Hirotsugu Hamamoto

Allogeneic Mesenchymal Precursor Cell Therapy to Limit Remodeling After Myocardial Infarction : The Effect of Cell Dosage

BACKGROUND This experiment assessed the dose-dependent effect of a unique allogeneic STRO-3-positive mesenchymal precursor cell (MPC) on postinfarction left ventricular (LV) remodeling. The MPCs were administered in a manner that would simulate an off-the-self, early postinfarction, preventative approach to cardiac cell therapy in a sheep transmural myocardial infarct (MI) model. METHODS Allogeneic MPCs were isolated from male crossbred sheep. Forty-six female sheep underwent coronary ligation to produce a transmural LV anteroapical infarction. One hour after infarction, the borderzone myocardium received an injection of 25, 75, 225, or 450 x 10(6) MPCs, or cell medium. Echocardiography was performed at 4 and 8 weeks after MI to quantify LV end-diastolic (LVEDV) and end-systolic volumes (LVESV), ejection fraction (EF), and infarct expansion. CD31 and smooth muscle actin (SMA) immunohistochemical staining was performed on infarct and borderzone specimens to quantify vascular density. RESULTS Compared with controls, low-dose (25 and 75 x 10(6) cells) MPC treatment significantly attenuated infarct expansion and increases in LVEDV and LVESV. EF was improved at all cell doses. CD31 and SMA immunohistochemical staining demonstrated increased vascular density in the borderzone only at the lower cell doses. There was no evidence of myocardial regeneration within the infarct. CONCLUSION Allogeneic STRO-3 positive MPCs attenuate the remodeling response to transmural MI in a clinically relevant large-animal model. This effect is associated with vasculogenesis and arteriogenesis within the borderzone and infarct and is most pronounced at lower cell doses.

Mild Hypothermia to Limit Myocardial Ischemia-Reperfusion Injury: Importance of Timing

BACKGROUND Hypothermia during ischemia has been shown to reduce myocardial reperfusion injury. We sought to establish the cardioprotective effect of very mild total-body hypothermia (<or= 2.5 degrees C) and to determine whether the application of hypothermia at different points during the ischemia-reperfusion period influenced the degree of myocardial salvage. METHODS Rabbits were subjected to 30 minutes of myocardial ischemia followed by 3 hours of reperfusion. Twenty-five animals were maintained at normal temperature (39.5 degrees C) throughout the experiment (W-W-W group). All other animals were cooled to reduce left atrial temperature 2.0 degrees C to 2.5 degrees C. Eleven animals reached goal temperature before coronary occlusion (C-C-C group), in 14 animals cooling was initiated at coronary occlusion (W-C0-C group), in 8 animals cooling was initiated 15 minutes after coronary occlusion (W-C15-C group), in 5 animals cooling was initiated 25 minutes after coronary occlusion (W-C25-C group), and in 13 animals cooling was started concurrently with reperfusion (W-W-C group). Infarct size as a percentage of the risk area (I/AR) was determined by a double staining-planimetry technique. RESULTS Goal temperature was achieved before reperfusion in the C-C-C and W-C0-C groups but was not achieved until the reperfusion period in the other treatment groups. Infarct size was 59.0 +/- 1.2% in the W-W-W group and was reduced in all cooling groups (C-C-C = 30.4 +/- 4.9%; W-C0-C = 33.4 +/- 5.0%; W-C15-C = 42.4 +/- 1.4%; W-C25-C = 44.1 +/- 2.3%; W-W-C = 50.5 +/- 4.1%). The temperature at reperfusion correlated most strongly with infarct size (r = 0.72, p < 1 x 10(-12)). CONCLUSIONS Very mild hypothermia affords a significant cardioprotective effect. Temperature at the time of reperfusion most strongly correlates with the degree of myocardial salvage.

Very Mild Hypothermia During Ischemia and Reperfusion Improves Postinfarction Ventricular Remodeling

BACKGROUND Mild hypothermia (< 4 degrees C) improves myocardial salvage after infarct reperfusion in animals and in early clinical studies. In this experiment the effect of mild hypothermia during ischemia and early reperfusion on long-term postinfarction left ventricular (LV) remodeling was assessed in an ovine infarct model. METHODS In the initial phase of the experiment the effect of progressive degrees of hypothermia on infarct size was quantified. Thirty-eight male sheep were subjected to 1 hour of ischemia using a standardized anteroapical infarct followed by 3 hours of reperfusion. Temperature was maintained at either 39.5 degrees C (n = 11), 38.5 degrees C (n = 7), 37.5 degrees C (n = 7), 36.5 degrees C (n = 7), or 35.5 degrees C (n = 6) for the entire period of ischemia and reperfusion. The area at risk (AR) and infarct size as a percentage of AR (I/AR) were determined with a double staining and planimetry technique. In the second phase of the study, chronic post-infarction remodeling was assessed in animals with nonreperfused infarcts (n = 6), 1 hour of ischemia followed by reperfusion at 39.5 degrees C (n = 6) and 1 hour of ischemia followed by reperfusion at 37.5 degrees C (n = 6). Remodeling was determined at 8 weeks after infarction using echocardiography. RESULTS The I/AR in the 39.5 degrees C, 38.5 degrees C, 37.5 degrees C, 36.5 degrees C, and the 35.5 degrees C groups was 71.8 +/- 3.0%, 63.1 +/- 1.9%, 49.4 +/- 1.4%, 38.7 +/- 1.4%, and 21.7 +/- 2.2%, respectively (p < 0.05 between all groups). In the chronic study LV end systolic volume at 8 weeks after infarction was 81 +/- 8 mL in the nonreperfused group, 57 +/- 4 mL in the 39.5 degrees C reperfusion group, and 41 +/- 3 mL in the 37.5 degrees C reperfusion group (p < 0.05 for between group differences). CONCLUSIONS Subtle degrees of hypothermia can significantly improve immediate myocardial salvage and long-term LV remodeling after infarct reperfusion.

Regional Heterogeneity of Myocardial Reperfusion Injury: Effect of Mild Hypothermia

BACKGROUND Mild hypothermia confers a myocardial protective effect that may make it a useful adjunct to reperfusion therapy for myocardial infarction (MI). The effect of temperature on the extent and distribution of myocardial reperfusion injury in a collateral deficient ovine model was studied. METHODS Topical cooling maintained left atrial temperature at 39.5 degrees C (n = 8), 38.5 degrees C (n = 5), 37.5 degrees C (n = 6), 36.5 degrees C (n = 6), or 35.5 degrees C (n = 5) in sheep prior to 1 hour of coronary occlusion to produce an anteroapical myocardial risk area (AR) followed by 3 hours of reperfusion. A dual staining and planimetry technique was used to assess infarct size as a percentage of the AR in 3 myocardial short axis slices that included the entire AR (slice 1= most apical; slice 3= most basal). The subendocardial, midmyocardial, and subepicardial extent in short axis of the infarct was also assessed in each slice. Microspheres assessed transmural blood flow. RESULTS At 39.5 degrees C there was a long-axis gradient in myocardial injury that was most severe at the apex and lessened toward the base. The midmyocardial region was most susceptible to injury at all long axis levels. Temperature reduction (as little as 1 degrees C) was associated with improved salvage that was most pronounced in the apical subendocardium and least in the basilar midmyocardium. Reperfusion at 39.5 degrees C resulted in severe transmural microvascular injury (no-reflow) that was completely obviated at temperatures below 38.5 degrees C. CONCLUSIONS Myocardial reperfusion injury varies over the long and short LV axes. Mild hypothermia preferentially improves myocardial salvage at the LV apex. Small temperature changes can dramatically affect microvascular integrity.

Limb ischemia and reperfusion during abdominal aortic aneurysm surgery

PurposeAbdominal aortic aneurysm (AAA) surgery involves ischemia and reperfusion of the lower extremities, but assessing the pathophysiological changes is difficult. We evaluated the extent and time course of ischemia–reperfusion injury of the lower extremities during AAA surgery.MethodsTo monitor oxygen metabolism, two near-infrared spectroscopy (NIRS) probes were positioned on each calf muscle of nine patients undergoing AAA surgery. Lactate and pH were also measured in both iliac veins.ResultsNear-infrared spectroscopy signals responded sensitively to aortic cross-clamping and declamping. Lactate increased gradually and exponentially during aortic cross-clamping, and reconstruction of the first iliac artery resulted in a further but transient increase in ipsilateral venous lactate. The time course of the pH level after declamping was almost a mirror image of that of lactate. Reconstruction of the first iliac artery did not affect the contralateral NIRS signals, lactate, or pH.ConclusionsNear-infrared spectroscopy may be useful for monitoring limb ischemia during AAA surgery. The transient increase in lactate and the transient decrease in pH after first declamping may contribute to the mechanism of declamping shock. The fact that first declamping did not affect measurements on the other side shows that contralateral ischemia progresses steadily after reconstruction of the first iliac artery. Therefore, reconstruction of the second iliac artery should be done as soon as possible.

Targeted Regional Injection of Biocomposite Microspheres Alters Post–Myocardial Infarction Remodeling and Matrix Proteolytic Pathways

Background— Although localized delivery of biocomposite materials, such as calcium hydroxyapatite (CHAM), have been demonstrated to potentially attenuate adverse left ventricular (LV) remodeling after myocardial infarction (MI), the underlying biological mechanisms for this effect remain unclear. This study tested the hypothesis that targeted CHAM injections would alter proteolytic pathways (matrix metalloproteinases [MMPs] and tissue inhibitors of MMPs [TIMPs]) and would be associated with parameters of post-MI LV remodeling. Methods and Results— MI was induced in adult sheep followed by 20 targeted injections of a total volume of 1.3 mL (n=6) or 2.6 mL of CHAM (n=5) or saline (n=13) and LV end-diastolic volume (EDV) and MMP/TIMP profiles in the MI region were measured at 8 weeks after MI. LV EDV decreased with 2.6 mL CHAM versus MI only (105.4±7.5 versus 80.6±4.2 respectively, P<0.05) but not with 1.3 mL CHAM (94.5±5.0, P=0.32). However, MI thickness increased by 2-fold in both CHAM groups compared with MI only (P<0.05). MMP-13 increased 40-fold in the MI only group (P<0.05) but fell by >6-fold in both CHAM groups (P<0.05). MMP-7 increased approximately 1.5-fold in the MI only group (P<0.05) but decreased to referent control values in both CHAM groups in the MI region (P<0.05). Collagen content was reduced by approximately 30% in the CHAM groups compared with MI only (P<0.05). Conclusions— Differential effects on LV remodeling and MMP/TIMP profiles occurred with CHAM. Thus, targeted injection of a biocomposite material can favorably affect the post-MI remodeling process and therefore holds promise as a treatment strategy in and of itself, or as a matrix with potentially synergistic effects with localized pharmacological or cellular therapies.

Effect of Prostaglandin E1 on Ischemia–Reperfusion Injury During Abdominal Aortic Aneurysm Surgery

ObjectiveAbdominal aortic aneurysm (AAA) surgery subjects the lower extremities to ischemia and reperfusion. Although it is not extensive or prolonged, ischemia of the lower extremities during aortic cross-clamping is gradually and steadily induced. We studied the effects of prostaglandin E1 (PGE1) on ischemia–reperfusion injury of the lower extremities during AAA repair.MethodsDuring AAA surgery, two near-infrared spectroscopy probes were positioned on each calf muscle to monitor oxygen metabolism in the lower extremities. We also measured lactate concentration in both iliac veins.ResultsNear-infrared spectroscopy signals responded sensitively to aortic cross-clamping and declamping. Lactate increased time-dependently during aortic cross-clamping. The continuous venous administration of PGE1 (20 ng/kg per minute) inhibited the accumulation of lactate during aortic cross-clamping. Declamping of the first iliac artery resulted in a further but transient increase in ipsilateral venous lactate, which may be one component in the mechanism of declamping shock. Prostaglandin E1 eliminated the transient increase in ipsilateral lactate. The administration of PGE1 inhibited the contralateral accumulation of lactate after first declamping, and the lactate level decreased gradually before the second declamping.ConclusionsProstaglandin E1 seems to have a protective effect against ischemia–reperfusion injury of the lower extremities during AAA surgery.

An easy, safe, and sure way of open stent grafting: chain-stitch bonding with a balloon catheter.

A modified transaortic graft insertion technique with a nephrostomy balloon catheter is presented herein. The graft, which has a Z stent at its end, is bound to the catheter with a chain stitch and then is inserted into the descending aorta under transesophageal echographic observation. Unlacing the chain stitch easily deploys the stented graft. This technique is safer and more reliable than other current methods.

Successful open stent grafting of a right aortic arch and a descending aortic aneurysm originating from a Kommerell's diverticulum: Report of a case

Abstract The case of a 43-year-old man found to have an aneurysm developing from a Kommerells diverticulum at the origin of an aberrant retroesophageal left subclavian artery is reported herein. The aneurysm was treated by the open stent grafting technique and complete revascularization was achieved.

An implantation of DDD epicardial pacemaker through ministernotomy in a patient with a superior vena cava occlusion.

SAKO, H., et al.: An Implantation of DDD Epicardial Pacemaker Through Ministernotomy in a Patient with a Superior Vena Cava Occlusion. We successfully implanted a DDD epicardial pacemaker through a limited lower sternotomy in a patient whose superior vena cava had been occluded. Both epicardial leads were connected to the generator placed in the existing subcutaneous pocket on the left pectoral region through the second intercostal space. This approach provided excellent exposure and easy access to both the right appendage and the right ventricle. The combined procedure of epicardial DDD pacemaker implantation through a limited lower sternotomy with placement of the generator in the pectoral subcutaneous pocket is one of the better methods when intravenous lead implantation is difficult. (PACE 2003; 26:778–780)