The preischemic combination of the sodium-hydrogen exchanger inhibitor cariporide and the adenosine agonist AMP579 acts additively to reduce porcine myocardial infarct size

BACKGROUND: We tested whether the combination of two known cardioprotective agents, the type-1 sodium-hydrogen exchanger inhibitor cariporide plus the adenosine A(1)/A(2a) receptor agonist AMP579 ([1S-[1a,2b,3b, 4a(S*)]]-4-[7-[[2-(3-chloro-2-thienyl)-1-methylpropyl]amino]-[(3)H]-imidazo[4,5-b]pyridyl-3-yl]cyclopentane carboxamide), acted additively to reduce myocardial infarct size. STUDY DESIGN: Pigs underwent 1 hour of coronary artery occlusion and 3 hours reperfusion. Vehicle-treated controls were compared with animals treated before ischemia with low-dose and high-dose cariporide and AMP579, and low-dose cariporide plus AMP579. The effects of both agents, alone and in combination, were also tested in isolated porcine polymorphonuclear neutrophils (PMNs). The PMN respiratory burst was induced with phorbol 12-myristate 13-acetate and quantified by the increase in 2',7'-dichlorofluorescein fluorescence, measured by flow cytometry. RESULTS: Infarct size in the control pigs was 65 +/- 1% of the area at risk. Cariporide dose-dependently reduced infarct size to 39 +/- 2% and 24 +/- 3% in the low- and high-dose groups, respectively. Infarct size was 54 +/- 3% in the low-dose AMP579 group and 47 +/- 3% with high dose. The combination of low doses of cariporide and AMP579 reduced infarction to 25 +/- 6% of the area at risk. In the PMN studies, cariporide and AMP579 alone had no effect on 2',7'-dichlorofluorescein fluorescence, but the combination of the two agents reduced the PMN 2',7'-dichlorofluorescein increase to 79 +/- 5% of the vehicle control response. CONCLUSIONS: The preischemic combination of low doses of cariporide and AMP579 decreased myocardial infarct size more than either agent used alone in low concentration, indicating an additive effect of the two agents. Given the effects that cariporide plus AMP579 combination exerted on PMN activity, it appears that this combination has the potential to reduce PMN-mediated effects during myocardial reperfusion.     

Coronary artery endothelial dysfunction after ischemia-reperfusion and acute untreated rejection in a canine heterotopic heart transplantation model

BACKGROUND: Acute rejection is a common problem in heart transplantation and may contribute to the development of cardiac allograft vasculopathy. This study was designed to evaluate the mechanisms of coronary endothelial dysfunction associated with ischemia-reperfusion and acute untreated rejection. METHODS: Two groups of mongrel dogs (n=7 per group) underwent heterotopic cervical heart transplantation without immunosuppression. Allografts were harvested on posttransplant day 1 (group 1) and day 5 (group 2). A third group of unoperated dogs served as control (group 3). After harvesting, epicardial coronary arteries were studied in organ chamber for endothelium-dependent and independent reactivity. RESULTS: Group 1 displayed multifocal ischemic damage without any rejection while hearts from group 2 reached grade IV rejection. Immunohistochemical studies for von Willebrand factor showed expression on coronary endothelial cells in all animals with scattered areas of denudation in transplanted groups. Endothelium-dependent responses to acetylcholine, calcium ionophore A23147, and bradykinin were unaffected in groups 1 and 2. Endothelial relaxations to sodium fluoride (Gi-protein activator) was significantly reduced in group 1 and significantly increased in group 2 compared with control. Responses to serotonin and UK14304 (receptors linked to Gi-protein) were significantly increased in group 2. Responses to thrombin were decreased in both groups. Endothelium-independent responses were unaffected. CONCLUSIONS: In the canine model of heterotopic heart transplantation, the early (24 hr) endothelial dysfunction seen after transplantation is specific to the thrombin receptor and the Gi-protein signaling pathway. Acute untreated rejection did not modify the alteration in endothelial reactivity to thrombin but enhanced the sensibility of the Gi-protein signaling pathways.     

Isoflurane causes more severe regional myocardial dysfunction than halothane in dogs with a critical coronary artery stenosis

The effects of 1) isoflurane (ISO)- and halothane (HAL)-induced hypotension to a mean aortic pressure (AoP) of 55 mmHg, and 2) of substituting ISO and HAL for each other at a mean AoP of 55 mmHg on global and regional left ventricular performance (ultrasonic dimension technique) and on coronary hemodynamics (electromagnetic flow probes) were studied in eight open-chest dogs (anesthetized and paralyzed by continuous infusions of fentanyl and pancuronium) with a critical coronary artery stenosis (micrometer-controlled snare) of the left anterior descending coronary artery (LAD). The stenosis reduced resting coronary blood flow by 5% (P less than 0.05) without affecting global or regional myocardial performance. HAL- and ISO-induced hypotension caused comparable decreases in global cardiac function, but regional myocardial dysfunction in the area of stenosis and the reduction in coronary flow through the stenosed LAD were more pronounced during ISO. Substitution of HAL for ISO at constant mean AoP, heart rate, end-diastolic dimensions and pressures, and stroke volume resulted in significant (P less than or equal to 0.05) amelioration of regional myocardial dysfunction (improvement in contraction amplitude, disappearance of paradoxical systolic lengthening and akinesis), a 20% increase in flow through the stenosed LAD, and a 20% decrease in flow through the unobstructed left circumflex coronary artery. These data suggest that, in the presence of a critical coronary artery stenosis: 1) ISO- and HAL-associated hypotension result in comparable decreases in global cardiac function, 2) ISO-associated hypotension is more likely to cause severe regional myocardial dysfunction suggestive of ischemia than equal degrees of HAL-associated hypotension, and 3) the different effects of HAL and ISO on ischemic myocardial segments at equally reduced coronary perfusion pressure are primarily related to their different effects on coronary vasomotor tone.     

High concentrations of N-BNP are related to non-infectious severe SIRS associated with cardiovascular dysfunction occurring after off-pump coronary artery surgery

Background. Procalcitonin (PCT) blood concentrations are knownto be an appropriate marker of severe systemic inflammatoryresponse syndrome (SIRS) induced by coronary artery surgerywith and without cardiopulmonary bypass. Pro-brain natriureticpeptide (N-BNP) is a newly described cardiac hormone consideredto be an effective marker of severity and prognosis of acutecoronary syndromes and congestive heart failure. We evaluatedthe perioperative time courses of PCT and N-BNP and investigatedtheir role as early markers of severe SIRS (SIRS with cardiovasculardysfunction) induced by off-pump coronary artery bypass (OPCAB). Methods. Sixty-three patients were prospectively included. TheAmerican College of Chest Physicians Classification was usedto diagnose SIRS and organ system failure to define severe SIRS.Serum concentrations of PCT and N-BNP were determined before,during and after surgery. Receiver operating characteristiccurves and cut-off values were used to assess the ability ofthese markers to predict postoperative severe SIRS. Results. SIRS occurred in 25 (39%) patients. Nine of them (14%)showed severe SIRS. Significantly higher serum concentrationsof N-BNP and PCT were found in patients with severe SIRS withpeak concentrations respectively at 8887 pg ml^–1 (range2940–29372 pg ml^–1) for N-BNP and 9.50 ng ml^–1(range 1–65 ng ml^–1) for PCT. The area under thecurve using N-BNP to detect postoperative severe SIRS was 0.799before surgery (0.408 for PCT; P<0.01) and 0.824 at the endof surgery (0.762 for PCT; P<0.05). Conclusions. N-BNP may be an appropriate marker indicating theearly development of non-infectious postoperative severe SIRSafter OPCAB.      

Hyperprocalcitonemia is related to noninfectious postoperative severe systemic inflammatory response syndrome associated with cardiovascular dysfunction after coronary artery bypass graft surgery

OBJECTIVE: To investigate the role of 3 inflammatory parameters as early markers of severe systemic inflammatory response syndrome (SIRS) induced by coronary artery bypass graft surgery. DESIGN: Prospective study. SETTING: University hospital. PARTICIPANTS: Patients (n = 63) undergoing elective coronary artery bypass graft surgery with cardiopulmonary bypass. MEASUREMENTS AND MAIN RESULTS: The American College of Chest Physicians/Society of Critical Care Medicine classification was used to diagnose SIRS. Organ system failures were used to define severe SIRS. Serum concentrations of the inflammatory parameters (procalcitonin [PCT], C-reactive protein, leukocyte count) were determined before, during, and after surgery. SIRS occurred in 30 (47%) patients after surgery. Seven patients (11%) showed SIRS with greater-than-or-equal1 organ dysfunction (severe SIRS), whereas patients without SIRS had no organ dysfunction. Significantly higher serum levels of PCT were found in patients with severe SIRS from the 6th postoperative hour until the 3rd postoperative day with a peak level of 10.7 plus minus 13.2 ng/mL. No significant difference was detected between serum PCT of patients with SIRS but without any organ dysfunction and patients without SIRS. PCT levels of these patients remained lower than 1.7 ng/mL. Compared with PCT, plasma concentrations of C-reactive protein peaked later on the 2nd postoperative day and were not able to confirm the severity of SIRS. Leukocyte counts were not significantly modified. CONCLUSIONS: PCT seems to be an appropriate marker to identify the early development of noninfectious postoperative severe SIRS after coronary artery bypass graft surgery with cardiopulmonary bypass.     

Normalization of coronary microvascular reactivity and improvement in myocardial perfusion by surgical vascular endothelial growth factor therapy combined with oral supplementation of l-arginine in a porcine model of endothelial dysfunction

OBJECTIVE: Vascular endothelial growth factor acts in part through nitric oxide release, the availability of which is decreased in endothelial dysfunction associated with advanced coronary artery disease. This could explain the relatively disappointing results of vascular endothelial growth factor therapy in clinical studies compared with animal studies. We examined the influence of L-arginine supplementation to vascular endothelial growth factor therapy on myocardial microvascular reactivity and perfusion in a porcine model of endothelial dysfunction. METHODS: Twenty-four pigs were fed either a normal (NORM, n = 8) or high-cholesterol diet with (CHOL-ARG, n = 8) or without (CHOL, n = 8) L-arginine. All pigs underwent ameroid placement on the circumflex artery and then 3 weeks later received surgical vascular endothelial growth factor treatment. Four weeks after treatment, endothelial-dependent coronary microvascular responses and lateral myocardial perfusion were assessed. Endothelial cell density was determined by means of immunohistochemistry. Vascular endothelial growth factor, endothelial nitric oxide synthase, and Akt levels were determined by means of immunoblotting. RESULTS: Pigs from the CHOL group showed endothelial dysfunction in the circumflex territory, which was normalized by L-arginine supplementation. Vascular endothelial growth factor treatment was ineffective in the CHOL group (circumflex/left anterior descending coronary artery blood flow ratios: 0.95 [rest] and 0.74 [pace] before-after treatment; P < .05 compared with the NORM group). Addition of L-arginine restored the angiogenic effect of vascular endothelial growth factor (ratios: 1.13 [rest] and 1.20 [pace]; P < .05) and was associated with increased endothelial cell density, as well as vascular endothelial growth factor, endothelial nitric oxide synthase, and Akt protein levels in the ischemic territory. CONCLUSIONS: L-Arginine supplementation can restore normal endothelium-dependent vasorelaxation and angiogenic response to vascular endothelial growth factor in a swine model of chronic myocardial ischemia with hypercholesterolemia-induced endothelial dysfunction. These findings suggest a putative role for L-arginine in combination with vascular endothelial growth factor therapy for end-stage coronary artery disease.     

Blood flow analysis in the left coronary artery in a patient with annulo-aortic-ectasia before and after Bentall's operation

It has not been established that Bentall's operation induces beneficial effect on a coronary circulation in a patient with Annulo-Aortic-Ectasia. Availability of a small subselective coronary Doppler catheter makes it possible to study the effects of the operation on coronary circulation. In a 49 year old man with Annulo-Aortic-Ectasia, phasic coronary flow velocity in the left main truncus was measured using a 3F steerable Doppler catheter (DC-101, Millar Inc.) pre- and postoperatively with assessment of vasodilator reserve capacity of individual coronary arteries. After the operation, the velocity wave form in the LMT changed to a diastolic-predominant normal pattern with a relatively small systolic component. That is, Bentall's operation caused a marked reduction of systolic- to diastolic flow component ratio from 0.32 to 0.19. The postoperative coronary flow configuration in the LMT was characterized by the presence of predominant diastolic spike. It coincided with "Water hammer wave" in the aortic pressure tracings caused by sudden closing of mechanical valve leaflets. Preoperative intracoronary papaverine increased the ratio of peak to resting velocity (coronary flow reserve) to 2.0 times at the rest, and 3.0 times after the operation. These results suggest that Bentall's operation seems to induce beneficial effect on the myocardial coronary circulation.     

Global myocardial ischemia and reperfusion impair endothelium-dependent relaxations to aggregating platelets in the canine coronary artery. A possible cause of vasospasm after cardiopulmonary bypass.

Experiments were designed to determine whether endothelial cell injury contributes to increased coronary vascular tone after global cardiac ischemia and reperfusion. Canine hearts were exposed to global ischemia for 45 minutes and were reperfused for 60 minutes. Rings (5 to 6 mm long) of the left anterior descending coronary artery from reperfused hearts and from normal (control) hearts were suspended for isometric force measurement in organ chambers containing physiologic salt solution (37 degrees C, and 95% oxygen and 5% carbon dioxide). After contraction with prostaglandin F2 alpha, reperfused coronary arteries had significant impairment of endothelium-dependent relaxations to aggregating platelets (52% +/- 12% relaxation versus 102% +/- 11% for control segments; p less than 0.05). Reperfused arterial rings also exhibited impaired endothelium-dependent relaxations to the receptor-dependent agonist acetylcholine and the platelet-derived compounds adenosine diphosphate and serotonin. Importantly, endothelium-dependent relaxations to the non-receptor-dependent agonist A23187 were normal after ischemia and reperfusion. Quiescent (noncontracted) reperfused arterial rings lost the ability to counteract the constrictive effect of aggregating platelets on the coronary vascular smooth muscle (24% +/- 7% contraction versus 5% +/- 2% relaxation for control segments; p less than 0.05). Endothelium-independent contractions to potassium chloride and prostaglandin F2 alpha were similar in reperfused and normal arteries. Also, endothelium-independent relaxations to nitric oxide and isoproterenol were comparable in reperfused arteries and normal vessels. Thus global cardiac ischemia and reperfusion impair the normal endothelium-dependent relaxations to aggregating platelets and other receptor-dependent vasoactive drugs. This impairment of platelet-mediated coronary vasodilation may explain increased coronary vascular tone after cardiopulmonary bypass and could be an important pathophysiologic mechanism of postoperative coronary vasospasm.     

左心功能中重度不全患儿行左冠状动脉异常起源矫治术后发生急性肾损伤的危险因素分析

目的回顾性分析左冠状动脉异常起源于肺动脉(anomalous origin of the left coronary artery from the pulmonary artery,ALCAPA)伴左心功能中重度不全的患儿行矫治术后发生急性肾损伤(acute kidney injury,AKI)的危险因素。方法选择2010年11月至2017年5月行ALCAPA矫治术伴术前左室射血分数(left ventricular ejection fraction,LVEF)低于50%的患儿43例,男25例,女18例,年龄3个月至14岁。查阅医院电子病例,收集相关围术期临床资料。根据KIDGO标准判断是否发生AKI,将患儿分为两组:非AKI组和AKI组。采用多因素Logistic回归分析术后AKI的危险因素。结果术后发生AKI 31例,AKI发生率为70.5%。AKI组术前Hb含量、术前LVEF和术前血浆肌酐(SCr)浓度明显低于非AKI组(P0.05)。多因素Logistic回归分析显示,术前Hb含量升高为保护性因素(OR=0.917,95%CI 0.848～0.992,P=0.031);术前LVEF升高为保护性因素(OR=0.902,95%CI 0.819～0.993,P=0.036);术前肾小球滤过率(GFR)升高为独立危险因素(OR=1.063,95%CI 1.014～1.113,P=0.011)。结论 ALCAPA伴左心功能中重度不全的患儿行矫治术,术前Hb含量升高和LVEF升高均是术后发生AKI的保护性因素,而术前GFR升高是术后AKI的独立危险因素。     

Surgical treatment of an infant with myocardial ischemia due to an anomalous origin of the right coronary artery from the main pulmonary artery: Report of a case

An anomalous origin of the right coronary artery from the main pulmonary artery (ARCAPA) is a rare cardiac malformation, and only three cases of isolated ARCAPA in patients younger than 2 years of age have been reported. This report describes the surgical treatment of a 12-month-old girl with myocardial ischemia due to ARCAPA. The diagnosis was made by echocardiography. A reimplantation of the aberrant coronary artery was performed, and the patient had a successful postoperative course.