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Eur J Cardiothorac Surg 2006;29:736-741
© 2006 Elsevier Science NL

Effects of purified poloxamer 407 gel on vascular occlusion and the coronary endothelium

Munir Boodhwani, Jun Feng, Shigetoshi Mieno, Basel Ramlawi, Neel Sodha, Richard Clements, Frank W. Sellke *

Division of Cardiothoracic Surgery, Harvard Medical School, Beth Israel Deaconess Medical Center, 110 Francis Street, LMOB 2A, Boston, MA 02215, United States

Received 30 August 2005; received in revised form 24 January 2006; accepted 9 February 2006.

* Corresponding author. Tel.: +1 617 632 8385; fax: +1 617 632 8387. (Email: fsellke{at}bidmc.harvard.edu).


   Abstract
Top
 Abstract
1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A
 References
 
Objective: Vascular occlusion during off-pump coronary surgery often results in sub-optimal visualization and endothelial damage of the target vessel. We have previously reported the safety of purified poloxamer 407, a gel with reverse thermosensitive properties, in a model of off-pump coronary occlusion. The aim of this study was to evaluate different gel concentrations and their effects on coronary occlusion time, myocardial contractility, endothelial function, and markers of myocardial injury and apoptosis. Methods: Yorkshire swine (30–35 kg) underwent sternotomy and mid-LAD occlusion using either microvascular clamps (n = 6) or varying quantities of three different concentrations (20%; n = 6, 22.5%; n = 3, and 25%; n = 3) of purified poloxamer 407 gel. Distal LAD flow, left ventricular pressure, and in vitro microvascular reactivity were assessed. Molecular markers of myocardial injury and apoptosis were assessed using Western blotting. Results: Duration of ischemia correlated significantly with the amount of injected gel for the 20% and 22.5% formulations (Spearman r = 0.64, p = 0.02 and r = 0.85, p = 0.03, respectively) but not for the 25% gel (r = 0.22, p = 0.66). There were no significant differences in LV contractility (maximum + dp/dt) (p = 0.86) as well as LAD flow (p = 0.25) during reperfusion in the four groups. Microvessel relaxation to adenosine diphosphate in the ischemic territory was impaired with higher concentrations of the gel, 22.5% (–14.8 ± 7.5% vs control at 10–5 mol/L, p < 0.05) and 25% gel (–24.0 ± 7.6% vs control at 10–5 mol/L, p < 0.001) but not with the 20% gel. Endothelium-independent relaxation to sodium nitroprusside was preserved in all groups. Cleaved poly(ADP-ribose) polymerase, a marker of myocardial injury and apoptosis, was elevated in the ischemic myocardium in all groups (p = 0.02 vs non-ischemic myocardium) with no significant differences between the groups (p = 0.70). Phosphorylation of Bad, an anti-apoptotic protein, was significantly reduced in the ischemic territory (p = 0.04). No changes were observed in other markers of myocardial apoptosis. Conclusions: Purified poloxamer 407 gel is effective for temporary coronary vascular occlusion. Coronary artery occlusion time is related to gel concentration and the quantity of gel injected. The higher gel concentrations may cause endothelial dysfunction of the distal vasculature and therefore should be avoided.

Key Words: Off-pump • Biomaterials • Endothelium • Coronary artery bypass grafts • CABG • Apoptosis


   1. Introduction
Top
 Abstract
 1. Introduction
2. Materials and methods
 3. Results
 4. Discussion
 Appendix A
 References
 
Despite the demonstrated efficacy of conventional on-pump coronary artery bypass grafting, off-pump coronary artery bypass grafting (CABG) offers advantages in certain patient populations [1]. The creation of a motionless and bloodless surgical field for the construction of coronary anastomoses remains a significant challenge in off-pump coronary surgery. Numerous techniques and devices, currently in use, are limited by their lack of efficacy and the potential to damage the endothelium. These include microvascular clamps, snare sutures, intra-coronary shunts, and gas jet blowers. We have previously demonstrated the feasibility of a novel gel, purified poloxamer 407, with reverse thermosensitive properties for coronary vascular occlusion in a porcine model [2].

Purified poloxamer 407 gel is part of a family of water soluble poloxamers, which possess reverse thermosensitive properties at certain concentrations [3]. Therefore, at room temperature, the gel is a thin liquid and when injected into a blood vessel, it comes into contact with warmer surroundings and becomes a hard gel plug. Over time, this gel plug dissolves in the bloodstream, reperfusing the previously occluded vessel. The dissolution time of the gel is an important property, especially in the context of controlled vascular occlusion as in off-pump surgery. The dissolution time is determined by a number of variables, the most important of which include gel concentration, amount of gel used, and surrounding temperature. In this study, we evaluated the effect of varying concentrations of purified poloxamer 407 on coronary occlusion time, left ventricular (LV) contractility, and endothelial function. In addition, we assessed myocardial expression of molecular markers of injury and apoptosis in a swine model of off-pump coronary vascular occlusion.


   2. Materials and methods
Top
 Abstract
 1. Introduction
 2. Materials and methods
3. Results
 4. Discussion
 Appendix A
 References
 
2.1 Animals
Animals were housed individually and provided with laboratory chow and water ad libitum. All experiments were approved by the Beth Israel Deaconess Medical Center Animal Care and Use Committee and the Harvard Medical Area Standing Committee on Animals (Institutional Animal Care and Use Committee) and conformed to the US National Institutes of Health guidelines regulating the care and use of laboratory animals (National Institutes of Health publication 5377-3; 1996). A total of 18 animals were used and each animal underwent two cycles of ischemia and reperfusion as described in the following sections. The animals were allocated to treatment groups as follows: control (n = 6), 20% gel (n = 6), 22.5% gel (n = 3), and 25% gel (n = 3).

2.2 Surgical procedure
Yorkshire swine (30–35 kg) were anesthetized with ketamine hydrochloride (20 mg/kg, i.m.) and xylazine (15 mg/kg, i.m.). After cannulation of the ear vein, they were intubated with a cuffed endotracheal tube and mechanically ventilated. Anesthesia was maintained using isoflurane gas throughout the procedure. The femoral artery was cannulated for arterial pressure monitoring and a median sternotomy was performed. A catheter-tipped manometer was introduced through the LV apex for pressure measurement and a 2 mm ultrasonic coronary flow probe (Transonic Systems Inc., Ithaca, NY, USA) was placed distal to the site of LAD occlusion. The animals were heparinized (100 u/kg, i.v.) and given lidocaine (1.5 mg/kg, i.v.). In the treatment groups, occlusion of the mid-LAD was performed by direct injection of purified poloxamer 407 (Pluromed Inc., Lincoln, MA, USA) using a 27-gauge needle in varying amounts (100–300 µL). Three different concentrations of gel were used: 20% (n = 6), 22.5% (n = 3), and 25% (n = 3). Upon contact with the warmer surrounding, the gel solidified causing LAD occlusion, and was allowed to dissolve spontaneously. In cases of persistent ventricular arrhythmias, ice was applied to the LAD artery at the injection site, which led to immediate liquefying of the gel and resumption of LAD flow. In the control group (n = 6), an atraumatic microvascular clamp (Micro DeBakey Bulldog Clamp, Biomedical Research Instruments, Malden, MA, USA) was used to induce 10 min of ischemia. This was followed by 30 min of reperfusion, and two cycles of ischemia and reperfusion were performed in each animal. At the end of the procedure, the animal was euthanized and the heart was harvested.

2.3 Left ventricular contractility and coronary flow
Left ventricular contractility was determined using a catheter-tipped manometer placed in the LV via the apex and measurements were taken at 5 min intervals during ischemia and reperfusion. Data were analyzed, as previously described [4], using CardioSoft (Sonometrics Corporation, London, Canada) to determine the maximum positive dp/dt (first derivative of LV pressure) normalized to baseline. Coronary flow was measured using a 2 mm ultrasonic flow probe (Transonic Systems Inc.) and was recorded at 5 min intervals.

2.4 Coronary microvessel studies
Coronary arterioles (60–180 µm internal diameter) were dissected from the LV tissue of the ischemic, distal LAD-dependent region and the non-ischemic circumflex territory region in all animals. Microvessel studies were performed using in vitro organ bath videomicroscopy, as previously described [4], by an observer blinded to treatment assignment. Endothelium-dependent relaxation to adenosine diphosphate (10–9 to 10–4 mol/L) and endothelium-independent relaxation responses to sodium nitroprusside (SNP; 10–9 to 10–4 mol/L) were examined.

2.5 Western blotting for markers of myocardial injury
In order to assess differences in myocardial injury, expression of three markers of early ischemia–reperfusion injury and apoptosis were assessed. Myocardial tissue was obtained at the time of harvest from ischemic LAD and non-ischemic circumflex artery territories, frozen using liquid nitrogen, and stored at –80 °C until processed. Western blotting was performed as previously described [5]. Briefly, whole-cell lysates were isolated from the homogenized myocardial samples with a RIPA buffer (Boston Bioproducts, Worcester, MA, USA) and centrifuged at 12,000 x g for 15 min at 4 °C to separate soluble from insoluble fractions. Protein concentration was measured spectrophotometrically at a 595 nm wavelength with a DC protein assay kit (Bio-Rad, Hercules, CA, USA). Sixty micrograms of total protein was fractionated by 4–12% gradient, SDS–polyacrylamide gel electrophoresis (Invitrogen, San Diego, CA, USA) and transferred to PVDF membranes (Millipore, Bedford, MA, USA). Each membrane was incubated with specific antibodies as follows: anti-VPF antibody (dilution—1:250) (Calbiochem, San Diego, CA, USA), anti-poly(ADP-ribose) polymerase (PARP) antibody (1:1000), anti-apoptosis inducing factor (AIF) antibody (1:1000), anti-Bcl-2 antibody (1:1000), anti-phospho-Bcl-2 antibodies (1:1000), anti-Bad antibody (1:1000), and anti-phospho-Bad antibody (1:2000) (Cell Signaling Technology, Beverly, MA, USA). Then, the membranes were incubated for 1 h in diluted appropriate secondary antibody (Jackson Immunolab, West Grove, PA, USA). Immune complexes were visualized with the enhanced chemiluminescence detection system (Amersham, Piscataway, NJ, USA). Bands were quantified by densitometry of radioautograph films using NIH ImageJ software version 1.33 (National Institutes of Health, Bethesda, MD, USA).

2.6 Statistical analysis
Data are shown as means ± SEM and medians (min, max) as appropriate. Coronary flow, microvessel reactivity, LV contractility, and Western blot data were analyzed using ANOVA or paired t-test as necessary. Statistical analysis was performed and graphs were constructed using GraphPad Prizm 4 (GraphPad Software Inc., San Diego, CA, USA).


   3. Results
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
4. Discussion
 Appendix A
 References
 
All animals successfully underwent the surgical procedure. Injection of the gel led to successful occlusion of the LAD in all animals as determined by the coronary flow measurements as well as cyanosis and blanching of the ischemic territory.

3.1 Coronary occlusion time
The coronary occlusion time increased with increasing concentration of purified poloxamer 407 (Fig. 1 ). The occlusion time significantly correlated with the amount on injected gel for the 20% (Spearman r = 0.64, p = 0.02) and the 22.5% (r = 0.85, p = 0.03) gel concentrations. The 25% gel, on the contrary, resulted in long occlusion times even when small quantities of gel were used and the occlusion time did not correlate with amount of gel injected (r = 0.22, p = 0.66). For a comparable range of gel volumes (75–150 µL), the mean ischemic times were as follows: 20% gel, 11.8 ± 2.0 min; 22.5% gel, 14.3 ± 3.6 min; and 25% gel, 16.2 ± 2.8 min. In cases of persistent ventricular arrhythmias, topical cooling of the occlusion site was successfully used in all cases to dissolve the gel within 5–15 s and resume flow in the LAD.


Figure 1
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  		Fig. 1. Duration of coronary occlusion using varying concentration and amounts of purified poloxamer 407 gel. For the 20% and 22.5% gel, occlusion time significantly correlated with amount injected (Spearman r = 0.64, p = 0.02 and r = 0.85, p = 0.03, respectively). The 25% resulted in prolonged occlusion and did not correlate with amount injected (r = 0.22, p = 0.66) ((Figure 1) denotes ischemic episodes during which gel was dissolved using topical cooling due to persistent arrhythmias).

 
3.2 Coronary flow and LV contractility
The hyperemic response to ischemia was characterized by a transient increase in LAD flow followed by a gradual return to baseline. The flow patterns were similar in all groups (p = 0.25) with an average maximal flow increase of 7.9 ± 0.8 fold compared to baseline.

Left ventricular contractility was calculated using maximum positive values of dp/dt (first derivative of LV pressure), normalized to baseline and is presented in Fig. 2 . Baseline measurements were similar in all groups. LV contractility was depressed during ischemia (–10.1 ± 1.5%, p < 0.001 vs baseline) and recovered completely during reperfusion (+1.9 ± 1.5%, p = 0.21 vs baseline). There were no significant differences in LV contractility between the groups (overall p = 0.86).


Figure 2
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  		Fig. 2. There were no significant differences in LV contractility between groups (overall p = 0.86) (A). Left ventricular contractility (maximum + dp/dt) was reduced during ischemia (p < 0.001 vs baseline) and normalized during reperfusion (p = 0.21 vs baseline) (B).

 
3.3 Microvessel relaxation studies
The results of the microvessel relaxation studies are displayed in Fig. 3 . Endothelium-independent relaxation response to sodium nitroprusside was preserved in all groups. In the ischemic LAD territory, the endothelium-dependent relaxation to adenosine diphosphate was similar between the control and the 20% gel groups (+2.6 ± 6.2% vs control at 10–5 mol/L, p = ns), but mildly impaired in the 22.5% (–14.8 ± 7.5% vs control at 10–5 mol/L, p < 0.05) and 25% gel (–24.0 ± 7.6% vs control at 10–5 mol/L, p < 0.01) groups. In the non-ischemic circumflex territory, microvessel responses to ADP were similar in all groups (p = 0.85).


Figure 3
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  		Fig. 3. Microvessel reactivity was similar between treatment and control groups in both ischemic (LAD) and non-ischemic (circumflex) territories to endothelium-independent vasodilator, SNP. Microvessel relaxation in response to endothelium-dependent vasodilator, ADP, was impaired in the ischemic territory in response to the 22.5% (* p < 0.05 vs control) and 25% (** p < 0.001 vs control) gel formulations, but preserved in the 20% group as well as in all groups in the non-ischemic territory.

 
3.4 Molecular markers of myocardial injury
Fig. 4 illustrates the results of the Western blotting. Poly(ADP-ribose) polymerase (PARP) cleavage (expressed as a proportion of total PARP) was significantly increased in the ischemic tissue (19 ± 3% vs 9 ± 3%, p = 0.02), but was not different between the control and gel treated groups (p = 0.70). Phosphorylation of anti-apoptotic protein Bad was significantly decreased in the ischemic territory (p = 0.04) but was not significantly different between treatment and control animals. Expression of vascular permeability factor, apoptosis inducing factor, Bad, BCL-2, and phosphorylated BCL-2 were similar between the ischemic and non-ischemic territories as shown in Fig. 4C.


Figure 4
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  		Fig. 4. Molecular markers of myocardial injury. (A) Poly(ADP-ribose) polymerase (PARP) cleavage (expressed as a percentage of total PARP) was increased in the ischemic myocardium (* p = 0.02) but was not significantly different between groups. (B) Bad phosphorylation, which has anti-apoptotic effects, was decreased in the ischemic territory (** p = 0.04) with no significant differences between treated and control groups. (C) Expression of apoptosis inducing factor (AIF), vascular permeability factor (VPF), Bcl-2, phospho-Bcl-2, and Bad were similar in the ischemic and non-ischemic territories.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
Appendix A
 References
 
In this study, we evaluated the effects of varying concentrations of purified poloxamer 407 on coronary occlusion time, left ventricular function, endothelial function, and molecular indices of myocardial injury. We found that purified poloxamer 407 gel is effective for complete vascular occlusion in this model and is not associated with abnormalities in global LV function. The coronary occlusion time correlated significantly with the amount of gel injected for the lower gel concentrations (20% and 22.5%). However, the 25% gel concentration led to prolonged occlusion times that did not correlate well with the amount of injected gel. In addition, endothelium-dependent coronary microvessel relaxation was impaired with the higher gel concentrations (22.5% and 25%) but not with the 20% gel. Endothelium-independent microvessel relaxation was preserved in all groups. Furthermore, two molecular markers of myocardial injury, namely cleaved PARP and phospho-Bad, were altered in response to myocardial ischemia but were not significantly different between the groups.

Poloxamers are a broad group of non-ionic surfactants [6] widely used in diverse industrial applications. These water-soluble, non-toxic and inert surfactants are copolymers of polyethylene oxidea–polypropylene oxideb–polyethylene oxidea. Their surfactant property has been useful in detergency, dispersion, stabilization, foaming, and emulsification. Previous medical applications have primarily been for cardiovascular indications [7,8]. In particular, poloxamer 407, a polymer with a 70% ratio of polyoxyethylene and 30% polyoxypropylene, shows reverse thermosensitivity [3]; therefore, aqueous polymer solutions above a critical concentration of about 12% are liquid at low temperatures but will gel at higher temperature. This property of the substance can be utilized in the context of controlled vascular occlusion as in off-pump coronary surgery. When the gel is injected into the artery it is in liquid form but upon contact with warmer surroundings, it becomes a hard gel plug occluding the vessel. Over time, the gel plug erodes in blood, as the polymer is highly water-soluble, with the dissolution time depending on the amount of polymer injected, the concentration of the polymer, and the surrounding temperature. Other factors that may affect dissolution time in this setting are the size of the vessel lumen and the presence of collateral vessels.

Poloxamer 407 has a reported acute systemic toxicity greater than 2.25 g/kg, a no-adverse-effect dose of approximately 400 mg/kg in dogs and rats, and possesses neither genotoxic nor mutagenic activity [9]. It is not metabolized and is excreted renally with a half-life of ~25 h. Purified poloxamer 407 has been shown to occlude blood vessels for up to 2 h [10]. In this study, purified poloxamer 407 was used at doses less than 10 µg/kg, which is many orders of magnitude less than the systemic toxic dose and the no-adverse-effect dose. We have previously reported the feasibility of purified poloxamer 407 use for coronary vascular occlusion [2]. The ideal gel formulation would have a predictable dose-dependent effect on the duration of vascular occlusion, provide complete reperfusion without distal embolization, have no adverse effects on ventricular or endothelial function, and should be readily dissolvable if necessary, in case of hemodynamic instability. In this report, we present our findings on the concentration-dependent effects of purified poloxamer 407 gel on ventricular function, coronary occlusion, and the endothelium which may help to design the optimal formulation for clinical use.

Existing techniques and devices used for vascular occlusion are limited by incomplete hemostasis which compromises visibility, potential for endothelial damage of the target vessel and can occasionally be technically difficult to use. External compression devices like snare sutures, which create a tourniquet around the vessel, and microvascular clamps are usually effective except in the setting of severely diseased and calcified arteries. They inevitably cause mechanical trauma to the vessel wall and specifically, the use of clamps can lead to endothelial dysfunction [11]. Although intraluminal shunts offer the advantage of distal perfusion [12], an adequately sized shunt, which provides a bloodless field, can be cumbersome to insert with definite risk of endothelial damage. Gas jet blowers, using either air or carbon dioxide, are also effective methods but carry the risk of air embolism [13]. In addition to their safety and efficacy, the ease with which these techniques can be applied is a major determinant of their use, particularly with a minimally invasive or closed chest approach to coronary artery bypass. Purified poloxamer 407 offers the advantages of complete vascular occlusion without the need for mechanical manipulation of the vessel, provides predictable dose-dependent effects on coronary occlusion and is non-toxic to the endothelium at low gel concentrations, is easy to administer, and is rapidly reversible with topical cooling of the affected area. In our model, higher gel concentrations were associated with prolonged and unpredictable occlusion times and impaired endothelium-dependent microvessel relaxation. Therefore, a 20% gel formulation appears to provide the optimal conditions for use in coronary vascular occlusion and higher gel concentrations, particularly 25%, should be avoided.

Myocardial apoptosis is thought to contribute to impaired myocardial function following ischemia and reperfusion [14] as well as following cardioplegic arrest [15]. In this study, we also examined the effects of short duration of ischemia and reperfusion on indices of myocardial apoptosis. We found that two early markers of the apoptosis were altered following short duration of ischemia and reperfusion with no significant differences between gel-treated and control groups. In response to various forms of injury, particularly ischemia–reperfusion injury, poly(ADP-ribose) polymerase (PARP), a DNA repair enzyme, undergoes cleavage primarily by caspase-3 from its 116 kD native form to an 89 kD fragment and is an early marker of myocardial apoptosis [16]. Bad is part of a family of Bcl-2 proteins, which have pro-apoptotic functions. However, phosphorylation of Bad prevents its binding to Bcl-2, thereby preventing its pro-apoptotic effects [17]. Thus, Bad phosphorylation is anti-apoptotic. In response to ischemia, we found an increase in cleaved PARP and a decrease in Bad phosphorylation in the ischemic territory. These findings suggest that myocardial apoptotic signaling may be activated following even short duration of ischemia and may contribute to the depressed cardiac function occasionally observed following off-pump coronary surgery.

In conclusion, we have demonstrated the feasibility of purified poloxamer 407 use as well as established its efficacy in our model. Furthermore, we have demonstrated potential detrimental effects of higher gel concentrations on coronary occlusion time and the endothelium. Limitations of this model include the disease-free coronary vasculature of the swine, absence of significant collateral circulation, and method of gel delivery into a closed artery. Further evaluation of the efficacy of this gel needs to be performed in clinical settings. However, purified poloxamer 407 has a potentially significant role in off-pump coronary surgery and may overcome limitations of existing technologies.


   Appendix A
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A
References
 
Conference discussion

Dr L. Von Segesser (Lausanne, Switzerland): Did you inject the gel into the perfused vessel or did you clamp it for injection?

Dr Boodhwani : In our model we injected it into the perfused vessel.

Dr Von Segesser : And how can you determine how far it will go into the parts that you cannot cool later; septal arteries, for instance?

Dr Boodhwani : When we inject the gel, it's easy to observe the area in which the gel migrates because the gel has a certain consistency. You can actually palpate it on the artery. Secondly, it has a certain appearance when injected into the artery that allows you to define the limits within which it's grossly visible. It is possible that microscopic quantities of the gel do go into the distal circulation; however, in vitro testing has demonstrated that this gel is completely water-soluble, which we suspect would have no adverse effect. It would simply go through the circulation and eventually be cleared by the kidneys.


   Acknowledgments
 
Financial support for this study was provided, in part, by Pluromed Inc. (Lincoln, MA, USA), along with purified poloxamer 407. This study was also supported by a grant from the National Institutes of Health (HL 46716). Dr Boodhwani and Dr Ramlawi are recipients of the Irving Bard Memorial Fellowship. The authors had full control of study design, implementation, data analysis, and manuscript preparation.


   Footnotes
 
{star} Presented at the joint 19th Annual Meeting of the European Association for Cardio-thoracic Surgery and the 13th Annual Meeting of the European Society of Thoracic Surgeons, Barcelona, Spain, September 25–28, 2005.


   References
Top
 Abstract
 1. Introduction
 2. Materials and methods
 3. Results
 4. Discussion
 Appendix A
 References
 

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  5. Ruel M, Wu GF, Khan TA, Voisine P, Bianchi C, Li J, Laham RJ, Sellke FW. Inhibition of the cardiac angiogenic response to surgical FGF-2 therapy in a Swine endothelial dysfunction model. Circulation 2003;108(Suppl. 1):II335-II340.
  6. Marcel D. Nonionic surfactants: polyoxyalkylene block copolymers. In: Nace V, editor. Surfactant science series. Marcel Dekker, New York; 1996. p. 280..
  7. Maynard C, Swenson R, Paris JA, Martin JS, Hallstrom AP, Cerqueira MD, Weaver WD. Randomized, controlled trial of RheothRx (poloxamer 188) in patients with suspected acute myocardial infarction. RheothRx in Myocardial Infarction Study Group. Am Heart J 1998;135:797-804.[Medline]
  8. O’Keefe JH, Grines CL, DeWood MA, Schaer GL, Browne K, Magorien RD, Kalbfleisch JM, Fletcher Jr. WO, Bateman TM, Gibbons RJ. Poloxamer-188 as an adjunct to primary percutaneous transluminal coronary angioplasty for acute myocardial infarction. Am J Cardiol 1996;78:747-750.[CrossRef][Medline]
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  12. Muraki S, Morris CD, Budde JM, Otto RN, Zhao ZQ, Puskas JD, Guyton RA, Vinten-Johansen J. Preserved myocardial blood flow and oxygen supply–demand balance with active coronary perfusion during simulated off-pump coronary artery bypass grafting. J Thorac Cardiovasc Surg 2002;123:53-62.[Abstract/Free Full Text]
  13. Nollert G, Oberhoffer M, Reichart B, Vicol C. Combination of the HEARTSTRING proximal seal system with a blower mister: a possible source of gas emboli. J Thorac Cardiovasc Surg 2003;126:1192-1194.[Free Full Text]
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