018, stratifying by prothesis type. Propensity score matching was used to compare risk-adjusted outcomes. Readmission at 1 y was estimated with Kaplan-Meier (KM) analysis. RESULTS: Patients (n = 109,744) who underwent AVR (90,574 B-AVR and 19,170 M-AVR) were included. B-AVR patients were older (median 68 versus 57 y; P < 0.001) and had more comorbidities (mean Elixhauser score: 11.8 versus 10.7; P < 0.001) compared to M-AVR patients. After matching (n = 36,951), there was no difference in age (58 versus 57 y; P = 0.6) and Elixhauser score (11.0 versus 10.8; P = 0.3). B-AVR patients had similar in-hospital mortality (2.3% versus 2.3%; P = 0.9) and cost (mean: $50,958 versus $51,200; P = 0.4) compared with M-AVR patients. However, B-AVR patients had shorter length of stay (8.3 versus 8.7 d; P < 0.001) and fewer readmissions at 30 d (10.3% versus 12.6%; P < 0.001) and 90 d (14.8% versus 17.8%; P < 0.001), and 1 y (P < 0.001, KM analysis). Patients undergoing B-AVR were less likely to be readmitted for bleeding or coagulopathy (5.7% versus 9.9%; P < 0.001) and effusions (9.1% versus 11.9%; P < 0.001). CONCLUSIONS: B-AVR patients had similar early outcomes compared to M-AVR patients, but lower rates of readmission. Bleeding, coagulopathy, and effusions are drivers of excess readmissions in M-AVR patients. Readmission reduction strategies targeting bleeding and improved anticoagulation management are warranted in the first year following AVR.
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Bioprótesis , Implantación de Prótesis de Válvulas Cardíacas , Humanos , Válvula Aórtica/cirugía , Readmisión del Paciente , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Resultado del Tratamiento , Anticoagulantes/uso terapéutico , Estudios Retrospectivos , Diseño de PrótesisRESUMEN
Cardiovascular disease is one of the leading causes of morbidity and mortality worldwide, with myocardial infarctions being amongst the deadliest manifestations. Reduced blood flow to the heart can result in the death of cardiac tissue, leaving affected patients susceptible to further complications and recurrent disease. Further, contemporary management typically involves a pharmacopeia to manage the metabolic conditions contributing to atherosclerotic and hypertensive heart disease, rather than regeneration of the damaged myocardium. With modern healthcare extending lifespan, a larger demographic will be at risk for heart disease, driving the need for novel therapeutics that surpass those currently available in efficacy. Transdifferentiation and cellular reprogramming have been looked to as potential methods for the treatment of diseases throughout the body. Specifically targeting the fibrotic cells in cardiac scar tissue as a source to be reprogrammed into induced cardiomyocytes remains an appealing option. This review aims to highlight the history of and advances in cardiac reprogramming and describe its translational potential as a treatment for cardiovascular disease.
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Cardiopatías , Infarto del Miocardio , Humanos , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Reprogramación Celular/genética , Cardiopatías/metabolismo , Infarto del Miocardio/metabolismo , TecnologíaRESUMEN
INTRODUCTION: Thrombosis is frequently manifested in critically ill patients with systemic inflammation, including sepsis and COVID-19. The coagulopathy in systemic inflammation is often associated with increased levels of fibrinogen and D-dimer. Because elevated levels of vimentin have been detected in sepsis, we sought to investigate the relationship between vimentin and the increased fibrin formation potential observed in these patients. MATERIALS AND METHODS: This hypothesis was examined by using recombinant human vimentin, anti-vimentin antibodies, plasma derived from healthy and critically ill patients, confocal microscopy, co-immunoprecipitation assays, and size exclusion chromatography. RESULTS: The level of vimentin in plasma derived from critically ill subjects with systemic inflammation was on average two-fold higher than that of healthy volunteers. We determined that vimentin directly interacts with fibrinogen and enhances fibrin formation. Anti-vimentin antibody effectively blocked fibrin formation ex vivo and caused changes in the fibrin structure in plasma. Additionally, confocal imaging demonstrated plasma vimentin enmeshed in the fibrin fibrils. Size exclusion chromatography column and co-immunoprecipitation assays demonstrated a direct interaction between extracellular vimentin and fibrinogen in plasma from critically ill patients but not in healthy plasma. CONCLUSIONS: The results describe that extracellular vimentin engages fibrinogen in fibrin formation. In addition, the data suggest that elevated levels of an apparent aberrant extracellular vimentin potentiate fibrin clot formation in critically ill patients with systemic inflammation; consistent with the notion that plasma vimentin contributes to the pathogenesis of thrombosis.