Cees W.J. Verlaan

Exenatide Reduces Infarct Size and Improves Cardiac Function in a Porcine Model of Ischemia and Reperfusion Injury

OBJECTIVES This study sought to examine whether exenatide is capable of reducing myocardial infarct size. BACKGROUND Exenatide is a glucagon-like peptide (GLP)-1 analogue with insulinotropic and insulinomimetic properties. Because insulin and GLP-1 have been described as reducing apoptosis, exenatide might confer cardioprotection after acute myocardial infarction (MI). METHODS Pigs were randomized to exenatide or phosphate-buffered saline (PBS) treatment after 75 min of coronary artery ligation and subsequent reperfusion. Infarct size was assessed with Evans Blue (Sigma-Aldrich, St. Louis, Missouri) and triphenyltetrazolium chloride. Cardiac function was measured with epicardial ultrasound and conductance catheter-based pressure-volume loops. Western blotting, histology, and activity assays were performed to determine markers of apoptosis/survival and oxidative stress. RESULTS Exenatide reduced myocardial infarct size (32.7 +/- 6.4% vs. 53.6 +/- 3.9%; p = 0.031) and prevented deterioration of systolic and diastolic cardiac function (systolic wall thickening: 47.3 +/- 6.3% vs. 8.1 +/- 1.9%, p < 0.001; myocardial stiffness: 0.12 +/- 0.06 mm Hg/ml vs. 0.22 +/- 0.07 mm Hg/ml; p = 0.004). After exenatide treatment, myocardial phosphorylated Akt and Bcl-2 expression levels were higher compared with those after PBS treatment, and active caspase 3 expression was lower. In addition, fewer cells were terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling-positive. In addition, nuclear oxidative stress as assessed with an 8-hydroxydeoxyguanosine staining was reduced in the exenatide treatment arm, and superoxide dismutase activity and catalase activity were increased. Serum insulin levels increased after exenatide treatment, without affecting glucose levels. CONCLUSIONS These data identify exenatide as a potentially effective compound to reduce infarct size in adjunction to reperfusion therapy in patients with acute MI.

Vertical Displacement of the Beating Heart by the Octopus Tissue Stabilizer: Influence on Coronary Flow

BACKGROUND In beating heart coronary artery bypass graft operations, biventricular pump failure, as observed after exposure of the posterior circumflex branches by sternotomy, may originate from mechanical obstruction to coronary flow. METHODS Regional coronary blood flow was measured in 8 anesthetized, paced, beta-blocked pigs, and the beating heart was fully retracted. RESULTS Displacement decreased cardiac output from 4.8 +/- 1.1 L/min (mean +/- standard deviation) to 2.8 +/- 1.2 L/min (p < 0.001), a 42% +/- 6% decrease that resulted in a decrease in mean arterial pressure by 48% +/- 6% (mean +/- standard error of the mean; p < 0.001) and a reduction in coronary blood flow in the left anterior descending coronary artery, the right coronary artery, and the circumflex coronary artery by 34% +/- 6%, 25% +/- 8%, and 50% +/- 10%, respectively (all p < 0.05 versus baseline). Relative circumflex coronary artery flow was 20.1% +/- 8.3% lower than the combined relative value of left anterior descending coronary artery and right coronary artery flows (p = 0.046). Subsequent 20 degrees head-down tilt significantly increased ventricular preload pressures and restored cardiac output and mean arterial pressure as well as coronary blood flow. CONCLUSIONS It is inferred that coronary blood flow was not mechanically obstructed during anterior displacement of the porcine beating heart, because augmentation of preloads by the maneuver of Trendelenburg restored coronary flow parallel to the recovery of cardiac output and mean arterial pressure while the heart remained retracted by 90 degrees.

Exposure of circumflex branches in the tilted, beating porcine heart: echocardiographic evidence of right ventricular deformation and the effect of right or left heart bypass.

OBJECTIVE In off-pump coronary surgery, exposure of posterior vessels via sternotomy causes deterioration of cardiac function. Changes in ventricular geometry, valve competence, and hemodynamics after retraction of the beating heart were studied. Subsequently, the modifying effect of right or left heart bypass was investigated. METHODS In six 80-kg pigs, an ultrasound probe was attached to the backside of the left ventricle and the heart was fully retracted with a suction tissue stabilizer. Five pigs underwent additional pump support. RESULTS During retraction, the right ventricle was squeezed between the pericardium and interventricular septum, thereby decreasing its diastolic cross-sectional area by 62% +/- 6% (P <.001) while, concomitantly, right ventricular end-diastolic pressure increased to 165% +/- 19% (P =.004) of basal values. Stroke volume and mean arterial pressure decreased by 29% +/- 6% and 23% +/- 8% (P =.007 and P =.02, respectively). Left ventricular shape became somewhat elliptic without changes in preload pressure, and its diastolic cross-sectional area decreased by 20% +/- 3% (P =.001). All valves were competent. Right heart bypass restored left ventricular cross-sectional area, stroke volume, and mean arterial pressure. In contrast, left heart bypass increased blood pressure only marginally. CONCLUSIONS Ninety-degree anterior displacement of the beating porcine heart caused primarily right ventricular dysfunction as a result of mechanical interference with diastolic expansion without concurring valvular incompetence. Right heart bypass normalized stroke volume and mean arterial pressure by increasing left ventricular preload; in contrast, left heart bypass failed to restore systemic circulation.

Cyclooxygenase-2 Inhibition Increases Mortality, Enhances Left Ventricular Remodeling, and Impairs Systolic Function After Myocardial Infarction in the Pig

Background— Cyclooxygenase (COX)-2 expression in the heart increases after myocardial infarction (MI). In murine models of MI, COX-2 inhibition preserves left ventricular dimensions and function. We studied the effect of selective COX-2 inhibition on left ventricular remodeling and function after MI in a pig model. Methods and Results— Twenty-two pigs were assigned to COX-2 inhibition with a COX-2 inhibitor (COX-2i; celecoxib 400 mg twice daily; n=14) or a control group (n=8). MI was induced by left circumflex coronary artery ligation, and the animals were euthanized 6 weeks later. Cardiac dimensions and function were assessed with echocardiography and conductance catheters. Infarct size and collagen density were analyzed with triphenyltetrazolium chloride staining and picrosirius red staining, respectively. COX-2 inhibition increased mortality compared with controls (50% versus 0%, P=0.022), whereas infarct size was similar (13.1±0.7% versus 14.1±0.1%, P=0.536). The decrease in thickness of the infarcted myocardial wall was more pronounced in the COX-2i group (60.6±9.6% versus 36.2±5.7%, P=0.001). End-diastolic volume was higher in the COX-2i group (133.9±33.5 versus 91.1±24.0 mL; P=0.021), as was the end-systolic volume at 100 mm Hg (81.7±27.8 versus 56.3±21.1 mL; P=0.037), which indicates that systolic function was more severely impaired. Infarct collagen density was lower after COX-2i treatment (25.3±3.9 versus 56.1±23.8 gray value/mm2; P=0.005). Conclusions— In pigs, COX-2 inhibition after MI is associated with increased mortality, enhanced left ventricular remodeling, and impaired systolic function, probably due to decreased infarct collagen fiber density.

Ninety-degree anterior cardiac displacement in off-pump coronary artery bypass grafting: the Starfish cardiac positioner preserves stroke volume and arterial pressure

PURPOSE In off-pump coronary surgery through sternotomy, exposure of posterior circumflex branches causes circulatory deterioration in both patients and pigs. We assessed cardiac pump function when displacing the pig heart anteriorly with a suction cardiac positioner. DESCRIPTION Six pigs (+/-80 kg) underwent sternotomy for hemodynamic instrumentation using catheter-tipped manometers and paced at 80 beats/min. Ultrasound flow probes were placed around the aorta and proximal coronary arteries. The heart was retracted anteriorly to 90 degrees with the Starfish cardiac positioner attached to the apex by means of suction (-400 mm Hg). Retraction was guided by cardiac output monitoring. EVALUATION Anterior displacement to 90 degrees facilitated full exposure of posterior arteries. Stroke volume and mean arterial pressure decreased to 94% +/- 13% (mean +/- SD, p = 0.135) and 95% +/- 13% (p = 0.09) of control values, respectively. Right and left ventricular end-diastolic pressure increased to 129% +/- 37% (p = 0.009) and to 128% +/- 57% (p = 0.235), respectively. Coronary flow remained unchanged. Additional 15-degree head-down positioning increased stroke volume to 113% +/- 17% (p = 0.015) and mean arterial pressure to 113% +/- 25% (p = 0.087) at the expense of further increased right and left ventricular end-diastolic pressure (186% +/- 63%, p < 0.001 and 157% +/- 49%, p < 0.001, respectively). CONCLUSIONS When lifting the porcine heart ninety degrees anteriorly, the Starfish cardiac positioner facilitated exposure of posterior branches and, when guided by cardiac output, preserved stroke volume and arterial pressure.

Coronary end-to-side sleeve anastomosis using adhesive in off-pump bypass grafting in the pig

BACKGROUND In the exploration of facilitated coronary anastomosis strategies, we assessed a new octylcyanoacrylate adhesive in combination with a modified end-to-side sleeve anastomosis in off-pump bypass grafting in the pig. METHODS Sleeve-adhesive anastomoses (n = 20) were evaluated intraoperatively, at 3 days (n = 4), and at 5 weeks (n = 16) in an off-pump, low (< or = 15 mL/min; n = 10) and high flow (approximately 60 mL/min; n = 10) porcine bypass model. All anastomoses were examined by flow measurement, angiography, and histology. RESULTS Anastomosis construction took 8.5 minutes (6.7 to 10.2 minutes; median [15th to 85th percentile]). At 5 weeks, all anastomoses were fully patent (FitzGibbon grade A). The adhesive did not cause impaired vessel wall healing, but was surrounded by a focal acute and limited chronic (foreign body giant cells occasionally seen) inflammatory reaction at the adventitial application site. CONCLUSIONS Octyl-cyanoacrylate tissue adhesive combined with end-to-side internal mammary to coronary artery sleeve anastomosis construction proved to be feasible, even in low bypass graft flow conditions (< or = 15 mL/min; prothrombotic milieu) in the pig and deserves interest in exploration of facilitated anastomosis strategies in coronary artery bypass grafting.

Temporary Luminal Arteriotomy Seal for Bypass Grafting

BACKGROUND To enable off-pump coronary operations in a bloodless surgical field without ischemic complications, we developed and assessed a temporary luminal arteriotomy seal in a porcine carotid artery bypass graft model. METHODS In 16 consecutive pigs (25 kg, 32 anastomoses) the arteriotomy was sealed luminally by a polyurethane elliptic convex seal. Endothelial denudation, medial necrosis, and intimal hyperplasia were measured quantitatively and compared with those seen in conventionally sutured anastomoses. RESULTS The median occlusive time upon insertion or retrieval was 90 and 82 seconds, including the arteriotomy and securing the anastomosis, respectively. Once properly positioned, the seal provided a bloodless arteriotomy in all anastomoses. Microsurgical suturing was performed without leakage of the seal and with unimpeded flow. In the recipient artery, endothelial denudation was limited to one third of its circumference. No medial necrosis was found. Intimal hyperplasia at heel and toe was not significantly different from that seen in conventionally sutured anastomoses. CONCLUSIONS During end-to-side bypass grafting, the temporary luminal arteriotomy seal provided a bloodless surgical field without interfering with recipient artery blood flow and with minimal damage to the arterial wall.

Temporary luminal arteriotomy seal: II. coronary artery bypass grafting on the beating heart

BACKGROUND This study assessed the feasibility of applying a temporary luminal arteriotomy seal during end-to-side coronary artery bypass grafting on the beating heart. METHODS In 18 consecutive pigs, the left internal mammary artery was grafted to the left anterior descending coronary artery, and the arteriotomy was temporarily sealed luminally by a 200-microm-thick polyurethane seal. Endothelial denudation, medial necrosis, and intimal hyperplasia were measured quantitatively and compared with conventionally sutured anastomoses (n=4 pigs). RESULTS Insertion and retrieval of the seal required 28+/-12 and 11+/-6 seconds, respectively. Including the arteriotomy, coronary artery occlusion was limited to about 80 seconds. The seal provided a bloodless arteriotomy in all anastomoses with unimpeded coronary artery blood flow. Endothelial denudation was limited to two thirds of the circumference of the coronary artery. No medial necrosis was found. Intimal hyperplasia at the suture line was small, although more pronounced when compared with conventionally sutured anastomoses. CONCLUSIONS In off-pump, beating-heart coronary artery bypass grafting, the temporary luminal arteriotomy seal provided a bloodless arteriotomy with negligible obstruction to coronary artery blood flow, and with a minimum of arterial wall damage. It is conceivable that this seal may expand the indications for coronary surgical procedures without cardiopulmonary bypass.

Hemodynamic changes with right lateral decubitus body positioning in the tilted porcine heart

BACKGROUND In beating-heart coronary surgical procedures, exposure of posterior vessels through sternotomy causes cardiac function to deteriorate. We hypothesized that turning the subject to the right lateral decubitus position before cardiac retraction improves exposure of posterior vessels and preserves cardiac pump function on displacement. METHODS Eight 80-kg open-chest pigs were instrumented with catheter-tip manometers. After a stepwise 60-degree turn to the right lateral decubitus position of the body, the heart was retracted anteriorly to 90 degrees with a suction stabilizer. RESULTS Right lateral body positioning caused an approximately 45-degree right deviation of the apex, thereby exposing the left atrial groove. Stroke volume, mean arterial pressure, right atrial pressure, and right ventricular end-diastolic pressure increased to 106% +/- 5% (mean +/- standard error of the mean, p = 0.31), 106% +/- 3% (p = 0.01), 129% +/- 8% (p = 0.001), and 171% +/- 14% (p = 0.002), respectively, compared with control values. In contrast, left atrial pressure decreased to 73% +/- 6% (p = 0.007), whereas left ventricular preload remained unchanged (110% +/- 8%, p = 0.26). Additional anterior displacement to 90 degrees fully exposed the posterior vessels, and stroke volume decreased to 90% +/- 3% (p = 0.01) and mean arterial pressure to 93% +/- 5% (p = 0.07) at the expense of further increased right ventricular preload (256% +/- 28%, p < 0.001). CONCLUSIONS By placing the subject in the right lateral decubitus position, exposure through sternotomy of posterior vessels in the beating porcine heart was facilitated while mean arterial pressure was maintained.

S2 Connector Versus Suture Distal Coronary Anastomosis Remodeling, Patency, and Function in the Pig

Background— Anastomotic connectors could be the key to less invasive bypass surgery, including endoscopic procedures, but equivalence to conventional suturing needs to be established. A novel distal coronary connector was tested pre-clinically for safety and efficacy in comparison to conventional suturing. Methods and Results— Left internal thoracic to left anterior descending coronary artery bypasses were constructed off-pump in 35 pigs (73±8 kg). An intraluminal metal connector (S2AS) was used in 21 and conventional suturing in 14 animals. S2AS anastomosis construction was easier achieved in one-fourth of the conventional construction time (3.7±0.7 versus 16.5±2.6 minutes; P<0.001). Acute patency tended to be better (P=0.15). All anastomoses were evaluated intraoperatively, and subgroups at 90 and at 180 days. Patency was 100%. An effective remodeling response was observed in all groups, resulting in unobstructed anastomoses with excellent hemodynamic performance (fractional flow reserve ≥0.93 at 180 days). At 6 months, the noncompliant connector was covered with stabilized neointima that was thinner than found on the suture line (0.10±0.04 versus 0.31±0.13 mm; P=0.01). The connector induced less lumen loss (−0.6±6.5 versus 21.6±19%; P=0.03). The initial side-to-side configuration had remodeled to an end-to-side shape as intended. Conclusions— In the porcine model, the connector rapidly and consistently produced high-quality anastomoses that fully met current standards on patency and function. Unconventional aspects like a noncompliant intraluminal ring and a side-to-side to end-to-side converted configuration did not interfere with favorable anastomosis remodeling. These findings shed a new light on the anatomical prerequisites for anastomosis patency.