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Lancet Respir Med. 2022 Oct 11:S2213-2600(22)00353-8. doi: 10.1016/S2213-2600(22)00353-8. Online ahead of print.

ABSTRACT

BACKGROUND: In patients receiving venovenous (VV) extracorporeal membrane oxygenation (ECMO) packed red blood cell (PRBC) transfusion thresholds are usually higher than in other patients who are critically ill. Available guidelines suggest a restrictive approach, but do not provide specific recommendations on the topic. The main aim of this study was, in a short timeframe, to describe the actual values of haemoglobin and the rate and the thresholds for transfusion of PRBC during VV ECMO.

METHODS: PROTECMO was a multicentre, prospective, cohort study done in 41 ECMO centres in Europe, North America, Asia, and Australia. Consecutive adult patients with acute respiratory distress syndrome (ARDS) who were receiving VV ECMO were eligible for inclusion. Patients younger than 18 years, those who were not able to provide informed consent when required, and patients with an ECMO stay of less than 24 h were excluded. Our main aim was to monitor the daily haemoglobin concentration and the value at the point of PRBC transfusion, as well as the rate of transfusions. The practice in different centres was stratified by continent location and case volume per year. Adjusted estimates were calculated using marginal structural models with inverse probability weighting, accounting for baseline and time varying confounding.

FINDINGS: Between Dec 1, 2018, and Feb 22, 2021, 604 patients were enrolled (431 [71%] men, 173 [29%] women; mean age 50 years [SD 13·6]; and mean haemoglobin concentration at cannulation 10·9 g/dL [2·4]). Over 7944 ECMO days, mean haemoglobin concentration was 9·1 g/dL (1·2), with lower concentrations in North America and high-volume centres. PRBC were transfused on 2432 (31%) of days on ECMO, and 504 (83%) patients received at least one PRBC unit. Overall, mean pretransfusion haemoglobin concentration was 8·1 g/dL (1·1), but varied according to the clinical rationale for transfusion. In a time-dependent Cox model, haemoglobin concentration of less than 7 g/dL was consistently associated with higher risk of death in the intensive care unit compared with other higher haemoglobin concentrations (hazard ratio [HR] 2·99 [95% CI 1·95-4·60]); PRBC transfusion was associated with lower risk of death only when transfused when haemoglobin concentration was less than 7 g/dL (HR 0·15 [0·03-0·74]), although no significant effect in reducing mortality was reported for transfusions for other haemoglobin classes (7·0-7·9 g/dL, 8·0-9·9 g/dL, or higher than 10 g/dL).

INTERPRETATION: During VV ECMO, there was no universally accepted threshold for transfusion, but PRBC transfusion was invariably associated with lower mortality only when done with haemoglobin concentration of less than 7 g/dL.

FUNDING: Extracorporeal Life Support Organization.

PMID:36240836 | DOI:10.1016/S2213-2600(22)00353-8

Pediatr Int. 2022 Jan;64(1):e15270. doi: 10.1111/ped.15270.

ABSTRACT

BACKGROUND: We aimed to compare the frequency of acute kidney injury (AKI) and its effects on mortality and morbidity with different classification systems in pediatric patients who had surgery under cardiopulmonary bypass for congenital heart disease.

METHODS: This study included children younger than 18 years old who were followed up in the pediatric cardiac intensive care unit between September 1 and December 1, 2020, after congenital heart surgery with cardiopulmonary bypass. Each case was categorized postoperatively in terms of AKI using Pediatric-Modified Risk, Injury, Failure, Loss, and End-Stage (pRIFLE), Acute Kidney Injury Network (AKIN), and Kidney Disease: Improving Global Outcomes (KDIGO). Hospital mortality (developed within the first 30 days postoperatively) and morbidity (longer than 7 days intensive care unit stay) were compared by three model classes. Results were evaluated statistically.

RESULTS: One hundred patients were included in the study. The median age was 3 months (1 day-180 months). Acute kidney injury was diagnosed in 49% of the cases according to the pRIFLE classification. It was diagnosed in 31% of the patients by AKIN classification. It was diagnosed in 41% of the patients with the KDIGO criteria. Morbidity was observed in 25% (n = 25) of all cases. The morbidity predictor was 0.800 for pRIFLE, 0.747 for AKIN and 0.853 for KDIGO by receiver operating characteristics analysis. All three categories predicted morbidity significantly (P < 0.001). Mortality was 10% (n = 10) for all groups. The mortality predictor was 0.783 for pRIFLE, 0.717 for AKIN and 0.794 for KDIGO by receiver operating characteristics analysis, and all three categories predicted mortality significantly (P < 0.001).

CONCLUSIONS: Regardless of the three methods used, AKI was commonly detected in pediatric patients undergoing congenital heart surgery. pRIFLE classification diagnosed more patients with AKI than AKIN and KDIGO. The KDIGO and pRIFLE classifications were better in predicting hospital mortality.

PMID:36239168 | DOI:10.1111/ped.15270

Ann Cardiothorac Surg. 2022 Sep;11(5):533-537. doi: 10.21037/acs-2022-rmvs-11.

ABSTRACT

BACKGROUND: This study evaluates the clinical outcome of patients with robotic mitral valve replacement (MVR).

METHODS: Between January 2010 and April 2022, 117 consecutive patients underwent robotic MVR with or without additional cardiac procedures. All procedures were completed by a single surgical team with Da Vinci Robotic Systems. Perioperative variables and early clinical outcomes were recorded.

RESULTS: Mean age and EuroScore II of the patients were 57.1±12.9 and 5.1±5.7, respectively. Isolated MVR was performed in 55 (47.0%) patients and combined cardiac procedures were performed in 62 (53.0%) patients. Additional procedures included: ablation for atrial fibrillation, tricuspid valve replacement, tricuspid valve repair, left atrial appendix ligation, patent foramen ovale closure, left atrial thrombectomy and septal myectomy for hypertrophic obstructive cardiomyopathy. Mean cardiopulmonary bypass time and cross clamp time were 143±54 and 93±37 minutes, respectively. Mean intensive care unit stay time was 26.5±26.0 hours. Postoperative stroke was observed in one (0.9%) patient and new onset renal failure was observed in two (1.7%) patients. Perioperative and postoperative early mortality was observed in three (2.6%) patients, which was lower than expected.

CONCLUSIONS: Robotic MVR is feasible and can be performed with good early postoperative outcomes. A majority of the patients require additional cardiac procedures.

PMID:36237592 | PMC:PMC9551377 | DOI:10.21037/acs-2022-rmvs-11

J Clin Med. 2022 Sep 23;11(19):5585. doi: 10.3390/jcm11195585.

ABSTRACT

BACKGROUND: Intraoperative hypotension is common in patients having non-cardiac surgery and associated with postoperative acute myocardial injury, acute kidney injury, and mortality. Avoiding intraoperative hypotension is a complex task for anesthesiologists. Using artificial intelligence to predict hypotension from clinical and hemodynamic data is an innovative and intriguing approach. The AcumenTM Hypotension Prediction Index (HPI) software (Edwards Lifesciences; Irvine, CA, USA) was developed using artificial intelligence-specifically machine learning-and predicts hypotension from blood pressure waveform features. We aimed to describe the incidence, duration, severity, and causes of intraoperative hypotension when using HPI monitoring in patients having elective major non-cardiac surgery.

METHODS: We built up a European, multicenter, prospective, observational registry including at least 700 evaluable patients from five European countries. The registry includes consenting adults (≥18 years) who were scheduled for elective major non-cardiac surgery under general anesthesia that was expected to last at least 120 min and in whom arterial catheter placement and HPI monitoring was planned. The major objectives are to quantify and characterize intraoperative hypotension (defined as a mean arterial pressure [MAP] &lt; 65 mmHg) when using HPI monitoring. This includes the time-weighted average (TWA) MAP &lt; 65 mmHg, area under a MAP of 65 mmHg, the number of episodes of a MAP &lt; 65 mmHg, the proportion of patients with at least one episode (1 min or more) of a MAP &lt; 65 mmHg, and the absolute maximum decrease below a MAP of 65 mmHg. In addition, we will assess causes of intraoperative hypotension and investigate associations between intraoperative hypotension and postoperative outcomes.

DISCUSSION: There are only sparse data on the effect of using HPI monitoring on intraoperative hypotension in patients having elective major non-cardiac surgery. Therefore, we built up a European, multicenter, prospective, observational registry to describe the incidence, duration, severity, and causes of intraoperative hypotension when using HPI monitoring in patients having elective major non-cardiac surgery.

PMID:36233455 | PMC:PMC9571548 | DOI:10.3390/jcm11195585

Front Cardiovasc Med. 2022 Sep 26;9:901396. doi: 10.3389/fcvm.2022.901396. eCollection 2022.

ABSTRACT

Promoting cardiomyocyte proliferation is a promising strategy to regenerate the heart. Yet, so far, it is poorly understood how cardiomyocyte proliferation is regulated, and no factor identified to promote mammalian cardiomyocyte proliferation has been translated into medical practice. Therefore, finding a novel factor will be vital. Here, we established a live cell screening based on mouse embryonic stem cell-derived cardiomyocytes expressing a non-functional human geminin deletion mutant fused to Azami Green (CM7/1-hgem-derived cardiomyocytes). We screened for a subset of compounds of the small molecule library Spectrum Collection and identified 19 potential inducers of stem cell-derived cardiomyocyte proliferation. Furthermore, the pro-proliferative potential of identified candidate compounds was validated in neonatal and adult rat cardiomyocytes as well as human induced pluripotent stem cell-derived cardiomyocytes. 18 of these compounds promoted mitosis and cytokinesis in neonatal rat cardiomyocytes. Among the top four candidates were two cardiac glycosides, peruvoside and convallatoxin, the flavonoid osajin, and the selective α-adrenoceptor antagonist and imidazoline I1 receptor ligand efaroxan hydrochloride. Inhibition of PTEN and GSK-3β enhanced cell cycle re-entry and progression upon stimulation with cardiac glycosides and osajin, while inhibition of IP3 receptors inhibited the cell cycle-promoting effect of cardiac glycosides. Collectively, we established a screening system and identified potential compounds to promote cardiomyocyte proliferation. Our data suggest that modulation of calcium handling and metabolism promotes cardiomyocyte proliferation, and cardiac glycosides might, besides increasing myocardial contraction force, contribute to cardiac repair by inducing cardiomyocyte proliferation.

PMID:36225954 | PMC:PMC9549374 | DOI:10.3389/fcvm.2022.901396

Curr Stem Cell Res Ther. 2022 Oct 11. doi: 10.2174/1574888X17666221011085745. Online ahead of print.

ABSTRACT

Introduction of an animal experimental model for myocardial infarction (MI) has particular importance. Research done on large animals provides valuable information for the researchers because of the similar characteristics of their hearts compared with human, but the cost of purchasing and maintenance of them is high. In comparison, using small animals has advantages such as they are easy to work with and have low purchase and maintenance cost. However, in some of these animals, due to less similarity of the heart to human, cannot simulate the natural pathogenesis of human MI. Moreover, there are different methods for induction of MI in animals, each has its own advantages and disadvantages. However, the method must be chosen that can simulate the natural pathogenesis of MI with minimal complication. Today, attempts are being made for myocardial regeneration after MI using the direct transplantation of stem cells or with an engineered scaffold. The scaffold creates a 3D ambience for the cultured cells. The task of tissue engineering is to optimize the scaffold with appropriate systems for separation, proliferation, and differentiation of the desired cells until they are capable to promote the three-dimensional and appropriate growth of the tissue.The purpose of tissue engineering in cardiac is use of scaffold and cell in the damaged area, followed by the improvement of the heart function through the automatic pulsation, communication with the host vessels, and electrical coupling with the myocardium, eventually creating a force to increase the heart function.

PMID:36221884 | DOI:10.2174/1574888X17666221011085745

Elife. 2022 Oct 11;11:e76781. doi: 10.7554/eLife.76781.

ABSTRACT

Each heartbeat is triggered by the sinoatrial node (SAN), the primary pacemaker of the heart. Studies in animal models have revealed that pacemaker cells share a common progenitor with the (pro)epicardium, and that the pacemaker cardiomyocytes further diversify into 'transitional', 'tail', and 'head' subtypes. However, the underlying molecular mechanisms, especially of human pacemaker cell development, are poorly understood. Here, we performed single cell RNA sequencing (scRNA-seq) and trajectory inference on human induced pluripotent stem cells (hiPSCs) differentiating to SAN-like cardiomyocytes (SANCMs) to construct a roadmap of transcriptional changes and lineage decisions. In differentiated SANCM, we identified distinct clusters that closely resemble different subpopulations of the in vivo SAN. Moreover, the presence of a side population of proepicardial cells suggested their shared ontogeny with SANCM, as also reported in vivo. Our results demonstrate that the divergence of SANCM and proepicardial lineages is determined by WNT signaling. Furthermore, we uncovered roles for TGFβ and WNT signaling in the branching of transitional and head SANCM subtypes, respectively. These findings provide new insights into the molecular processes involved in human pacemaker cell differentiation, opening new avenues for complex disease modeling in vitro and inform approaches for cell therapy-based regeneration of the SAN.

PMID:36217819 | PMC:PMC9553210 | DOI:10.7554/eLife.76781

FASEB J. 2022 Nov;36(11):e22587. doi: 10.1096/fj.202200289RR.

ABSTRACT

Cellular senescence is the irreversible arrest of normally dividing cells and is driven by the cell cycle inhibitors Cdkn2a, Cdkn1a, and Trp53. Senescent cells are implicated in chronic diseases and tissue repair through their increased secretion of pro-inflammatory factors known as the senescence-associated secretory phenotype (SASP). Here, we use spatial transcriptomics and single-cell RNA sequencing (scRNAseq) to demonstrate that cells displaying senescent characteristics are "transiently" present within regenerating skeletal muscle and within the muscles of D2-mdx mice, a model of Muscular Dystrophy. Following injury, multiple cell types including macrophages and fibrog-adipogenic progenitors (FAPs) upregulate senescent features such as senescence pathway genes, SASP factors, and senescence-associated beta-gal (SA-β-gal) activity. Importantly, when these cells were removed with ABT-263, a senolytic compound, satellite cells are reduced, and muscle fibers were impaired in growth and myonuclear accretion. These results highlight that an "acute" senescent phenotype facilitates regeneration similar to skin and neonatal myocardium.

PMID:36190443 | DOI:10.1096/fj.202200289RR

World J Stem Cells. 2022 Sep 26;14(9):700-713. doi: 10.4252/wjsc.v14.i9.700.

ABSTRACT

BACKGROUND: Heart diseases are the primary cause of death all over the world. Following myocardial infarction, billions of cells die, resulting in a huge loss of cardiac function. Stem cell-based therapies have appeared as a new area to support heart regeneration. The transcription factors GATA binding protein 4 (GATA-4) and myocyte enhancer factor 2C (MEF2C) are considered prominent factors in the development of the cardiovascular system.

AIM: To explore the potential of GATA-4 and MEF2C for the cardiac differentiation of human umbilical cord mesenchymal stem cells (hUC-MSCs).

METHODS: hUC-MSCs were characterized morphologically and immunologically by the presence of specific markers of MSCs via immunocytochemistry and flow cytometry, and by their potential to differentiate into osteocytes and adipocytes. hUC-MSCs were transfected with GATA-4, MEF2C, and their combination to direct the differentiation. Cardiac differentiation was confirmed by semiquantitative real-time polymerase chain reaction and immunocytochemistry.

RESULTS: hUC-MSCs expressed specific cell surface markers CD105, CD90, CD44, and vimentin but lack the expression of CD45. The transcription factors GATA-4 and MEF2C, and their combination induced differentiation in hUC-MSCs with significant expression of cardiac genes i.e., GATA-4, MEF2C, NK2 homeobox 5 (NKX2.5), MHC, and connexin-43, and cardiac proteins GATA-4, NKX2.5, cardiac troponin T, and connexin-43.

CONCLUSION: Transfection with GATA-4, MEF2C, and their combination effectively induces cardiac differentiation in hUC-MSCs. These genetically modified MSCs could be a promising treatment option for heart diseases in the future.

PMID:36188117 | PMC:PMC9516467 | DOI:10.4252/wjsc.v14.i9.700

EBioMedicine. 2022 Nov;85:104274. doi: 10.1016/j.ebiom.2022.104274. Epub 2022 Sep 28.

ABSTRACT

BACKGROUND: Homeodomain-Interacting Protein Kinase 2 (HIPK2) has been reported to maintain basal cardiac function, however, its role in pathological cardiac remodeling remains unclear.

METHODS: HIPK2 inhibitors (tBID and PKI1H) treated mice and two lines of HIPK2-/- mice were subjected to transverse aortic constriction (TAC). HIPK2 knockdown were performed in neonatal rat cardiomyocytes (NRCMs), neonatal rat cardiac fibroblasts (NRCFs), and human embryonic stem cell-derived cardiomyocytes (hESC-CMs). Microarray analysis was used to screen HIPK2 targets. Overexpression of early growth response 3 (EGR3) and C-type lectin receptor 4D (CLEC4D) were performed in NRCMs, while an activator of Smad3 was used in NRCFs, to rescue the effects of HIPK2 knockdown. Finally, the effects of EGR3 and CLEC4D knockdown by AAV9 in TAC were determined.

FINDINGS: HIPK2 was elevated in TAC mice model, as well as cardiomyocyte hypertrophy and NRCFs fibrosis model. Pharmacological and genetic inhibition of HIPK2 improved cardiac function and suppressed cardiac hypertrophy and fibrosis induced by TAC. In vitro, HIPK2 inhibition prevented cardiomyocyte hypertrophic growth and NRCFs proliferation and differentiation. At the mechanistic level, we identified EGR3 and CLEC4D as new targets of HIPK2, which were regulated by ERK1/2-CREB and mediated the protective function of HIPK2 inhibition in cardiomyocytes. Meanwhile, inhibition of phosphorylation of Smad3 was responsible for the suppression of cardiac fibroblasts proliferation and differentiation by HIPK2 inhibition. Finally, we found that inhibition of EGR3 or CLEC4D protected against TAC.

INTERPRETATION: HIPK2 inhibition protects against pathological cardiac remodeling by reducing EGR3 and CLEC4D with ERK1/2-CREB inhibition in cardiomyocytes, and by suppressing the phosphorylation of Smad3 in cardiac fibroblasts.

FUNDING: This work was supported by the grants from National Key Research and Development Project (2018YFE0113500 to J.X.), National Natural Science Foundation of China (82020108002 and 81911540486 to J.X., 81400647 to MJ Xu), the grant from Science and Technology Commission of Shanghai Municipality (21XD1421300 and 20DZ2255400 to J.X.), the "Dawn" Program of Shanghai Education Commission (19SG34 to J.X.), and Shanghai Sailing Program (21YF1413200 to Q.Z.).

PMID:36182775 | PMC:PMC9526139 | DOI:10.1016/j.ebiom.2022.104274

Stem Cell Res. 2022 Oct;64:102924. doi: 10.1016/j.scr.2022.102924. Epub 2022 Sep 20.

ABSTRACT

S100 calcium binding protein beta (S100B) is an S-100 low molecular weight binding protein that regulates intracellular processes. This protein is involved in myocardial contractility and calcium handling capacity. In this study, a human embryonic stem cell (hESC) line with homozygous S100B knockout (S100B-KO) was generated using the CRISPR/Cas9 editing system. This S100B-KO hESC line maintained normal cell morphology and karyotype, expressed pluripotency markers, and could differentiate into cells of all three germ layers.

PMID:36182708 | DOI:10.1016/j.scr.2022.102924

ACS Biomater Sci Eng. 2022 Oct 10;8(10):4486-4496. doi: 10.1021/acsbiomaterials.2c00766. Epub 2022 Sep 30.

ABSTRACT

Stromal cell-derived factor-1 alpha (SDF-1α, CXCL12) mediates the migration of circulating cells to desired sites for tissue development, homeostasis, and regeneration and can be used to promote cardiac regeneration by recruiting stem cells. However, the use of SDF-1α in the injured heart necessitates not only higher binding affinity to its receptor, CXCR4+, but also better robustness against enzymatic degradation than other SDF-1 isoforms. Here, we conduct a screening of SDF-1α analog peptides that were designed by structure-based drug design (SBDD), a type of computer-aided drug design (CADD). We have developed in vitro and in vivo methods that enable us to estimate the effect of peptides on the migration of human mesenchymal stem cells (hMSCs) and cardiac regeneration in acute myocardial infarction (AMI)-induced animals, respectively. We demonstrate that one type of SDF-1α analog peptide, SDP-4, among the four analog peptides preselected by SBDD, is more potent than native SDF-1α for cardiac regeneration in myocardial infarction. It is interesting to note that the migratory effects of SDP-4 determined by a wound healing assay, a Transwell assay, and a 2D migration assay are comparable to those of SDF-1α. These results suggest that in vivo, as well as in vitro, screening of peptides developed by SBDD is a quintessential process to the development of a novel therapeutic compound for cardiac regeneration. Our finding also has an implication that the SDP-4 peptide is an excellent candidate for use in the regeneration of an AMI heart.

PMID:36178141 | DOI:10.1021/acsbiomaterials.2c00766

J Cardiovasc Surg (Torino). 2022 Dec;63(6):742-748. doi: 10.23736/S0021-9509.22.12337-2. Epub 2022 Sep 28.

ABSTRACT

BACKGROUND: Ascending aorta manipulation during on-pump coronary artery bypass grafting (CABG) surgery can release embolic matter and may cause stroke. Strategies for lowering the stroke rate associated with coronary artery bypass grafting surgery include off-pump surgery without cardiopulmonary bypass and pump-assisted surgery with minimal aortic manipulation (i.e., without aortic cross-clamping). We examined whether one approach is superior to the other in reducing stroke and perioperative mortality rates.

METHODS: We reviewed consecutive elective, urgent, and emergency off-pump/no-bypass and pump-assisted/no-clamp coronary artery bypass grafting procedures performed by a single surgeon at our institution from June 2011 through October 2017.

RESULTS: Of 570 patients analyzed, 395 (69.3%) underwent off-pump/no-bypass surgery, 43 (7.5%) underwent pump-assisted/no-clamp surgery, and 132 (23.2%) transitioned mid-procedure from off-pump/no-bypass to pump-assisted/no-clamp surgery. Patients who were >70 years old, were female, or had diabetes, cardiomegaly, or a history of myocardial infarction or congestive heart failure were more likely to undergo pump-assisted/no-clamp surgery or the combined technique. None of the pump-assisted/no-clamp patients had a stroke, versus 0.3% of the off-pump/no-bypass patients and 0.8% of the combination patients. Stroke and in-hospital mortality rates did not differ by technique.

CONCLUSIONS: A hybrid strategy incorporating off-pump, pump-assisted, and combined off-pump/pump-assisted techniques achieved very low stroke rates in patients undergoing coronary revascularization. Perioperative mortality was similar for all three techniques. Avoiding aortic clamping may be crucial for decreasing CABG-related stroke rates. Off-pump/no-bypass surgery had no significant advantage over the pump-assisted/no-clamp or combined techniques in reducing the stroke rate after coronary artery bypass grafting surgery.

PMID:36168952 | DOI:10.23736/S0021-9509.22.12337-2

Paediatr Anaesth. 2023 Jan;33(1):52-58. doi: 10.1111/pan.14561. Epub 2022 Oct 17.

ABSTRACT

INTRODUCTION: The Plethysmographic Variability Index can be measured by both finger and forehead probes. Vasoconstriction may jeopardize the reliability of finger PVI measurements in pediatric patients undergoing surgery. However, forehead vasculature exhibits more marked resistance to alterations in the vasomotor tonus.

OBJECTIVE: Our aim was to compare the Plethysmographic Variability Index measured via finger or forehead probes in mechanically ventilated pediatric surgery patients in terms of their ability to predict fluid responsiveness as well as to determine the best cut-off values for these two measurements.

MATERIALS AND METHODS: A total of 50 pediatric patients undergoing minor elective surgery were included after provision of parental consent and ethics committee approval. Perfusion index measured at the finger or forehead and Plethysmographic Variability Index monitoring comprised the primary assessments. Hemodynamic parameters monitored included perfusion index, Plethysmographic Variability Index, and cardiac output. A ≥ 15% increase in cardiac output following passive leg raise maneuver was considered to show fluid responsiveness. Two groups were defined based on fluid responsiveness: Group R (responsive) and Group NR (non-responsive). Student's t-test, Mann-Whitney U test, DeLong test, and ROC were used for statistical analysis.

RESULTS: The area under curve for finger and forehead Plethysmographic Variability Index prior to passive leg raise maneuver were 0.699 (p = .011) and 0.847 (p < .001), respectively. The sensitivity for finger and forehead measurements at a cut-off value of ≤14% was 92.9% and 96.4%, and 45.4% and 72.7%, respectively.

CONCLUSION: Although forehead and finger Plethysmographic Variability Index monitoring were similarly sensitive in predicting fluid responsiveness in pediatric surgical patients, the former method provided higher specificity. The best cut-off value for PVI measurements with forehead and finger probes was found to be 14%.

PMID:36168810 | DOI:10.1111/pan.14561

Turk Gogus Kalp Damar Cerrahisi Derg. 2022 Apr 27;30(2):160-166. doi: 10.5606/tgkdc.dergisi.2022.23347. eCollection 2022 Apr.

ABSTRACT

BACKGROUND: This study aims to investigate the effect of cardiopulmonary bypass on antibody titers in patients vaccinated against the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) undergoing cardiac surgery with cardiopulmonary bypass.

METHODS: Between October 2021 and October 2022, a total of 70 patients (44 males, 26 females; mean age 59.9±10.3; range, 26 to 79 years) who completed their recommended COVID-19 vaccinations and underwent elective cardiac surgery with cardiopulmonary bypass were prospectively included. Serum samples for antibody titer measurements were taken at anesthesia induction and the end of cardiopulmonary bypass after decannulation. The SARS-CoV-2 total immunoglobulin antibodies against N-protein were measured. The antibody titer measurements at anesthesia induction and at the end of cardiopulmonary bypass were compared in all patients.

RESULTS: The median levels after cardiopulmonary bypass were lower than the preoperative levels (1,739.0 vs. 857.0, respectively; p<0.001). There was a drop of 40.0% (21.2%-62.6%) in the antibody titers among all patients. The decrease in antibody titers was consistent regardless of the number of vaccine doses or whether the last dose was received within the last three months. Among the studied factors, no parameter was significantly associated with a lesser or higher decrease in antibody titers.

CONCLUSION: Cardiac surgery with cardiopulmonary bypass causes a decrease in SARS-CoV-2 antibody titers at the end of cardiopulmonary bypass. Revaccination after cardiac operations may be considered in this patient group that is highly vulnerable due to their comorbidities and lowered antibody levels.

PMID:36168572 | PMC:PMC9473596 | DOI:10.5606/tgkdc.dergisi.2022.23347

World J Stem Cells. 2022 Aug 26;14(8):633-657. doi: 10.4252/wjsc.v14.i8.633.

ABSTRACT

BACKGROUND: Cardiovascular diseases are the major cause of mortality worldwide. Regeneration of the damaged myocardium remains a challenge due to mechanical constraints and limited healing ability of the adult heart tissue. Cardiac tissue engineering using biomaterial scaffolds combined with stem cells and bioactive molecules could be a highly promising approach for cardiac repair. Use of biomaterials can provide suitable microenvironment to the cells and can solve cell engraftment problems associated with cell transplantation alone. Mesenchymal stem cells (MSCs) are potential candidates in cardiac tissue engineering because of their multilineage differentiation potential and ease of isolation. Use of DNA methyl transferase inhibitor, such as zebularine, in combination with three-dimensional (3D) scaffold can promote efficient MSC differentiation into cardiac lineage, as epigenetic modifications play a fundamental role in determining cell fate and lineage specific gene expression.

AIM: To investigate the role of collagen scaffold and zebularine in the differentiation of rat bone marrow (BM)-MSCs and their subsequent in vivo effects.

METHODS: MSCs were isolated from rat BM and characterized morphologically, immunophenotypically and by multilineage differentiation potential. MSCs were seeded in collagen scaffold and treated with 3 μmol/L zebularine in three different ways. Cytotoxicity analysis was done and cardiac differentiation was analyzed at the gene and protein levels. Treated and untreated MSC-seeded scaffolds were transplanted in the rat myocardial infarction (MI) model and cardiac function was assessed by echocardiography. Cell tracking was performed by DiI dye labeling, while regeneration and neovascularization were evaluated by histological and immunohistochemical analysis, res pectively.

RESULTS: MSCs were successfully isolated and seeded in collagen scaffold. Cytotoxicity analysis revealed that zebularine was not cytotoxic in any of the treatment groups. Cardiac differentiation analysis showed more pronounced results in the type 3 treatment group which was subsequently chosen for the transplantation in the in vivo MI model. Significant improvement in cardiac function was observed in the zebularine treated MSC-seeded scaffold group as compared to the MI control. Histological analysis also showed reduction in fibrotic scar, improvement in left ventricular wall thickness and preservation of ventricular remodeling in the zebularine treated MSC-seeded scaffold group. Immunohistochemical analysis revealed significant expression of cardiac proteins in DiI labeled transplanted cells and a significant increase in the number of blood vessels in the zebularine treated MSC-seeded collagen scaffold transplanted group.

CONCLUSION: Combination of 3D collagen scaffold and zebularine treatment enhances cardiac differentiation potential of MSCs, improves cell engraftment at the infarcted region, reduces infarct size and improves cardiac function.

PMID:36157910 | PMC:PMC9453269 | DOI:10.4252/wjsc.v14.i8.633

World J Stem Cells. 2022 Jul 26;14(7):473-489. doi: 10.4252/wjsc.v14.i7.473.

ABSTRACT

With advances in the fields of regenerative medicine, cell-free therapy has received increased attention. Exosomes have a variety of endogenous properties that provide stability for molecular transport across biological barriers to cells, as a form of cell-to-cell communication that regulates function and phenotype. In addition, exosomes are an important component of paracrine signaling in stem-cell-based therapy and can be used as a stand-alone therapy or as a drug delivery system. The remarkable potential of exosomes has paved the pathway for cell-free treatment in bone regeneration. Exosomes are enriched in distinct noncoding RNAs (ncRNAs), including microRNAs, long ncRNAs and circular RNAs. Different ncRNAs have multiple functions. Altered expression of ncRNA in exosomes is associated with the regenerative potential and development of various diseases, such as femoral head osteonecrosis, myocardial infarction, and cancer. Although there is increasing evidence that exosome-derived ncRNAs (exo-ncRNAs) have the potential for bone regeneration, the detailed mechanisms are not fully understood. Here, we review the biogenesis of exo-ncRNA and the effects of ncRNAs on angiogenesis and osteoblast- and osteoclast-related pathways in different diseases. However, there are still many unsolved problems and challenges in the clinical application of ncRNA; for instance, production, storage, targeted delivery and therapeutic potency assessment. Advancements in exo-ncRNA methods and design will promote the development of therapeutics, revolutionizing the present landscape.

PMID:36157529 | PMC:PMC9350624 | DOI:10.4252/wjsc.v14.i7.473

Mech Ageing Dev. 2022 Dec;208:111740. doi: 10.1016/j.mad.2022.111740. Epub 2022 Sep 20.

ABSTRACT

Cardiovascular diseases (CVD) are predominantly an aging disease. Important sex-specific differences exist and the mechanism(s) by which this sex-by-age interaction influences CVD development and progression remains elusive. Accordingly, it is still unknown whether cell senescence, a main feature of cardiac male aging, is a significant feature also of the female aged mouse heart and whether senolytics, senescence-clearing compounds, promote myocardial repair and regeneration after myocardial infarction (MI) in aged female mice. To this aim, the combination of two senolytics, dasatinib and quercetin (D+Q) or just their vehicle was administered to 22-24 months old C57BL/6 female mice after MI. D+Q improved global left ventricle function and myocardial performance after MI whereby female cardiac aging is characterized by accumulation of cardiac senescent cells that are further increased by MI. Despite their terminal differentiation nature, also cardiomyocytes acquire a senescent phenotype with age in females. D+Q removed senescent cardiac non-myocyte and myocyte cells ameliorating cardiac remodeling and regeneration. Senolytics removed aged dysfunctional cardiac stem/progenitor cells (CSCs), relieving healthy CSCs with normal proliferative and cardiomyogenic differentiation potential. In conclusions, cardiac senescent cells accumulate in the aged female hearts. Removing senescent cells is a key therapeutic target for efficient repair of the aged female heart.

PMID:36150603 | DOI:10.1016/j.mad.2022.111740

J Clin Med. 2022 Sep 15;11(18):5430. doi: 10.3390/jcm11185430.

ABSTRACT

The decline in cardiac contractility due to damage or loss of cardiomyocytes is intensified by changes in the extracellular matrix leading to heart remodeling. An excessive matrix response in the ischemic cardiomyopathy may contribute to the elevated fibrotic compartment and diastolic dysfunction. Fibroproliferation is a defense response aimed at quickly closing the damaged area and maintaining tissue integrity. Balance in this process is of paramount importance, as the reduced post-infarction response causes scar thinning and more pronounced left ventricular remodeling, while excessive fibrosis leads to impairment of heart function. Under normal conditions, migration of progenitor cells to the lesion site occurs. These cells have the potential to differentiate into myocytes in vitro, but the changed micro-environment in the heart after infarction does not allow such differentiation. Stem cell transplantation affects the extracellular matrix remodeling and thus may facilitate the improvement of left ventricular function. Studies show that mesenchymal stem cell therapy after infarct reduces fibrosis. However, the authors did not specify whether they meant the reduction of scarring as a result of regeneration or changes in the matrix. Research is also necessary to rule out long-term negative effects of post-acute infarct stem cell therapy.

PMID:36143077 | PMC:PMC9502668 | DOI:10.3390/jcm11185430

Int J Mol Sci. 2022 Sep 7;23(18):10314. doi: 10.3390/ijms231810314.

ABSTRACT

Because of cardiomyocyte death or dysfunction frequently caused by myocardial infarction (MI), heart failure is a leading cause of morbidity and mortality in modern society. Paradoxically, only limited and non-curative therapies for heart failure or MI are currently available. As a result, over the past two decades research has focused on developing cell-based approaches promoting the regeneration of infarcted tissue. Cell-based therapies for myocardial regeneration include powerful candidates, such as multipotent stem cells (mesenchymal stem cells (MSCs), bone-marrow-derived stem cells, endothelial progenitor cells, and hematopoietic stem cells) and induced pluripotent stem cells (iPSCs). These possess unique properties, such as potency to differentiate into desired cell types, proliferation capacity, and patient specificity. Preclinical and clinical studies have demonstrated modest improvement in the myocardial regeneration and reduced infarcted areas upon transplantation of pluripotent or multipotent stem cells. Another cell population that need to be considered as a potential source for cardiac regeneration are telocytes found in different organs, including the heart. Their therapeutic effect has been studied in various heart pathologies, such as MI, arrhythmias, or atrial amyloidosis. The most recent cell-free therapeutic tool relies on the cardioprotective effect of complex cargo carried by small membrane-bound vesicles-exosomes-released from stem cells via exocytosis. The MSC/iPSC-derived exosomes could be considered a novel exosome-based therapy for cardiovascular diseases thanks to their unique content. There are also other cell-free approaches, e.g., gene therapy, or acellular cardiac patches. Therefore, our review provides the most recent insights into the novel strategies for myocardial repair based on the regenerative potential of different cell types and cell-free approaches.

PMID:36142245 | PMC:PMC9499607 | DOI:10.3390/ijms231810314