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.

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 > or = 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.

Quality assessment of distal S(2)AS connector anastomosis by 13 MHz epicardial ultrasound.

OBJECTIVE: During application of a distal coronary bypass connector, we employed 13 MHz epicardial ultrasound to evaluate quantitative caliper measurements for vessel size matching and to assess anastomosis quality after connector deployment. METHODS: Two S(2)AS connector anastomoses were constructed on ex vivo pressure-perfused porcine hearts. Epicardial ultrasound measurements of the connector ring and anastomosis were compared to intravascular ultrasound measurement and cast dimensions. In 21 pigs, anastomotic sites with internal diameter of 2.25-3.0mm (internal mammary artery, IMA) and 1.8-2.2mm (left anterior descending coronary artery, LAD) were selected using external caliper and epicardial ultrasound measurements. Anastomoses were visualized and assessed intraoperatively (beating heart, n=21) and at 3 and 6 months' follow-up (explanted heart, n=10 each). RESULTS: Epicardial ultrasound underestimated connector dimension by < or =5% versus intravascular ultrasound and deviated < or =13% from cast dimensions for other anastomotic measurements. Caliper estimates of internal IMA and LAD diameter differed from ultrasound by -3+/-6% and -2+/-7% (mean+/-SD), respectively. Intraoperatively, the anastomotic orifice was flawless in all animals. It remained fully patent at 3 and 6 months by ultrasound, which was confirmed by histology. The connector to LAD percentage diameter stenosis changed from -12+/-5% intraoperatively to -1+/-7% at 3 months and from -5+/-6% intraoperatively to -16+/-13% at 6 months, in the growing pig model. CONCLUSIONS: In the pig, external caliper measurements provided a reliable quantitative estimate of inner graft and coronary diameter for connector size matching. Epicardial 13 MHz ultrasound is a promising method to assess coronary anastomosis quality even when connector metal is present.

Briefly occlusive coronary anastomosis with tissue adhesive.

OBJECTIVE: We assessed the feasibility of a facilitated, briefly occlusive, sutureless coronary anastomosis technique in which side-to-side preglued (octylcyanoacrylate adhesive) bounded walls were opened by a conventional arteriotomy. METHODS: In low-flow (prothrombotic milieu,

Unconventional vessel wall apposition in off-pump porcine coronary artery bypass grafting: low versus high graft flow.

OBJECTIVE: Facilitated coronary anastomosis techniques may involve unconventional vessel wall apposition in contrast to standard intima-intima apposition. We assessed the patency, anastomotic thrombus formation, and intimal hyperplasia of unconventional intima-adventitia apposition versus conventional suturing techniques in beating heart coronary bypass grafting under low versus high graft flow conditions. METHODS: The intima-adventitia (n = 28) and conventional anastomoses (n = 28) were evaluated intraoperatively (n = 56), at 4 hours (n = 20), and at 5 weeks (n = 36) in a new off-pump low-flow (n = 28) and high-flow (n = 28) porcine bypass model (< or = 15 mL/min and about 60 mL/min, respectively). The anastomoses were assigned to the animals by means of randomized stratification and examined by means of flow measurements, angiography, and histology. RESULTS: Mean graft flows in intima-adventitia and in conventional anastomoses were similar (P =.709). All but 1 of 56 anastomoses (low flow conventional) were fully patent at the time of death. At 4 hours, only small platelet depositions were found at the exposed media and adventitia in the unconventional anastomoses. At 5 weeks, little streamlining intimal hyperplasia was found, which was comparable between the anastomoses (P =.600). CONCLUSIONS: In low-flow conditions (< or = 15 mL/min) unconventional intima-adventitia apposition was not detrimental to the internal thoracic-coronary artery anastomosis in the pig. This finding may expand design strategies of facilitated coronary artery bypass anastomosis techniques.

Stapled coronary anastomosis with minimal intraluminal artifact: The S2 Anastomotic System in the off-pump porcine model.

OBJECTIVE: A reliable, easy-to-use, 1-shot anastomotic device will significantly push the barrier for less invasive coronary bypass surgery. The current study was designed to test the safety, efficacy, and early patency of a novel distal anastomotic device. METHODS: The S2 Anastomotic System (iiTech BV, Amsterdam, The Netherlands) was used in 10 consecutive pigs (73 kg) on a mild antiplatelet regimen. In each animal, the device was used to create an internal thoracic artery to left anterior descending bypass on the beating heart. The anastomoses were evaluated intraoperatively (n = 10), at 2 days (n = 2), and at 5 weeks (n = 8) by functional flow measurements, postmortem angiography, and histomorphologic examination. RESULTS: In all pigs, the S2 Anastomotic System rapidly created successful anastomoses at the first attempt (graft loading and coronary ischemia time: 1.2 +/- 0.3 minutes and 3.0 +/- 0.6 minutes) on target vessels of 1.6 to 2 mm inner diameter. There were no technical failures or anastomotic leaks requiring additional sutures. Both intraoperatively and at the time of death, ischemically induced peak hyperemic flow responses demonstrated widely patent bypasses, which were confirmed by postmortem angiography (FitzGibbon grade A, n = 10) and macroscopic evaluation (anastomotic orifice: 2 mm). Histomorphologic evaluation showed a normal healing response with negligible neointima covering the connector and limited streamlining repair tissue formation between the staple-like elements of the connector. CONCLUSIONS: The S2 Anastomotic System consistently created automated, fast, and reliable internal thoracic to coronary artery anastomoses on the porcine beating heart with excellent graft patency and healing characteristics at the 5-week follow-up.

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.

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.

Transmural differences in myocardial function and metabolism during direct left ventricular to coronary artery sourcing.

BACKGROUND: We investigated the hypothesis that in the absence of collateral circulation, a left ventricle-coronary artery (LV-CA) bypass will maintain normal LV wall function and metabolism transmurally, both at rest and during stress, when the left anterior descending coronary artery (LAD) is acutely occluded proximally. METHODS: In 18 anesthetized pigs (74 +/- 7 kg, mean +/- standard deviation), a covered stent was placed transmurally in the lateral wall of the beating LV and connected to the proximal LAD via an arterial graft. Subepicardial and subendocardial segmental shortening as well as interstitial lactate and glucose concentrations were measured regionally by sonomicrometry and microdialysis, respectively. RESULTS: When the LAD was occluded proximally, direct left ventricular sourcing decreased the net LAD flow to 64 +/- 25% of the native flow (n = 18, all animals). In the subepicardium, systolic shortening (SS) decreased to 87 +/- 18% of baseline (p = 0.124), with the appearance of minor postsystolic shortening (PSS), and minor changes in interstitial lactate and glucose levels. In the subendocardium, in contrast, SS decreased to 54 +/- 20% (p = 0.001). Marked PSS concurred with a sixfold increase in lactate (p = 0.008), and a 65 +/- 31% decrease in glucose (p = 0.003), indicating subendocardial anaerobic metabolism. Stress induced by infusion of dobutamine increased lactate and decreased glucose concentration in the subepicardium to subendocardial levels, indicating transmural anaerobic metabolism. CONCLUSIONS: In the anesthetized pig, direct sourcing by a LV-CA bypass distal to an acute coronary occlusion resulted in a 36% decrease in net forward coronary flow, subendocardial anaerobic metabolism, and loss of subendocardial contractile function at rest. These adverse effects extended into the subepicardium when the heart was stressed.

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.