Katsuhiko Nakanishi

Antineutrophil and myocardial protecting actions of a novel nitric oxide donor after acute myocardial ischemia and reperfusion of dogs.

BackgroundIt has recently been demonstrated that myocardial ischemia and reperfusion results in a marked decrease in the release of nitric oxide (NO) by the coronary endothelium. NO may possess cardioprotective properties, possibly related to inhibition of neutrophil-related activities. We tested the hypothesis that a cysteine-containing nitric oxide donor compound, SPM-5185, would reduce infarct size and inhibit neutrophil-related activities (adherence to coronary vascular endothelium, accumulation). Methods and ResultsThe effects of intracoronary infusion of SPM-5185 were investigated in a 5.5-hour model of myocardial ischemia (1 hour) and reperfusion (4.5 hours) (MI-R) in anesthetized, open-chest dogs. SPM-5185 (500 nmol/L) or saline vehicle was infused for 4.5 hours into the left anterior descending coronary artery (LAD) at the time of reperfusion after 1 hour of LAD occlusion. MI-R in dogs receiving saline vehicle resulted in severe myocardial injury characterized by dyskinesis, a profound elevation of plasma creatine kinase, marked myocardial necrosis, and high cardiac myeloperoxidase (MPO) activity in the ischemic and necrotic zones. In contrast, treatment with SPM-5185 resulted in a modest restoration of regional function, a reduction of myocardial necrosis expressed as a percentage of the area at risk (12.5±3.2% versus 41.7±5.4%, P<.001), and significant reductions of MPO activity in the ischemic zone (0.8±0.1 versus 2.5±0.7 U/100 mg tissue, P<.05) and the necrotic zone (1.6±0.2 versus 3.3±0.6 U/100 mg tissue, P<.05). In additional studies, SPM-5185 (500 nmol/L) significantly (P<.001) attenuated the adherence of LTB4-stimulated canine neutrophils to autologous segments of coronary artery and attenuated the neutrophil-induced contraction of isolated coronary arterial rings. ConclusionsSPM-5185 reduces myocardial necrosis and neutrophil accumulation in an acute model of canine myocardial ischemia and reperfusion. This reduction in myocardial cell injury may be partially related to the inhibitory actions of this novel NO donor on neutrophil adherence to the coronary endothelium.

Endothelial and myocardial cell protection by a cysteine-containing nitric oxide donor after myocardial ischemia and reperfusion.

The cardioprotective actions of SPM-5185, a novel cysteine-containing nitric oxide (NO) donor, were investigated in two models of myocardial ischemia-reperfusion (MI-R) injury. In the first study, dogs were subjected to 60 min of left anterior descending (LAD) coronary artery occlusion followed by 270 min of reperfusion. During reperfusion, animals were randomly assigned to receive intracoronary SPM–5185 (500 nM) or the NO-deficient analogue of SPM–5185, SPM–5267 (500 nM). Transmural myocardial blood flow to the ischemic zone was not different between the SPM–5185 group of dogs and the SPM–5267 group (0.04 ± 0.01 and 0.03 ± 0.01 ml/min/g, respectively). Similarly, the area of left ventricular myocardium placed at risk by LAD coronary artery occlusion was equivalent in dogs receiving SPM-5185 (33.6 ± 3%) and SPM–5267 (30.4 ± 2%). However, the necrotic area, expressed as a percentage of the area at risk, was reduced by 70% in the SPM–5185-treated dogs(14.5 ± 4 vs. 47.5 ± 9%; p < 0.001). Furthermore, cardiac myeloperoxidase activity indicated that fewer neutrophils accumulated in the necrotic zone of the SPM–5185-treated dogs. In the second study, dogs were subjected to 30 min of global myocardial ischemia followed by 1 h of cardioplegic arrest and 1 h of reperfusion. SPM–5185 (10 μM) added to the blood cardioplegia solution resulted in a 95 ± 14% post-ischemic recovery of contractile function compared with 36 ± 8% (p < 0.05) in vehicle-treated dogs. Additionally, SPM-5185 treatment completely preserved coronary arterial vasorelaxation to acetylcholine after ischemia and reperfusion and resulted in a 62% reduction in cardiac tissue myeloperoxidase activity (p < 0.05). We conclude that (a) SPM-5185 exerts significant cardioprotection from MI-R injury after regional or global ischemia, and (b) this cardioprotection appears to be related to the inhibition of neutrophil-mediated injury.

Coronary artery endothelial dysfunction after global ischemia, blood cardioplegia, and reperfusion

This study tests the hypothesis that blood cardioplegia (BCP) attenuates endothelial dysfunction related to nitric oxide after global normothermic ischemia, cardioplegic arrest, and reperfusion in anesthetized open-chest dogs placed on cardiopulmonary bypass. The dogs were divided into five groups to identify the time when endothelial injury occurred: group 1 = control without ischemia; group 2 = 45 minutes of normothermic ischemia only; group 3 = 45 minutes of normothermic ischemia plus unmodified reperfusion; group 4 = 45 minutes of ischemia plus intermittent BCP without reperfusion; and group 5 = ischemia plus BCP and reperfusion. In vitro coronary vascular relaxation responses to the nitric oxide stimulator acetylcholine (endothelium-dependent, receptor-dependent), the calcium ionophore A23187 (endothelium-dependent, receptor-independent), and acidified NaNO2 (endothelium-independent) were measured at the end of the protocol. Maximum in vitro coronary vascular responses to acetylcholine were similar among groups 1, 2, and 4, indicating an absence of endothelial injury. In contrast, significantly impaired relaxations to acetylcholine were demonstrated in the two reperfused groups (groups 3 and 5). Relaxation responses to A23187 and NaNO2 were not altered markedly in any group. Electron microscopy showed intact endothelium in groups 1, 2, and 4. However, moderately severe endothelium damage was seen in groups 3 and 5. We conclude that morphologic and functional endothelial damage occurs after blood reperfusion with or without BCP, and 1-hour hypothermic BCP arrest after normothermic ischemia is not associated with extension of endothelial damage.

Does Intensive Management of Cerebral Hemodynamics and Atheromatous Aorta Reduce Stroke After Coronary Artery Surgery

BACKGROUND Atheromatous aorta and carotid artery disease are known predictors for stroke after coronary artery bypass grafting (CABG). The clinical significance of intracranial cerebral artery disease is not known. This study was designed to determine whether a therapeutic strategy based on perioperative detection of intracranial and extracranial occlusive cerebrovascular disease and atheromatous aorta could reduce perioperative stroke. METHODS We studied 485 patients who underwent isolated CABG. The control group was 247 patients who underwent standard-protocol CABG. The 238 subjects in the intervention group underwent preoperative magnetic resonance angiography of the head and neck and intraoperative epiaortic scanning. Cerebral hemodynamics were evaluated by single photon emission computed tomography and acetazolamide tests in patients with significant occlusive cerebrovascular disease. Surgical outcomes were compared. RESULTS In the intervention group, magnetic resonance angiography detected significant intracranial or extracranial occlusive cerebrovascular disease, or both, in 40 patients. Prophylactic cerebrovascular interventions were performed in 7 patients who had disturbed cerebral hemodynamics. Aorta no-touch off-pump coronary artery bypass (OPCAB) was chosen intraoperatively in 37 patients with moderate to severe atheromatous aorta. The in-hospital stroke rate was 0.42% in the intervention group vs 2.8% in the control group (p = .068). A multivariate analysis revealed that the perioperative interventional protocol was the most powerful predictor of reduced risk of perioperative stroke (odds ratio, 0.023; 95% confidence interval, 0.001 to 0.469). CONCLUSIONS Prophylactic cerebrovascular interventions and the selective use of aorta no-touch OPCAB can significantly reduce the incidence of perioperative stroke. Careful vascular evaluation before and during CABG can improve surgical outcomes.

Blood cardioplegia enhanced with nitric oxide donor SPM-5185 counteracts postischemic endothelial and ventricular dysfunction

This study tested the hypothesis that enhancement of blood cardioplegia with the nitric oxide donor agent SPM-5185 inhibits postischemic left ventricular and coronary endothelial dysfunction. Eighteen anesthetized dogs supported by total vented bypass were subjected to 30 minutes of normothermic ischemia followed by 4 degrees C multidose blood cardioplegia. Hearts received either standard blood cardioplegia (vehicle group; n = 6), blood cardioplegia with 1 mumol/L SPM-5185 (low-dose group; n = 6), or 10 mumol/L SPM-5185 (high-dose group; n = 6). After 60 minutes of cardioplegic arrest, the heart was reperfused for a total of 60 minutes, first in the beating empty state for 30 minutes and then after discontinuation of bypass for 30 minutes. Baseline and postischemic left ventricular function was assessed by the slope of the end-systolic pressure-volume (impedance catheter) relation. Postischemic end-systolic pressure-volume relation was depressed by 53.7% of preischemic values in the vehicle group (from 8.2 +/- 1.0 to 3.8 +/- 0.3 mm Hg/ml) and by 33.7% (from 9.2 +/- 1.1 to 6.1 +/- 0.5 mm Hg/ml) in the low-dose group. In contrast, there was complete postischemic functional recovery in the high-dose group (from 7.6 +/- 1.1 to 7.2 +/- 1.2 mm Hg/ml). In coronary arteries isolated from these hearts, endothelium-dependent maximal relaxation to acetylcholine was impaired by 27% in the vehicle group and by 18% in the low-dose group, whereas the high-dose group showed complete endothelium-dependent relaxation. Myeloperoxidase activity, an index of neutrophil accumulation in postischemic myocardium, was elevated in the vehicle and low-dose groups (3.36 +/- 0.58 and 2.56 +/- 0.68 U/100 mg tissue) but was significantly reduced in the high-dose group to 1.27 +/- 0.45 U/100 mg tissue. We conclude that inclusion of 10 mumol/L nitric oxide donor SPM-5185 in blood cardioplegia improves postischemic ventricular performance and endothelial function in ischemically injured hearts, possibly via inhibition of neutrophil-mediated damage.

Adenosine in blood cardioplegia prevents postischemic dysfunction in ischemically injured hearts

Adenosine (ADO) is an endogenous cardioprotective autacoid that exerts receptor-mediated cardioprotection from ischemic-reperfusion injury. This study tested the hypothesis that blood cardioplegia (BCP) supplemented with ADO reduces postischemic left ventricular dysfunction in ischemically injured hearts. Twenty-one anesthetized dogs on total bypass were subjected to 30 minutes of normothermic global ischemia. Cold (4 degrees C) potassium BCP was then delivered every 20 minutes for 60 minutes of cardioplegic arrest. In 7 dogs, unsupplemented BCP was used; in 7 dogs, BCP was supplemented with 400 mumol/L ADO; and, in 7 dogs, ADO receptors were blocked with 8-p-sulfophenyltheophylline (30 mg/kg) given with 400 mumol/L ADO in BCP. Preischemic and postischemic left ventricular systolic function was assessed by the slope and volume axis intercept of the end-systolic pressure-volume (impedance catheter) relationship (ESPVR). In unsupplemented BCP, the postischemic slope of the ESPVR was significantly depressed by 42% versus the preischemic value (from 6.8 +/- 1.2 mm Hg/mL to 3.9 +/- 0.4 mm Hg/mL; p < 0.05 versus the preischemic value). In contrast, BCP supplemented with ADO was found to restore the postischemic ESPVR slope to preischemic levels (7.7 +/- 1.0 mm Hg/mL versus 7.4 +/- 1.2 mm Hg/mL, respectively). This cardioprotection was reversed by 8-p-sulfophenyltheophylline (9.9 +/- 1.5 mm Hg/mL versus 4.5 +/- 0.7 mm Hg/mL; p < 0.05 versus the preischemic value). Postischemic plasma creatinine kinase activity was elevated equally in all groups over the baseline values. We conclude that ADO in BCP attenuates postcardioplegia dysfunction in severely injured hearts through the operation of receptor-mediated mechanisms.

Thoracic Endovascular Aortic Repair for Challenging Aortic Arch Diseases Using Fenestrated Stent Grafts From Zone 0

BACKGROUND Although previous reports have described the repair of distal aortic arch aneurysms through debranching and chimney techniques, these methods invariably involve surgical management of the carotid artery. We report clinical results of thoracic endovascular aortic repair (TEVAR) using fenestrated stent grafts in the treatment of aortic arch aneurysms located less than 15 mm from the left common carotid artery. METHODS A semi-custom-made fenestrated stent graft designed to fit aortic arch tortuosity and preserve blood flow at least into the brachiocephalic and left common carotid arteries was placed from zone 0. RESULTS From 2007 through 2013, TEVAR from zone 0 was performed on 37 high-risk patients for open surgery (mean age 78.2 years). The mean length between the left common carotid artery and aortic aneurysm was 11.1 mm (range, 5 to 15 mm). The left subclavian artery was preserved for 26 patients (70.3%) through surgical reconstruction (n = 19) and graft fenestration (n = 7). The early mortality rate was 0%. Postoperative strokes and spinal cord ischemia occurred in 2 (5.4%) and 3 (8.1%) patients, respectively. Although type I endoleaks at discharge were noted in 12 (32.4%) patients, aneurysm enlargement was noted during follow-up in 6 (16.2%). Four patients (10.8%) underwent secondary interventions consisting of 3 coil embolization procedures; 2 re-TEVARs and 1 open conversion. There were no aorta-related late deaths. Survival and aorta-related event-free rates at 2 years were 86.3% and 88.8%, respectively. CONCLUSIONS Thoracic endovascular aortic repair using fenestrated stent graft from zone 0 can be considered as one of therapeutic options for high-risk patients with aortic arch diseases.

Pentostatin-augmented interstitial adenosine prevents postcardioplegia injury in damaged hearts

This study tests the hypothesis that the adenosine deaminase inhibitor pentostatin (2-deoxycoformycin), when given before ischemia or during infusions of blood cardioplegia, augments interstitial adenosine levels and prevents postcardioplegia dysfunction in hearts with antecedent ischemia. Twenty-one anesthetized dogs were placed on cardiopulmonary bypass, and the hearts were made globally ischemic for 30 minutes. Dogs received blood cardioplegia with no pentostatin (BCP group, n = 6), pretreatment pentostatin (0.2 mg/kg) infused 5 minutes before global ischemia (PS-PTx group, n = 7), or pentostatin included only in the blood cardioplegia without pretreatment (PS-BCP group, n = 8). Microdialysate myocardial adenosine levels (an index of interstitial fluid levels) increased only modestly in the BCP group (from 0.55 +/- 0.13 microM to 2.64 +/- 0.50 microM) and the PS-BCP group (from 0.55 +/- 0.18 microM to 1.08 +/- 0.48 microM) during normothermic ischemia, but interstitial adenosine levels were not augmented further during cardioplegic arrest in either group. In contrast, the adenosine level in the PS-PTx group was significantly (p < 0.05) augmented during global ischemia (from 0.50 +/- 0.13 microM to 63.16 +/- 28.08 microM) and cardioplegia infusion (to 15.26 microM +/- 5.61 microM). Relative to baseline, postischemic left ventricular performance (end-systolic pressure-volume relation) was depressed in both the BCP (from 5.5 +/- 1.2 mm Hg/mL to 3.8 +/- 0.4 mm Hg/mL) and PS-BCP groups (from 7.1 +/- 0.9 mm Hg/mL to 3.8 +/- 0.7 mm Hg/mL). In contrast, PS-PTx restored postischemic performance (from 6.2 +/- 0.5 mm Hg/mL to 7.5 +/- 0.9 mm Hg/mL).(ABSTRACT TRUNCATED AT 250 WORDS)

Aortic root replacement with left main trunk reconstruction using autologous pericardial cuff technique for ostial stenosis in Takayasu's arteritis

A 58-year-old female with Takayasus arteritis was evaluated for congestive heart failure. A transthoracic echocardiogram (TTE) revealed severe aortic regurgitation and aortic root enlargement. Computed tomography (CT) showed a 5.3-cm ascending aorta and aortic root, and occlusionof the left carotidand left subclavianarteries (Figures1Aand1B), and severe circumferential calcification of the ascending aorta and left main trunk (LMT) (Figure 1C). At the time of surgery, cardiopulmonary bypass (CPB) was instituted by cannulating the greater curvature of the ascending aorta and the bicaval drainage. During a period of deep hypothermic circulatory arrest (22 degrees Centigrade) with antegrade cerebral perfusion, the aortic arch was replaced with a 26-mm Gelweave graft (Vascutek, Inchinnan, Scotland) and the innominate artery was reconstructed with a 12-mm Gelweave interposition graft. CPB was reinstituted and the aortic root replaced with a #23-mm St. Jude mechanical composite graft. Because the LMT was circumferentially calcified,acircularpieceofglutaraldehyde-treatedautologouspericardium was preparedwith an 8-mm central orifice and the cuff was anastomosed totheLMTwitha6-0polypropylenesuture (Figure2A).Thisnewlycreated LMTbuttonwas thenanastomosedasapatch to thecomposite graft using a 5-0 polypropylene suture (Figure 2B). The right coronary button, which was not so calcified, was anastomosed directly to the composite graft using a 5-0 polypropylene suture. CPB, aortic cross clamp, cerebral perfusion, and circulatory arrest timeswere 354, 250, 68, and 41min. The patient tolerated the procedure well and had an uncomplicated postoperative course. A postoperative CT revealed a patent LMT ostium (Figure 3), and a TTE showed normal prosthetic valve function.

Postoperative initial 2-day blood pressure management facilitates the shrinkage of abdominal aortic aneurysm after endovascular aneurysm repair by reducing the incidence of type II endoleak

Objective The aim of this study was to evaluate the effect of initial 2‐day blood pressure management (BPM) after endovascular aneurysm repair (EVAR) for the incidence of subsequent type II endoleak (T2E) and shrinkage of abdominal aortic aneurysm (AAA) sac diameter. Methods We reviewed 136 patients who underwent EVAR for atherosclerotic AAA between July 2008 and July 2014 with one of three stent grafts (Excluder [W. L. Gore & Associates, Flagstaff, Ariz], Powerlink [Endologix Inc, Irvine, Calif], and Endurant [Medtronic Vascular, Santa Rosa, Calif]). Starting from 2013, the mean blood pressure of 76 participating patients (treatment group) was maintained at 75 to 90 mm Hg for the initial 48 hours after EVAR. The incidence of T2E at 7 days and AAA sac diameter 12 months after EVAR were evaluated using computed tomography scanning. The results so obtained were then compared with those of the control group composed of 60 consecutive patients who underwent EVAR before 2013. Results The incidence of T2E at 7 days was significantly lower in patients who received treatment (treatment group, 19.7%; control group, 40.0%; P = .013), and AAA sac diameter at 12 months in the treatment group had a mean decrease of 5.1 mm compared with the mean 2.2 mm in the control group (P = .004). In multivariate regression analysis, BPM was significantly related to the reduction of incidence of T2E at 7 days (odds ratio, 0.31; P = .007) and a decrease in AAA sac diameter at 12 months (P = .005). In addition, although the use of Endurant had less effect, the use of Excluder under controlled blood pressure conditions improved the incidence of T2E from 80% to 23% compared with those under normal postoperative management (P = .001). Conclusions The initial 2‐day postoperative BPM might have positive effects, such as lower incidence of T2E and facilitation of AAA sac shrinkage.