Theodoros Kofidis

Enhanced infarct stabilization and neovascularization mediated by VEGF-loaded PEGylated fibrinogen hydrogel in a rodent myocardial infarction model.

Most tissue engineering therapies require biomaterials that are able to induce an angiogenic response to support tissue regeneration. In addition angiogenic growth factor signaling plays an essential role in controlling the process of angiogenesis and matrices have the potential of regulating the concentration of growth factors within the cellular microenvironment. Here we demonstrated myocardial protection and improved post-infarct vascularization of the infarcted hearts using a biosynthetic injectable hydrogel consisting of polyethylene glycol and fibrinogen (PEG-fibrinogen) loaded with vascular endothelial growth factor-A (VEGF-A). Our data revealed PEG-fibrinogen hydrogel was able to store and release VEGF-A in a sustained and controlled fashion. Upon injection after coronary artery ligation, the VEGF-loaded hydrogel significantly improved arteriogenesis and cardiac performance at 4 weeks post-infarction. The results support the future application of PEG-fibrinogen for regulating growth factor signaling in cellular microenvironment and may demonstrates a new strategy for cardiovascular repair with potential for future clinical applications.

Biohybrid cardiac ECM-based hydrogels improve long term cardiac function post myocardial infarction

Injectable scaffolds for cardiac tissue regeneration are a promising therapeutic approach for progressive heart failure following myocardial infarction (MI). Their major advantage lies in their delivery modality that is considered minimally invasive due to their direct injection into the myocardium. Biomaterials comprising such scaffolds should mimic the cardiac tissue in terms of composition, structure, mechanical support, and most importantly, bioactivity. Nonetheless, natural biomaterial-based gels may suffer from limited mechanical strength, which often fail to provide the long-term support required by the heart for contraction and relaxation. Here we present newly-developed injectable scaffolds, which are based on solubilized decellularized porcine cardiac extracellular matrix (pcECM) cross-linked with genipin alone or engineered with different amounts of chitosan to better control the gels mechanical properties while still leveraging the ECM biological activity. We demonstrate that these new biohybrid materials are naturally remodeled by mesenchymal stem cells, while supporting high viabilities and affecting cell morphology and organization. They exhibit neither in vitro nor in vivo immunogenicity. Most importantly, their application in treating acute and long term chronic MI in rat models clearly demonstrates the significant therapeutic potential of these gels in the long-term (12weeks post MI). The pcECM-based gels enable not only preservation, but also improvement in cardiac function eight weeks post treatment, as measured using echocardiography as well as hemodynamics. Infiltration of progenitor cells into the gels highlights the possible biological remodeling properties of the ECM-based platform. STATEMENT OF SIGNIFICANCE This work describes the development of new injectable scaffolds for cardiac tissue regeneration that are based on solubilized porcine cardiac extracellular matrix (ECM), combined with natural biomaterials: genipin, and chitosan. The design of such scaffolds aims at leveraging the natural bioactivity and unique structure of cardiac ECM, while overcoming its limited mechanical strength, which may fail to provide the long-term support required for heart contraction and relaxation. Here, we present a biocompatible gel-platform with custom-tailored mechanical properties that significantly improve cardiac function when injected into rat hearts following acute and chronic myocardial infarction. We clearly demonstrate the substantial therapeutic potential of these scaffolds, which not only preserved heart functions but also alleviated MI damage, even after the formation of a mature scar tissue.

Sleep apnea is associated with new-onset atrial fibrillation after coronary artery bypass grafting

PURPOSE New-onset atrial fibrillation (AF) after coronary artery bypass grafting (CABG) remains a prevalent problem. We investigated the relationship between sleep apnea and new-onset post-CABG AF during inhospital stay. MATERIALS AND METHODS We prospectively recruited 171 patients listed for an elective CABG for an overnight sleep study. Sleep apnea was defined as apnea-hypopnea index greater than or equal to 5. RESULTS Among the 160 patients who completed the study, those in the sleep apnea group (n=128; 80%) had larger left atrial diameter (40.4±5.4 vs 38.4±6.0 mm; P=.03) and left ventricular end-diastolic dimension (52.6±7.9 vs 49.2±6.8 mm; P=.03) than those in the non-sleep apnea group. The incidence of new-onset post-CABG AF was higher for the sleep apnea than non-sleep apnea groups (24.8% vs 9.7%; P=.07). There was 1 inhospital death and 2 patients with acute renal failure requiring dialysis after CABG in the sleep apnea group. None of the patients developed inhospital stroke. Multiple logistic regression analysis showed that sleep apnea was an independent predictor of post-CABG AF (odds ratio, 4.4; 95% confidence interval, 1.1-18.1; P=.04). CONCLUSION Sleep apnea is prevalent in patients undergoing CABG. It increases the susceptibility to new-onset AF after CABG, probably related to atrial and ventricular remodeling.

Design of a Novel Flexible Endoscope—Cardioscope

In this paper, we present a novel flexible endoscope which is well suited to minimally invasive cardiac surgery (MICS). It is named ‘the Cardioscope’. The Cardioscope is composed of a handle, a rigid shaft, a flexible section and the imaging system. The flexible section is composed of an elastic tube, a number of spacing discs, a constraint tube and four tendons. Compared with other flexible endoscopes, the Cardioscope is much more dexterous. The maximum bending angle of the Cardioscope is 190°. Ex-vivo tests show that the cardioscope is well suited to (MICS), it provides much larger scope of vision than rigid endoscopes and provides good manipulation inside the confined environment. In the test, the Cardioscope successfully explores the full heart through a single hole, which shows the design is promising. Despite it was designed for MICS, the Cardioscope can also be applied to other minimally invasive surgeries, such as laparoscopy, neurosurgery, transnasal and transoral surgery.Copyright

Dual delivery of VEGF and ANG-1 in ischemic hearts using an injectable hydrogel

Acute myocardial infarction (MI) caused by ischemia is the most common cause of cardiac dysfunction. While growth factor therapy is promising, the retention in the highly vascularized myocardium is limited and prevents sustained activation needed for adequate cellular responses. Here, we demonstrated the use of polyethylene glycol-fibrinogen (PF) hydrogels for sustained dual delivery of vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANG-1) to enhance myocardial repair and function. VEGF and ANG-1 were incorporated in PF hydrogels and their in vitro characteristics were studied. Acute MI was generated in a rodent model with rats randomly assigned to 4 groups; sham, saline, PF and PF-VEGF-ANG1 (n=10 each group). Saline or hydrogel was injected in infarct and peri-infarct areas of the myocardium. After 4weeks, myocardial function was assessed using echocardiography. Tissue samples were harvested for Hematoxylin and Eosin, Masson Trichrome and capillary staining to assess the extent of fibrotic scar and arteriogenesis. Both VEGF and ANG-1 were released in a sustained and controlled manner over 30days. PF-VEGF-ANG1 treated animals showed the best improvement in cardiac function, highest degree of cardiac muscle preservation, and arteriogenesis. This study demonstrates that PF hydrogels can simultaneously provide mechanical support to attenuate adverse myocardial remodelling, and a pro-angiogenic benefit from the sustained VEGF and ANG1 delivery that culminates in a restorative effect following MI. The utility of this synergistic, biomaterial-based growth factor delivery may have clinical implications in the prevention of post-MI cardiac dysfunction. STATEMENT OF SIGNIFICANCE Acute myocardial infarction (MI) caused by ischemia is the most common cause of cardiac dysfunction. Here, we demonstrated the use of polyethylene glycol-fibrinogen (PF) hydrogels for sustained dual delivery of vascular endothelial growth factor (VEGF) and angiopoietin-1 (ANG-1) to enhance myocardial repair and function. Treated animals showed the best improvement in cardiac function, highest degree of cardiac muscle preservation, and arteriogenesis. This study demonstrates that PF hydrogels can simultaneously provide mechanical support to attenuate adverse myocardial remodelling, and a pro-angiogenic benefit from the sustained VEGF and ANG1 delivery that culminates in a restorative effect following MI.

Sleep apnoea is a risk factor for acute kidney injury after coronary artery bypass grafting

OBJECTIVES Acute kidney injury (AKI) is a common complication in patients who undergo coronary artery bypass grafting (CABG). Sleep apnoea is associated with sympathetic activation, inflammatory reaction and plaque burden. The possible status of sleep apnoea as a risk factor for AKI after CABG has not been studied. METHODS We recruited 169 patients for an overnight sleep study using a Food and Drug Administration-approved portable device before they underwent elective CABG. AKI after CABG was defined as a relative increase of greater than 25% or an absolute increase of greater than 0.5 mg/dl in the serum creatinine level from baseline within 5 days after CABG. A generalized structural equation model (gSEM) was then applied to ascertain whether sleep apnoea, defined as an Apnoea-Hypopnoea index (AHI) of 15 or higher, was associated with AKI after CABG after adjusting for the effects of confounding variables. RESULTS Of the 150 patients (88.8%) who completed the study, the incidence of AKI after CABG was 22.7%. The mean AHI was higher in the AKI group (27.4 ± 19.8) than that in the non-AKI group (18.3 ± 16.5; P < 0.01). The prevalence of sleep apnoea was higher in the AKI group (64.7%) than that in the non-AKI group (45.7%; P = 0.05). The patients in the AKI group were older (P < 0.01) and shorter (P = 0.03) and had higher systolic blood pressures (P = 0.01), greater waist circumferences (P = 0.04) and larger left atrial diameters (P < 0.01) than those in the non-AKI group. The patients in the AKI group had higher serum haemoglobin levels (P = 0.04) and lower glucose levels (P < 0.01) than those in the non-AKI group. A gSEM based on binomial distributions showed that sleep apnoea was an independent predictor of AKI after CABG (adjusted odds ratio, 2.89; confidence interval, 1.09-7.09; P = 0.03) after adjustment for the effects of haemoglobin, glucose levels, the left atrial diameter and systolic blood pressure. CONCLUSIONS Sleep apnoea is prevalent and is associated with AKI after CABG. The data presented here provide the first insights into the potential of treating sleep apnoea to attenuate the risk of AKI after CABG.

Sleep apnoea and unscheduled re-admission in patients undergoing coronary artery bypass surgery

INTRODUCTION Although it has been recognised as a cardiovascular risk factor, data on sleep apnoea screening before coronary artery bypass grafting (CABG) are scarce. This study sought to determine the prevalence, predictors and effects of sleep apnoea on re-admission in patients undergoing CABG. METHOD We prospectively recruited 152 patients to undergo an overnight sleep study before CABG. Sleep apnoea was defined as an apnoea-hypopnoea index of ≥15 events per hour. Data on unscheduled re-admission due to cardiovascular events were collected. RESULTS Among the 138 patients who completed the sleep study, sleep apnoea was diagnosed in 69 (50%). The patients who had sleep apnoea had a lower left ventricular ejection fraction (p = 0.029), a larger left atrial diameter (p = 0.014) and a larger left ventricular end-systolic dimension (p = 0.019) than those who did not. Angiographic SYNTAX and Gensini scores were similar in patients with and without sleep apnoea. The generalised structural equation model revealed that hypertension, a high body mass index and chronic renal failure were independent predictors of sleep apnoea (p < 0.05). After an average follow-up of 6 ± 3 months, 12 patients with sleep apnoea (17.3%) and three patients without sleep apnoea (4.3%) were involved in unscheduled re-admission. Patients with sleep apnoea were almost five times more likely to have an unscheduled re-admission due to cardiovascular events (adjusted odds ratio: 4.63, 95% CI: 1.24-17.31, p = 0.023) than those without sleep apnoea. CONCLUSIONS Sleep apnoea was prevalent and predictive of unscheduled re-admissions in patients scheduled for CABG.

A Score for Predicting Acute Kidney Injury After Coronary Artery Bypass Graft Surgery in an Asian Population.

OBJECTIVE To develop a scoring system to predict acute kidney injury in Asian patients after coronary artery bypass grafting. DESIGN A retrospective analysis of data collected in an institutional cardiac database. SETTING A tertiary academic hospital in a large metropolitan city. PARTICIPANTS The study comprised 954 patients with coronary artery disease. INTERVENTIONS All patients underwent coronary artery bypass surgery with cardiopulmonary bypass but did not undergo any other concomitant procedures. MEASUREMENTS AND MAIN RESULTS The main outcome measured was acute kidney injury as defined by the Acute Kidney Injury Network criteria. The following 6 clinical variables were independent predictors of kidney injury: age>60 years, diabetes requiring insulin, estimated glomerular filtration rate<60 mL/min/1.73 m(2), ejection fraction<40%, cardiopulmonary bypass time>140 minutes, and aortic cross-clamp time>100 minutes. These variables were used to develop the Singapore Acute Kidney Injury score. CONCLUSION The Singapore Acute Kidney Injury score is a simple way to predict, at the time of admission to the intensive care unit, an Asian patients risk of developing acute kidney injury after coronary artery bypass surgery.

Difficulties With the Use of Thromboelastometry in a Patient With Antiphospholipid Syndrome Undergoing Cardiac Surgery

Tautoimmune syndrome characterized by a hypercoagulable state with vascular thrombosis and the persistent presence of phospholipid-directed autoantibodies. Cardiac surgery in such patients carries significant morbidity and mortality and is fraught with both thromboembolic and bleeding complications. Management of perioperative anticoagulation is complicated by an intrinsic prothrombotic state and the paradoxical tendencies of lupus anticoagulant antibodies (LAC) to inhibit phospholipiddependent coagulation during in vitro lab testing superimposed on the complex effects of cardiopulmonary bypass on coagulation and low tolerance for postoperative bleeding risk. The use of viscoelastic hemostatic testing in this setting previously has been proposed as a possible adjunct to mitigate these complexities. However, there are little published data on its use in APLS patients and, in particular, in those undergoing cardiac surgery requiring cardiopulmonary bypass. The authors describe a case of a patient with primary APLS undergoing mitral valve replacement and their experience with the use of rotational thromboelastometry (ROTEM), and they provide a brief overview of the literature regarding its use in such patients.

Fiber Optic Projection-Imaging System for Shape Measurement in Confined Space

A fiber-based projection-imaging system is proposed for shape measurement in confined space. Owing to the flexibility of imaging fibers, the system can be used in special scenarios that are difficult for conventional experimental setups. Three experiments: open space, closed space, and underwater are designed to demonstrate the strength and weakness of the system. It is shown that when proper alignment is possible, relatively high accuracy can be achieved; the error is less than 2% of the overall height of a specimen. In situations where alignment is difficult, significantly increased error is observed. The error is in the form of gross-scale geometrical distortion; for example, flat surface is reconstructed with curvature. In addition, the imaging fibers may introduce fine-scale noise into phase measurement, which has to be suppressed by smoothing filters. Based on results and analysis, it is found that although a fiber-based system has its unique strength, existing calibration and processing methods for fringe patterns have to be modified to overcome its drawbacks so as to accommodate wider applications.