Dominique Shum-tim - Academia.edu (original) (raw)

Papers by Dominique Shum-tim

The Journal of Thoracic and Cardiovascular Surgery, Dec 1, 1996

Background: Various degrees of hemodilution are currently in clinical use during deep hypothermic... more Background: Various degrees of hemodilution are currently in clinical use during deep hypothermic circulatory arrest to counteract deleterious rheologic effects linked with brain injury by previous reports. Material and methods: Seventeen piglets were randomly assigned to three groups. Group I piglets (n = 7) received colloid and crystalloid prime (hematocrit < 10%), group II piglets (n = 5) received blood and crystalloid prime (hematocrit 20%), group III piglets (n = 5) received blood prime (hematocrit 30%). All groups underwent 60 minutes of deep hypothermic circulatory arrest at 15 ° C. with continuous magnetic resonance spectroscopy and near-infrared spectroscopy Neurologic recovery was evaluated for 4 days (neurologic deficit score 0, normal, to 500, brain death; overall performance category 1, normal, to 5, brain death). Neurohistologic score (0, normal, to 5+, necrosis) was assessed after the animals were euthanized on day 4. Results: Group I had significant loss of phosphocreatine and intracellular acidosis during early cooling (phosphocreatine in group I, 86.3%-26.8%; group II, 117.3%-+ 8.6%; group III, 110.9%-2.68%;p = 0.0008; intracellular pH in group I, 6.95-0.18; group II, 7.28-+ 0.04; group HI, 7.49 + 0.04; p-0.0048). Final recovery was the same for all groups. Cytochrome aa 3 was more reduced in group I during deep hypothermic circulatory arrest than in either of the other groups (group I,-43.6-2.6; group II,-16.0-5.2; group Ill, 1.3 _+ 3.1; p < 0.0001). Neurologic deficit score was best preserved in group Ill (p < 0.05 group II vs group HI) on the first postoperative day, although this difference diminished with time and all animals were neurologically normal after 4 days. Histologic assessment was worst among group I in neocortex area (group I, 1.33-0.3; group II, 0.22-0.1; group III, 0.40 _+ 0.2, p < 0.05, group I vs group II; p = 0.0287, group I vs group Ill). Conclusion: Extreme hemodilution during cardiopulmonary bypass may cause inadequate oxygen delivery during early cooling. The higher hematocrit with a blood prime is associated with improved cerebral recovery after deep hypothermic circulatory arrest.

The Journal of extra-corporeal technology, 2004

There is a very limited published material about experience with long-term pediatric mechanical c... more There is a very limited published material about experience with long-term pediatric mechanical circulatory support as a bridge to heart transplant. We report on a 2-year-old, 12 kg boy admitted with 2-week history of low-grade fever, ear pain, pulmonary edema, and congestive heart failure. Trans-thoracic echocardiography confirmed severe myocardial dysfunction with a left ventricular ejection fraction of 0.20 and percentage shortening of 13. After 2 days of ventilatory and inotropic support, the patient continued to deteriorate and subsequently required femoro-femoral extracorporeal life support (ECLS). This was later complicated by a progressive coagulopathy and massive bleeding. On day 17, a pulsatile pediatric paracorporeal biventricular assist device (VAD) (Berlin Heart) was implanted. The patient's condition improved significantly with all coagulopathies corrected, and the patient was extubated 21 days later. After 109 days of bi-VAD support, the patient was successfully t...

European Journal of Cardio-Thoracic Surgery, 2003

Objectives: The contact of cardiopulmonary bypass surface and patient's blood activates systemic ... more Objectives: The contact of cardiopulmonary bypass surface and patient's blood activates systemic inflammatory response which aggravates ischemia-reperfusion injury. This study evaluates the effects of cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA) on cerebral protection using different steroid administration protocols. Methods: Eighteen (n ¼ 6/group) 4 week-old piglets were divided in three groups. Methylprednisolone (30 mg/kg) was administered intravenously 4 h prior to CPB in Group I, or added in pump prime in group II. Group III received no steroid. All animals were cooled to 158C followed by 100 min of DHCA, then rewarmed over 40 min and sacrificed 6 h after CPB. Post-operative weight gain, bioelectrical impedance, colloid oncotic pressure (COP) and interleukin-6 (IL-6) were evaluated. Determination of cerebral trypan blue and immunohistochemical assays of transforming growth factor (TGF)-b 1 and caspase-3 activities were performed. Results: Post-operative % weight gain (13.0^3.8 (I) versus 26.4^9.9 (II) versus 22.6^6.4 (III), P ¼ 0:02); % bioimpedance reduction (14.5^8.0 (I) versus 38.3^13.3 (II) versus 30.5^8.0 (III), P ¼ 0:003); mean COP (mmHg) (14.9^1.8 (I) versus 10.9^2.0 (II) versus 6.5^1.8 (III), P ¼ 0:0001) and systemic IL-6 levels (pg/ml) (208.2^353.0 (I) versus 1562.1^1111.4 (II) versus 1712.3^533.2 (III), P ¼ 0:01) were significantly different between the groups. Spectrophotometric analysis of cerebral trypan blue (ng/g dry weight) was significantly different between the groups (0.0053^0.0010 (I) versus 0.0096^0.0026 (II) versus 0.0090^0.0019 (III), P ¼ 0:004). TGF-b 1 scores were 3.3^0.8 (I) versus 1.5^0.8 (II) versus 1.5^0.5 (III), P , 0:05, groups I versus II and I versus III. Remarkable perivascular caspase-3 activity was observed in groups II and III. Conclusion: Different timing of steroid administration results in different inflammatory mediator response. Steroid in CPB prime is not significantly better than no steroid treatment, while systemic steroid pre-treatment significantly decreases systemic manifestation of inflammatory response and brain damage.

The Journal of Thoracic and Cardiovascular Surgery, 2006

Direct intramyocardial injection is a common route of donor cell administration for myocardial ce... more Direct intramyocardial injection is a common route of donor cell administration for myocardial cell therapy. Studies have demonstrated a significant and rapid loss of implanted cells, which is thought to be biologically caused. We hypothesized that mechanical loss of cells from the contracting myocardium might actually be the main culprit. Methods: Intramyocardial injections of fluorescent microspheres (10 m) were carried out in both small and large animal models. The hearts of Lewis rats (250-350 g) received 3 ϫ 10 6 microspheres injected into the left ventricular myocardium. Rats were divided evenly between two experienced operators. The nonbeating (n ϭ 2) and beating (n ϭ 5) hearts of piglets (7.5-7.8 kg) received 3 ϫ 10 6 microspheres. The hearts were excised within 10 minutes, and the microspheres retained in the myocardium were quantified with fluorescent flow cytometry. Results: In the beating-heart rat model, the microsphere retention rates after a single injection were similar with and without purse-string occlusion of needle puncture sites and slightly lower than after multiple site injections (6.19% Ϯ 4.05% vs 5.44% Ϯ 5.66% vs 8.83% Ϯ 3.29%). There were no significant operatordependent differences. The retention rates in beating porcine hearts were higher than those in the rats (P Ͻ .05) but markedly lower than those in nonbeating porcine hearts (11.1% vs 67.4%). Conclusion: Mechanical leakage and washout may account for a major portion of cell loss after cell implantation, and efforts aimed at reducing mechanical loss in the beating heart may yield a greater benefit than those targeting biologic loss alone. S urvival of cells after intramyocardial injection is crucial to the efficacy of therapeutic cell transplantation. In an attempt to increase the number of cells surviving after injection, many researchers have targeted cell deaths (due to apoptosis, ischemia, free radical formation, etc). However, recent studies suggest a massive loss of cells in the first minutes after injection. 1-4 In light of the early time frame in which this loss takes place, it is unlikely to be accounted for solely by cell death. Cells can be delivered in a variety of ways, and one of the most common methods is direct intramyocardial injection. The technique of injection may result in mechanical loss, in the form of cells leaking from the site through the puncture hole, cells retained in the syringe, or vascular washout. Because the heart differs from other organs in that it is constantly contracting, it is possible that this may contribute to the mechanical loss by squeezing the injected cells out of the myocardium. As a result, the cells retained in the myocardium immediately postinjection represent only a fraction of those initially implanted. It is from this subset that biologic loss and gain, through cell death and proliferation, can then affect the quantity of surviving cells.

The Open Cardiovascular Medicine Journal, 2007

Studies have shown that adult bone marrow derived stem cells (MSCs) can participate in repair of ... more Studies have shown that adult bone marrow derived stem cells (MSCs) can participate in repair of myocardial injury in adult hearts, as well as in cardiac growth during fetal development in utero. Yet, no studies have evaluated the role of MSCs with respect to normal growth or tissue repair in immature hearts after birth. The present study examines whether MSCs may participate in the myocardial growth and injury in the post-natal immature hearts. MSCs were isolated from adult Lewis rats and labeled with Lac-Z gene using retroviral vectors. These MSCs were injected systemically into groups of neonatal (NB=2days-old), immature (B=30days-old) and adult (A=>3months-old) isogeneic Lewis rats. Additionally, left coronary artery ligation was carried out in subgroups of immature (BL) and adult (AL) rats one week after MSCs injection. The hearts were harvested serially from 2-days to 6-weeks, stained with X-Gal for labeled MSCs. Cardiomyocyte phenotypic expression was evaluated by immunohistological staining for Troponin I-C and Connexin-43. Labeled MSCs were found to home into the bone marrow in all rats of different developmental stages. They could be recruited from bone marrow into the infarcted site of myocardium only in groups AL and BL. They were also capable of differentiating into cardiomyocyte phenotype after myocardial injury. In contrast to that reported in the developing fetus, MSCs did not appear to contribute to the growth of non-injured hearts after birth. However, they can be recruited from the bone marrow and regenerate damaged myocardium both in the adult and in the immature hearts.

The Annals of Thoracic Surgery, 2001

This study evaluates whether systemic steroid pretreatment enhances neuroprotection during deep h... more This study evaluates whether systemic steroid pretreatment enhances neuroprotection during deep hypothermic circulatory arrest (DHCA) compared with steroid in cardiopulmonary bypass (CPB) prime. Four-week-old piglets randomly placed into two groups (n = 5 per group) were given methylprednisolone (30 mg/kg) into the pump prime (group PP), or pretreated intravenously 4 hours before CPB (group PT). All animals underwent 100 minutes of DHCA (15 degrees C), were weaned off CPB, and were sacrificed 6 hours later. Postoperative changes in body weight, bioimpedance, and colloid oncotic pressure (COP) were measured. Cerebral trypan blue content, immunohistochemical evaluation of transforming growth factor-beta1 (TGF-beta1) expression, and caspase-3 activity were performed. Percentage weight gain (group PP 25.0% +/- 10.4% versus group PT 12.5% +/- 4.0%; p = 0.036), and percentage decrease in bioimpedance (PP 37.2% +/- 14.5% versus PT 15.6% +/- 7.9%; p = 0.019) were significantly lower, whereas postoperative COP was significantly higher in group PT versus group PP (PT 15.3 +/- 1.8 mm Hg versus PP 11.6 +/- 0.8 mm Hg; p = 0.003). Cerebral trypan blue (ng/g dry tissue) was significantly lower in group PT (PT 5.6 x 10(-3) +/- 1.1 x 10(-3) versus PP 9.1 x 10(-3) +/- 5.7 x 10(-4); p = 0.001). Increased TGF-beta1 expression and decreased caspase-3 activity were shown in group PT. Systemic steroid pretreatment significantly reduced total body edema and cerebral vascular leak and was associated with better immunohistochemical indices of neuroprotection after DHCA.

American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, 2016

Cardiac surgery triggers an inflammatory stress response, leading to protein catabolism, a proces... more Cardiac surgery triggers an inflammatory stress response, leading to protein catabolism, a process that even high-dose insulin therapy alone cannot reverse. To determine whether hyperinsulinemic-normoglycemic clamp and perioperative amino acid (AA) supplementation improves whole body protein balance, 20 patients scheduled for elective coronary artery bypass grafting surgery were randomly assigned to have intra- and postoperative hyperinsulinemic-normoglycemic clamp, with or without intravenous AA supplementation. Primed continuous infusions of [6,6-2H2]glucose and l-[1-13C]leucine were used to quantify whole body protein and glucose metabolism before and after surgery. Adipose tissue and serum cytokines were also analyzed to measure their responsiveness to the anabolic effect of AA administration. During hyperinsulinemic-normoglycemic clamp, AA supplementation successfully stimulated whole body protein synthesis, resulting in a positive whole body protein balance after surgery (insu...

Background: Acute myocardial ischemia results in scar formation with ventricular dilatation and e... more Background: Acute myocardial ischemia results in scar formation with ventricular dilatation and eventually heart failure. Placental growth factor (PlGF) is reported to stimulate angiogenesis and improve cardiac function. In this study, it was hypothesized that intramyocardial injection of PlGF contained in nanoparticles can be released at the site of action for an extended time period as a sustained slow-release protective mechanism that accelerates myocardial recovery in a rat model of ischemic cardiomyopathy. Methods: PlGF-loaded chitosan-alginate nanoparticles were injected into an acute myocardial infarction model in rats (n = 10 per group). Transthoracic echocardiography was performed at different time intervals. Enzyme-linked immunosorbent assay was used to measure the serum cytokines levels at 8 weeks. Hearts were stained with Masson's trichrome for scar area analysis. Immunofluorostaining was performed to evaluate the extent of myocardial angiogenesis at the infarction border. PlGF enzyme-linked immunosorbent assay was used to measure the in vitro release kinetics of PlGF-loaded nanoparticles. Results: At 8 weeks after coronary ligation, hearts that were treated with PlGF-loaded chitosanalginate nanoparticles had significant increases in left-ventricular function (P , 0.01), vascular density (P , 0.01), and in the serum level of the anti-inflammatory cytokine interleukin-10 (P , 0.05). There was significant decrease in scar area formation (P , 0.05) and in serum levels of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-6 (P , 0.01). In vitro PlGF-release kinetic studies showed a sustained release of PlGF from the particles over a 120-hour period. Conclusion: The use of nanoparticles as a vehicle for PlGF delivery, as opposed to the direct injection of the growth factor after acute myocardial infarction, can provide sustained slowrelease PlGF therapy, enhancing the positive effects of the growth factor in the setting of acute myocardial ischemia.

Vascular and Endovascular Surgery, 1994

Stem Cells and Cloning: Advances and Applications, 2015

Stem cell therapy and tissue engineering represent a forefront of current research in the treatme... more Stem cell therapy and tissue engineering represent a forefront of current research in the treatment of heart disease. With these technologies, advancements are being made into therapies for acute ischemic myocardial injury and chronic, otherwise nonreversible, myocardial failure. The current clinical management of cardiac ischemia deals with reestablishing perfusion to the heart but not dealing with the irreversible damage caused by the occlusion or stenosis of the supplying vessels. The applications of these new technologies are not yet fully established as part of the management of cardiac diseases but will become so in the near future. The discussion presented here reviews some of the pioneering works at this new frontier. Key results of allogeneic and autologous stem cell trials are presented, including the use of embryonic, bone marrow-derived, adipose-derived, and resident cardiac stem cells.

Interactive CardioVascular and Thoracic Surgery, 2009

In this current 'stent era', cardiac surgeons are faced with a rapidly increasing number of patie... more In this current 'stent era', cardiac surgeons are faced with a rapidly increasing number of patients in whom previous percutaneous coronary interventions (PCIs) have been performed before they are finally referred for coronary artery bypass surgery. We herein describe a technique of surgical revascularization in two patients with diffusely diseased left anterior descending arteries (LAD), covered with multiple overlapping stents extending to their distal portion. The pertinent literature is reviewed and the technical steps and clinical presentation are discussed.

Cardiovascular Engineering and Technology, 2010

... Modified by Recombinant Baculovirus ARGHYA PAUL,1 DOMINIQUE SHUM-TIM,2 and SATYA PRAKASH 1,3 ... more ... Modified by Recombinant Baculovirus ARGHYA PAUL,1 DOMINIQUE SHUM-TIM,2 and SATYA PRAKASH 1,3 ... Cell Cultures Sf9 insect cells (Invitrogen Life Technologies, Carlsbad, CA) were maintained at 27 °C in SF900 III serum free medium in stationary flasks. ...

Scientific Reports, 2013

Present study, for the first time, reports the development of a nanohybridized baculovirus based ... more Present study, for the first time, reports the development of a nanohybridized baculovirus based stent that can locally promote vascular re-endothelialization by efficient delivery of pro-angiogenic vascular endothelial growth factor (Vegf) genes. In vitro data demonstrated rapid expression of functionally active Vegf by the bioactive stent-transduced vascular cells. In vivo site-specific transgene expression was observed at the stented regions of balloon-denuded canine femoral artery, which eventually lead to significant endothelial recovery at the injured sites. A significant reduction in neointima formation (2.23 6 0.56 mm 2 vs 2.78 6 0.49 mm 2 and 3.11 6 0.23 mm 2 , p , 0.05; n 5 8) and percent stenosis was observed in treated stent group compared to negative control and bare metal stent groups. These findings collectively implicate the potential of this newly developed baculovirus based biotherapeutic stent to ameliorate damaged vascular biology and attenuate re-narrowing of stented artery by inhibiting neointima formation. P ercutaneous coronary angioplasty and stenting is one of the most commonly employed interventional procedures for the treatment of coronary artery diseases 1 . A frequent long-term complication of this treatment is the phenomenon of in-stent restenosis (ISR) which occurs at the site of the atherosclerotic lesion, leading to the obstruction of dialated arteries. Designing advanced biotherapeutic material coated intravascular stents for promoting re-endothelialization of damaged stented arteries may offer a promising alternative therapy to the widely used drug eluting (DES) and bare metal stents 2-8 . DES and metal stents are currently limited by incomplete endothelial recovery due to antiproliferative drugs, inadvertent side effects 9-11 , and increased risk of late-stent thrombosis 12 . Recent studies have demonstrated the importance of such nano-biomaterials to develop new biotherapeutics which have the unique features to restore the natural vascular biology by promoting natural healing in contrary to the DES 13-19 . Such technologies have the unique potential to promote localized and sustained delivery of biomolecules, such as therapeutic genes, to the damaged arterial wall using the stent surface as the permanent scaffold structure and reservoir for prolonged arterial gene delivery 20-22 . In addition, recombinant baculovirus entrapment to the stent surface allows for increased local concentration of therapeutic agent at the targeted arterial segment without distal spread to non-target tissue, thereby avoiding systemic toxicity and increasing the chance of effective gene transfection to adjacent cells.

Interactive cardiovascular and thoracic surgery, 2008

Transvenous coronary sinus lead placement is currently the standard approach for left ventricular... more Transvenous coronary sinus lead placement is currently the standard approach for left ventricular pacing. The aim of this study is to assess whether a mini-thoracotomy approach would be feasible and safe when used for cases in which transvenous procedures were ineffective or judged unlikely to succeed. Biventricular pacing was performed in 138 consecutive patients with 47 patients undergoing a mini-thoracotomy procedure. NYHA status, quality of life, electrical and echocardiographic data were assessed in the two groups over a follow-up period of 17.6+/-4.2 weeks. There was no significant difference in the preoperative characteristics in both groups other than a greater prevalence of renal failure and previous cardiac surgery among the surgical patients. The mean procedure time was significantly longer in the transvenous group. No significant differences were noted in the immediate or long-term pacing parameters. Two mortalities were observed in the surgical group >2 weeks followi...

Regenerative medicine, 2009

Stem cells have the unique properties of self-renewal, pluripotency and a high proliferative capa... more Stem cells have the unique properties of self-renewal, pluripotency and a high proliferative capability, which contributes to a large biomass potential. Hence, these cells act as a useful source for acquiring renewable adult cell lines. This, in turn, acts as a potent therapeutic tool to treat various diseases related to the heart, liver and kidney, as well as neurodegenerative diseases such as Parkinson's and Alzheimer's disease. However, a major problem that must be overcome before it can be effectively implemented into the clinical setting is a suitable delivery system that can retain an optimal quantity of the cells at the targeted site for a maximal clinical benefit; a system that will give a mechanical as well as an immune protection to the foreign cells, while at the same time enhancing the yields of differentiated cells, maintaining cell microenvironments and sustaining the differentiated cell functions. To address this issue we opted for a novel delivery system, ter...

Journal of Trauma-injury Infection and Critical Care, 1991

Transvenous coronary sinus lead placement is currently the standard approach for left ventricular... more Transvenous coronary sinus lead placement is currently the standard approach for left ventricular pacing. The aim of this study is to assess whether a mini-thoracotomy approach would be feasible and safe when used for cases in which transvenous procedures were ineffective or judged unlikely to succeed. Biventricular pacing was performed in 138 consecutive patients with 47 patients undergoing a mini-thoracotomy procedure. NYHA status, quality of life, electrical and echocardiographic data were assessed in the two groups over a follow-up period of 17.6"4.2 weeks. There was no significant difference in the preoperative characteristics in both groups other than a greater prevalence of renal failure and previous cardiac surgery among the surgical patients. The mean procedure time was significantly longer in the transvenous group. No significant differences were noted in the immediate or long-term pacing parameters. Two mortalities were observed in the surgical group )2 weeks followi...

The Journal of Thoracic and Cardiovascular Surgery, Dec 1, 1996

The Journal of extra-corporeal technology, 2004

European Journal of Cardio-Thoracic Surgery, 2003

The Journal of Thoracic and Cardiovascular Surgery, 2006

The Open Cardiovascular Medicine Journal, 2007

The Annals of Thoracic Surgery, 2001

American Journal of Physiology - Regulatory, Integrative and Comparative Physiology, 2016

Vascular and Endovascular Surgery, 1994

Stem Cells and Cloning: Advances and Applications, 2015

Interactive CardioVascular and Thoracic Surgery, 2009

Cardiovascular Engineering and Technology, 2010

Scientific Reports, 2013

Interactive cardiovascular and thoracic surgery, 2008

Regenerative medicine, 2009

Journal of Trauma-injury Infection and Critical Care, 1991

Transvenous coronary sinus lead placement is currently the standard approach for left ventricular... more Transvenous coronary sinus lead placement is currently the standard approach for left ventricular pacing. The aim of this study is to assess whether a mini-thoracotomy approach would be feasible and safe when used for cases in which transvenous procedures were ineffective or judged unlikely to succeed. Biventricular pacing was performed in 138 consecutive patients with 47 patients undergoing a mini-thoracotomy procedure. NYHA status, quality of life, electrical and echocardiographic data were assessed in the two groups over a follow-up period of 17.6"4.2 weeks. There was no significant difference in the preoperative characteristics in both groups other than a greater prevalence of renal failure and previous cardiac surgery among the surgical patients. The mean procedure time was significantly longer in the transvenous group. No significant differences were noted in the immediate or long-term pacing parameters. Two mortalities were observed in the surgical group )2 weeks followi...