Rosuvastatin Lowers Systemic Inflammatory Response in Coronary Artery Bypass Graft Accompanied by Cardiopulmonary Bypass Surgery: A Randomized Controlled Study.

PURPOSE: Cardiopulmonary bypass (CPB) is commonly associated with a systemic inflammatory response that may lead to severe complications. Classic signs of systemic inflammatory response syndrome are complement activation and changes in cytokine and acute phase reactant levels. The effects of rosuvastatin after CPB on interleukin-6 (IL-6), interleukin-10 (IL-10), interleukin-18 (IL-18) and High Sensitivity C-Reactive Protein (hs-CRP) levels were investigated. METHODS: Thirty-seven male and thirteen female patients (total=50) aged 42 to 78 years, who had coronary bypass surgery due to coronary artery disease were randomly divided into two groups. The 25 patients in the control group were administered placebos. The 25 in the treatment group were administered 20 mg rosuvastatin tablets daily between preoperative day 7 and postoperative day 28. Blood samples were taken at six time points; before induction of anesthesia (T1), during CPB (T2), five minutes after removal of cross clamp (T3), after protamine infusion (T4), postoperative day three (T5) and postoperative day 28 (T6). Data points were expressed as mean ± standard deviation (SD). RESULTS: Rosuvastatin lowered IL-6 levels at T4, T5 and T6 time points (T4, T5, T6 p < 0.05), and elevated IL-10 levels at T3 and T4 (T3, T4 p < 0.05). IL-18 levels were also elevated at multiple time points. Rosuvastatin also lowered hs-CRP levels and cholesterol levels at T6 (p < 0.05). CONCLUSION: Administering 20 mg/day of rosuvastatin between preoperative day 7 and postoperative day 28 may result in fewer complications in certain (especially intraoperative) cases of systemic inflammatory response caused by the CPB technique used in coronary bypass surgery.

In vitro effects of sodium nitroprusside and leptin on norepinephrine-induced vasoconstriction in human internal mammary artery.

AIM: The biological and pharmacological properties of vessels used in coronary artery bypass graft (CABG) surgery are as important as their mechanical properties. The aim of this study was to investigate the possible role of protein kinase C (PKC)-dependent mechanisms in leptin-induced relaxation in the human internal mammary artery (IMA). METHODS: IMA rings, obtained from patients undergoing CABG surgery, were suspended in isolated tissue baths containing Krebs-Henseleit solution, which were continuously gassed with 95% O2 and 5% CO2 at 37(°)C. RESULTS: The IMA rings were pre-contracted with increasing concentrations of norepinephrine (NE 10(-9)-10(-4) mol/l) and the relaxation responses to sodium nitroprusside (SNP), a nitrosovasodilator, and leptin were studied in the presence and absence of a PKC inhibitor. Leptin (1 µM) caused a dose-dependent relaxation in NE pre-contracted IMA rings. Pre-treatment with a PKC inhibitor significantly attenuated this vasorelaxatory response to leptin in human isolated IMA. CONCLUSION: It was found that SNP and leptin caused significant relaxation of the NE pre-contracted human IMA rings, and PKC was probably the sub-cellular mediator for this effect. Our findings may have clinical or pharmacological importance as it could be hypothesised that obese subjects who have a left IMA bypass graft would have better myocardial perfusion.

Evaluation of systemic inflammatory response in cardiovascular surgery via interleukin-6, interleukin-8, and neopterin.

AIM: The aim of this study was to evaluate the serum levels of interleukin-6 (IL-6), IL-8, and neopterin as a sign of systemic inflammatory response syndrome after open-heart surgery. In this study, we evaluated the influences on the levels of IL-6, IL-8, and neopterin of coronary artery bypass grafting (CABG) and valve replacement surgeries with and without the use of extracorporeal circulation (ECC). MATERIALS AND METHODS: This prospective study was performed in 30 patients. In this study, we evaluated patients who underwent valve replacement surgery (group 1, n = 10), CABG with ECC (group 2, n = 10), or CABG using the beating-heart technique (group 3, n = 10). With the Human Investigation Ethics Committee consent, blood samples were obtained from the patients before the surgery (T0) and after 1 hour (T1), 4 hours (T2), 24 hours (T3), and 48 hours (T4) of protamine injection. IL-6, IL-8, and neopterin levels were measured using commercial enzyme-linked immunosorbent assay kits. RESULTS: The demographic data and preoperative and operative characteristics of the patients were similar. Neopterin IL-6 and IL-8 levels significantly increased first at the fourth hour after the surgery. When compared to the levels before the surgery, this increase was statistically significant. Unlike the other 2 groups of patients, those who experienced CABG with the beating-heart technique (group 3) had decreased neopterin levels at the first hour after the surgery, but this decrease was not statistically significant. Neopterin levels increased later in the OPCAB group, but these increased levels were not as high as the neopterin levels of groups 1 and 2. Neopterin reached maximum levels at the 24th hour and, unlike groups 1 and 2, in group started to decrease at the 48th. CONCLUSIONS: Complement activation, cytokine production, and related cellular responses are important factors during open-heart surgery. It is certain that ECC activates the complement systems, and activated complement proteins cause the production of several cytokines. In our study, neopterin levels in patients who underwent beating-heart method surgery were lower than those in the other groups, and these levels started to decrease at the 48th hour. These data suggest that the systemic inflammatory response was less activated in that patient group. The beating-heart method might be an important alternative in CABG surgery to minimize the complications and mortality related to surgery.

Effects of rosuvastatin on ADMA, rhokinase, NADPH oxidase, caveolin-1, hsp 90 and NFkB levels in a rat model of myocardial ischaemia-reperfusion.

AIM: Endothelial dysfunction, oxidative stress and inflammation are among the most important mechanisms of ischaemia-reperfusion (I/R) injury. Besides their cholesterol-lowering effects, statins are known to provide protection against myocardial dysfunction and vascular endothelial injury via nitric oxide-dependent mechanisms. The aim of this study was to investigate the effects of rosuvastatin on certain intermediates involved in the generation of nitric oxide (asymmetrical dimethyl arginin, ADMA, caveolin-1 and hsp 90), oxidative stress (rhokinase, NADPH oxidase) and inflammation (NFkB), using an in vivo model of myocardial infarction in the rat. METHODS: Adult male Sprague Dawley rats were divided into three groups (control, I/R and I/R after 15 days of rosuvastatin administration). Reperfusion was applied for 120 min following left anterior descending coronary artery ischaemia for 30 min. Caveolin-1, hsp 90 and NFkB levels were evaluated with the quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and ADMA, rhokinase and NADPH oxidase levels were evaluated with ELISA. RESULTS: While NFkB and hsp 90 levels were higher in the I/R group, their levels were significantly lower in the rosuvastatin group. While ADMA and NADPH oxidase levels significantly increased with I/R, they were lower in the rosuvastatin-treated group, but not statistically significant. Rhokinase levels were significantly lower in the rosuvastatin group. Caveolin-1 levels were not different between the groups. CONCLUSION: Our results suggest that ADMA, rhokinase, NADPH oxidase, hsp 90 and NFkB could facilitate I/R injury, and rosuvastatin significantly reduced levels of these parameters. These results indicate that rosuvastatin may have a protective role in I/R injury via mechanisms targeting inflammation, endothelial dysfunction and oxidative stress.

Alpha lipoic acid attenuates inflammatory response during extracorporeal circulation.

AIM: Extracorporeal circulation (ECC) of blood during cardiopulmonary surgery has been shown to stimulate various proinflammatory molecules such as cytokines and chemokines. The biochemical oxidation/reduction pathways of α-lipoic acid suggest that it may have antioxidant properties. METHODS: In this study we aimed to evaluate only patients with coronary heart disease and those planned for coronary artery bypass graft operation. Blood samples were obtained from the patients before the operation (P1) and one (P2), four (P3), 24 (P4) and 48 hours (P5) after administration of α-lipoic acid (LA). The patients were divided into two groups, control and LA treatment group. Levels of interleukin- 6 (IL-6) and -8 (IL-8), complement 3 (C3) and 4 (C4), anti-streptolysin (ASO), C-reactive protein (CRP) and haptoglobin were assessed in the blood samples. RESULTS: Cytokine IL-6 and IL-8 levels were significantly higher after surgery. Compared with the control groups, LA significantly decreased IL-6 and IL-8 levels in a time-dependent manner. CRP levels did not show significant variation in the first three time periods. CRP levels were higher after surgery, especially in the later periods. These results demonstrate that CRP formation depends on cytokine release. C3 and C4 levels were significantly higher after surgery than in the pre-operative period. LA treatment decreased C3 and C4 levels. Therefore, LA administration may be useful for the treatment of diseases and processes where excessive cytokine release could cause oxidative damage. CONCLUSION: Our findings suggest a possible benefit of using LA during cardiac surgery to reduce cytokine levels.

An experimental lymphoscintigraphy study in an acute unilateral deep venous thrombosis model.

BACKGROUND: The aim of this study is to investigate the effect of both inguinal exploration and deep venous thrombosis on lymphatic flow in an experimental model of unilateral acute obstruction of the femoral vein. METHODS AND RESULTS: Eighteen male New Zealand White rabbits were the subjects of this study. The rabbits were divided into three groups; Group 1 (n=6, control), Group 2 (n=6, sham), and Group 3 (n=6, operation). After the lymphoscintigraphy was performed on the Group 1 animals, the rabbits in Group 2 and Group 3 underwent intervention. In Group 3, the femoral vein was clipped and excised. In Group 2, an inguinal incision was performed and the clip materials were placed beneath the femoral vein. After the surgical intervention, lower extremity lymphoscintigraphy by subcutaneous administration of Tc-99m nanocolloid was performed in dynamic and static manner in Groups 2 and 3 on the second, fifteenth and thirtieth days after the operation. Unilateral impairment of the lymphatic flow in the operated extremity was observed in Group 3 in the early and late postoperative period but unilateral lymphatic impairment was observed in Group 2 in only the late postoperative period. CONCLUSION: The lymphatic impairment in an operated extremity might be the consequence of surgical intervention rather than acute venous obstruction in cases where both situations are observed.

Randomized comparison of vasodilator effects of iloprost versus diltiazem on flow and pathologic changes in radial arteries: mid-term angiographic control study of the comparison of vasodilators on radial artery vasospasm.

BACKGROUND: The increasing prevalence of routine radial artery (RA) use in coronary artery bypass grafting (CABG) has rendered the pharmacologic prevention of spasm of this artery a critical consideration in the early postoperative period and in the long-term outcome. In this study, we compared the effects of iloprost and diltiazem on vasospasm. METHODS: Seventy patients who underwent CABG with the RA were randomized into 2 groups, and the vasodilator effects of iloprost and diltiazem were studied prospectively. RA flow was measured with Doppler ultrasonography. Following harvesting, a 5-mm piece was removed from the RA distally for pathologic examination. In group B, diltiazem was infused before removing the RA, whereas in group A, iloprost infusion was initiated 5 days before surgery. At the end of a 2-year follow-up, each patient underwent coronary angiography. RESULTS: Doppler flow measurements made during harvesting revealed a statistically significant reduction in flow, and a pathologic examination of the RAs revealed significant luminal narrowing in group B. A 2-year angiographic follow-up revealed all of the RA grafts in group A to be patent. CONCLUSIONS: Our evaluation of the results revealed the superior efficacy of iloprost over diltiazem in preventing RA spasm in the early period, and the 2-year angiographic findings showed that the use of iloprost produced superior mid-term patency.

The effects of intra-operative amiodarone loading on the systemic inflammatory response syndrome induced by cardiopulmonary bypass.

OBJECTIVE: Cardiopulmonary bypass (CPB) leads to systemic inflammatory response syndrome (SIRS). In vitro studies showed that amiodarone blocked cytokine production. The aim of this study was to evaluate the effect of intra-operative amiodarone loading on SIRS. METHODS: This prospective randomized study included 24 patients who underwent on-pump coronary artery surgery. The patients were classified into control (n=12) and amiodarone (n=12) groups. Plasma levels of the pro-inflammatory (C-reactive protein - CRP, interleukin-6 - IL-6) and the anti-inflammatory markers (interleukin-10 - IL-10) were measured before the induction of anesthesia, 5 minutes after aortic declamping, after protamine administration and 24 hours after the CPB. The myocardial lactate production was calculated before CPB and 5 minutes after aortic declamping. Statistical analyses were performed using Mann-Whitney U, Fischer's exact and ANOVA tests. RESULTS: In both groups, the IL-6 levels significantly increased after declamping (91.18+/-16.27 pg/ml and 86.37+/-14.66 pg/ml, p<0.01) and reached peak values after infusion of protamine (329.07+/-32.24 pg/ml and 354.31+/-29.61 pg/ml, p<0.01). The highest values of IL-10 were detected after infusion of protamine in the control and amiodarone groups (265.58+/-85.63 pg/ml, p<0.01 and 287.44+/-65.26 pg/ml, p<0.01). Amiodarone did not have any significant effect on release of cytokines. The CRP levels were significantly elevated in both groups at 24th hour after CPB, but no significant difference was found between the groups. Compared with pre-CPB values, lactate production increased significantly in two groups after aortic declamping. However there was no significant difference between the groups. CONCLUSION: The results indicate that intraoperative loading of amiodarone, which is used for atrial fibrillation prophylaxis, does not seem to alter inflammatory response during CPB.

The effects of low dose N-acetylcysteine (NAC) as an adjunct to cardioplegia in coronary artery bypass surgery.

OBJECTIVE: We aimed to evaluate the efficacy of low dose N-acetylcysteine (NAC) against myocardial ischemia-reperfusion damage in coronary artery bypass surgery accompanied by cardiopulmonary bypass (CPB). METHODS: Thirty patients operated due to triple coronary artery disease were enrolled into this prospective randomized study (control group -n=15 and NAC group - n=15). N-acetylcysteine was added to induction cardioplegia solution in dose of 4 mmol/l and in dose of 2 mmol/l to maintenance cardioplegia solution in the NAC group. Hemodynamic measurements were performed before and after anesthesia with different intervals. Creatine kinase-MB (CK-MB) levels were analyzed during 24 hours postoperatively. Blood samples were obtained from coronary sinus before CPB (T1), just before the cross-clamp removed (T2) and 30 minutes later (T3). Malondialdehyde (MDA), glutathione peroxidase (GSH-Px), nitric oxide (NO) levels and neutrophil percentage were determined. Statistical analysis was performed using student's t test, Chi-square and two-way ANOVA tests. RESULTS: There were no significant differences between the two groups with regard to the hemodynamic parameters, and CK-MB levels. The MDA levels were significantly lower in NAC group than in control group during reperfusion period (0.75 nmol/l vs 0.88 nmol/l, p<0.05). Neutrophil percentage in coronary sinus blood was significantly lower in NAC group than in control group during the reperfusion period (77.6% vs 82.7%, p<0.05). The GSH-Px and NO levels were also not statistically different between groups. CONCLUSION: Low dose NAC as an adjunct to cardioplegic solutions effectively reduces myocardial oxidative stress in coronary bypass surgery with cardiopulmonary bypass, but may not restore the myocardial injury.

Melatonin protects myocardium from ischemia-reperfusion injury in hypertensive rats: role of myeloperoxidase activity.

Increased levels of reactive oxygen species, alterations in nitric oxide synthesis, and increased migration of neutrophils to the ischemic tissue play an important role in the pathophysiology of myocardial ischemia-reperfusion (IR) injury. In this study, we have evaluated the effects of melatonin on myeloperoxidase (MPO) activity, tissue glutathione (GSH), lipid peroxidation levels, and blood pressure in L-NAME-induced hypertensive rats with or without IR. NOS inhibitor L-NAME was administrated before inducing cardiac ischemia for 15 days intraperitoneally. For the cardiac ischemia, the left coronary artery was ligated for 30 min, and reperfusion was performed for 120 min after the ischemia. L-NAME treatment in non-ischemic animals increased blood pressure and lipid peroxidation, and decreased glutathione level in myocardial tissue significantly as compared with non-L-NAME-treated animals. Melatonin reversed L-NAME-induced blood pressure elevation and oxidative changes. Cardiac IR increased MDA levels and MPO activity and decreased GSH levels as compared with non-ischemic animals. L-NAME treatment did not change in IR-induced MDA and GSH levels as compared with ischemic control animals. However, MPO activity was significantly higher than control ischemic animals. MDA levels and MPO activity resulting from ischemic injury in melatonin-treated animals were significantly less than L-NAME-treated animals. Taken together-the ischemic and non-ischemic control and melatonin-treated animals-this study shows that neutrophil migration plays an important role on the development of ischemic injury in hypertensive rats.

Off-pump pulmonary valve implantation.

In congenital heart surgery, especially after Tetralogy of Fallot (TOF), problems from the right ventricular outflow tract may lead to serious complications as morbidity and mortality. To resolve these problems by reoperating using cardiopulmonary bypass (CPB) with valves or conduits is affecting surgical morbidity and mortality rates. The ability of a newly developed Shelhigh Pulmonic Valved Injectable No-React-Treated Conduit (NR 4000-PA MIS Shelhigh Inc., Union, NJ, USA) to be implanted into a beating heart provides great advantages for both patient and surgeon. Early results of the first application in our clinic are presented in this article.

Retrospective analysis of surgically treated infective endocarditis cases.

BACKGROUND: Prosthetic valve endocarditis (PVE) and native valve endocarditis (NVE) both cause high rates of morbidity and mortality and are significant health problems in our community. Optimal timing of the surgical intervention depends on the hemodynamic stability of the patient. In the present study, we retrospectively evaluated the clinical status, bacteriology, morbidity, and mortality parameters of infective endocarditis cases that were treated surgically. METHODS: Thirty patients (20 male and 10 female) who underwent cardiac valve surgery between April 2001 and December 2006 were included in the study. The mean (SD) age of the patients was 36.5 +/- 5.42 years. Thirty-five surgical operations were conducted on 30 patients. We evaluated the patient demographic, etiologic, and surgical data retrospectively with respect to mortality and morbidity. RESULTS: The mean time to develop PVE was 13 months. We recorded a mortality rate of 16.6% (2 deaths in NVE operations and 3 deaths in PVE operations). Repeat surgeries were performed in 2 aortic valve cases and 3 mitral valve cases in which paravalvular leakage was noticed in the prosthetic valves. CONCLUSION: Despite significant medical and surgical advances, both NVE and PVE still continue to be causes of high mortality and morbidity rates in cardiac surgery.

Predictive risk factors for early mortality in operative treatment for chronic ischemic mitral insufficiency.

BACKGROUND: The combination of coronary artery bypass grafting and mitral valve surgeries is closely associated with high in-hospital mortality and morbidity. In this study, we sought to analyze the factors that influence early mortality in 68 patients undergoing coronary artery bypass grafting + mitral valve surgery due to ischemic mitral insufficiency. METHODS: Of 1183 patients undergoing coronary bypass surgery between April 2002 and June 2006, 68 patients (42 male and 26 female) 42 to 78 years of age (mean +/- SD, 59.3 +/- 9.1) underwent mitral valve surgery accompanying coronary bypass surgery (survival, n = 59; mortality, n = 9). The cases were analyzed regarding the demographic, preoperative, and perioperative risk factors that influence mortality. RESULTS: The early mortality rate was found to be 13.2% (9/68) in patients with ischemic mitral regurgitation undergoing simultaneous coronary bypass and mitral valve surgeries. New York Heart Association class > or =3, left ventricle end-systolic volume, left ventricle end-systolic diameter, cardiopulmonary perfusion time, preoperative unstable angina pectoris, intra-aortic balloon application, and age >65 years were determined to be statistically significant risk factors that influence early in-hospital mortality.Conclusion. Surgery, despite having a high mortality risk in patients with ischemic mitral insufficiency, is considered to be a treatment measure that generally improves the quality of life and prolongs life.

Is Chlamydia pneumoniae a risk factor for peripheral atherosclerosis?

Seroepidemiological studies have shown a relationship between Chlamydia pneumoniae and coronary atherosclerosis. It is not clear whether Chlamydia pneumoniae is also a risk factor for peripheral atherosclerosis. Chlamydia pneumoniae antibodies were measured by a microimmunofluorescence method in 75 patients who underwent surgery for peripheral atherosclerosis, and the seroprevalence was compared with that in the normal population. Chlamydia pneumoniae immunoglobulin-G seroprevalence was 80% in the study group vs. 40% in controls. More foam cells were noted on light microscopy in atherosclerotic plaques from the infected patients. The 60 infected patients were divided into: group A (n = 35) given both anti-chlamydial and antiplatelet agents for 1 year; and group B (n = 25) given antiplatelet therapy only. The groups were compared on the basis of clinical findings, ankle-brachial index, and antibody titers. Decreasing Chlamydia pneumoniae immunoglobulin-G seroprevalence in group A correlated significantly with increasing ankle-brachial index and improvement in clinical findings. It was concluded that Chlamydia pneumoniae may be a risk factor for peripheral atherosclerosis.

Investigation of coronary arteries in the porcupine (Hystrix cristata) by latex injection and angiography.

Coronary arteries were investigated in the porcupine by means of angiography performed on each of 5 adult porcupines (3 male, 2 female) which was followed by injection of a colored latex mixture from the aortic arch for the demonstration of these arteries. The results showed that the aorta branched out at the level of the cardiac outlet to form the left and right coronary arteries and right ramus coni arteriosi. Coronary arteries coursed and ramified in the myocardium. The left coronary artery divided to form the paraconal interventricular artery and left circumflex artery when it reached the coronary sulcus. The interventricular septum was vascularized by the septal branch of the paraconal interventricular artery and by the small septal branches. The left and right coronary arteries gave off all the branches reported in the literature for other species. When the ramus coni arteriosi originates from the right coronary artery, it is designated a third coronary artery. In conclusion, it was found that the coronary arteries of the porcupine had an "intramyocardial course" as in other rodents. The coronary supply of the heart represented a "left coronary type" which was similar to those of carnivores and ruminants. The results of this study may contribute to the data in this area of science.

Determination of coronary failure with the application of FFT and AR methods.

In this study, Doppler signals recorded from the output of carotid artery of 30 patients were transferred to a personal computer (PC) by using a 16-bit sound card. Doppler difference frequencies were recorded from each of the patients, and then analyzed using fast Fourier transform (FFT) and least squares autoregressive (AR) methods to obtain their sonograms. These sonograms are then used to compare with the applied methods in terms of medical evaluation.

Iatrogenic vertebral artery pseudoaneurysm: US, CT and MRI findings.

Vertebral artery pseudoaneurysm (VAP) is the result of the penetrating neck trauma, chiropractic manipulation, vasculopathies and rarely iatrogenic due to internal jugular vein (IJV) catheterization. It should be identified and treated immediately because of its potential risk of rupture. We present a case of a right VAP resulting from jugular vein catheterization, with the Doppler ultrasonography (US), Computed tomography (CT) and magnetic resonance imaging (MRI) findings. Although angiography is a well known gold standard modality, Doppler US, CT and MRI findings can be sufficient to demonstrate VAP.

Corona mortis: incidence and location.

The right hemipelvis of 98 patients was examined by angiography to determine the occurrence and location of the corona mortis artery. This arterial anastomosis was found in 28.5% (28 of 98). Its incidence was 30.5% (18 of 59) in men and 25.6% (10 of 39) in women; this difference was not significant ( p>0.05). The distance from the symphysis pubis to the anastomotic artery averaged 33.4 mm (range 21.4-41 mm). It was 31.8 mm (range 21.4-39.3 mm) in men and 36.2 mm (range 25-41 mm) in women; this difference was significant ( p<0.05).