Predrag Milojevic

Mitochondrial Molecular Basis of Sevoflurane and Propofol Cardioprotection in Patients Undergoing Aortic Valve Replacement with Cardiopulmonary Bypass

Background/Aims: Study elucidates and compares the mitochondrial bioenergetic-related molecular basis of sevoflurane and propofol cardioprotection during aortic valve replacement surgery due to aortic valve stenosis. Methods: Twenty-two patients were prospectively randomized in two groups regarding the anesthetic regime: sevoflurane and propofol. Hemodynamic parameters, biomarkers of cardiac injury and brain natriuretic peptide (BNP) were measured preoperatively and postoperatively. In tissue samples, taken from the interventricular septum, key mitochondrial molecules were determined by Western blot, real time PCR, as well as confocal microscopy and immunohisto- and immunocyto-chemical analysis. Results: The protein levels of cytochrome c oxidase and ATP synthase were higher in sevoflurane than in propofol group. Nevertheless, cytochrome c protein content was higher in propofol than sevoflurane receiving patients. Propofol group also showed higher protein level of connexin 43 (Cx43) than sevoflurane group. Besides, immunogold analysis showed its mitochondrial localization. The mRNA level of mtDNA and uncoupling protein (UCP2) were higher in propofol than sevoflurane patients, as well. On the other hand, there were no significant differences between groups in hemodynamic assessment, intensive care unit length of stay, troponin I and BNP level. Conclusions: Our data indicate that sevoflurane and propofol lead to cardiac protection via different mitochondrially related molecular mechanisms. It appears that sevoflurane acts regulating cytochrome c oxidase and ATP synthase, while the effects of propofol occur through regulation of cytochrome c, Cx43, mtDNA transcription and UCP2.

Steroids and statins: an old and a new anti-inflammatory strategy compared

Objectives: This study compared the anti-inflammatory effects of methylprednisolone (MP) and atorvastatin and analysed their influences on clinical variables in patients undergoing coronary revascularization. Methods: Ninety patients with compromised left ventricular ejection fraction (≤30%) undergoing elective coronary surgery were equally randomized to one of three groups: statin group, treatment with atorvastatin (20 mg/day) 3 weeks before surgery; methylprednisolone group, a single shot of methylpredniosolone (10mg/kg); and control group. Results: Postoperative IL-6 was higher in the control group when compared to the methylprednisolone and statin groups (p<0.01). IL-6 was higher in the statin-treated patients (p<0.05 versus methylprednisolone). Administration of methylprednisolone as well as statin treatment increased postoperative cardiac index, left ventricular stroke work index, decreased postoperative atrial fibrilation rate and reduced ICU stay (p<0.05 versus control). The number of patients requiring inotropic support was lower in the methylprednisolone group when compared with the other two groups (p<0.01). Tracheal intubation time was reduced in patients who received methylprednisolone (p<0.01 versus control). Conclusions: Preoperative administration of either methylprednisolone or atorvastatin reduced pro-inflammatory cytokine release, improved haemodynamics, decreased postoperative atrial fibrilation rate and reduced ICU stay in patients with significantly impaired cardiac function undergoing coronary revascularization. Treatment with methylprednisolone was associated with less inotropic support requirements and reduced mechanical ventilation time.

Mechanisms underlying the vasorelaxation of human internal mammary artery induced by (-)-epicatechin.

Evidences have suggested that flavanol compound (-)-epicatechin is associated with reduced risk of cardiovascular diseases. One of the mechanisms of its cardioprotective effect is vasodilation. However, the exact mechanisms by which (-)-epicatechin causes vasodilation are not yet clearly defined. The aims of the present study were to investigate relaxant effect of flavanol (-)-epicatechin on the isolated human internal mammary artery (HIMA) and to determine the mechanisms underlying its vasorelaxation. Our results showed that (-)-epicatechin induced a concentration-dependent relaxation of HIMA rings pre-contracted by phenylephrine. Among the K(+) channel blockers, 4-aminopyridine (4-AP) and margatoxin, blockers of voltage-gated K(+) (KV) channels, and glibenclamide, a selective ATP-sensitive K(+) (KATP) channels blocker, partly inhibited the (-)-epicatechin-induced relaxation of HIMA, while iberiotoxin, a most selective blocker of large conductance Ca(2+)-activated K(+) channels (BKCa), almost completely inhibited the relaxation. In rings pre-contracted by 80mM K(+), (-)-epicatechin induced partial relaxation of HIMA, whereas in Ca(2+)-free medium, (-)-epicatechin completely relaxed HIMA rings pre-contracted by phenylephrine and caffeine. Finally, thapsigargin, a sarcoplasmic reticulum Ca(2+)-ATPase inhibitor, slightly antagonized (-)-epicatechin-induced relaxation of HIMA pre-contracted by phenylephrine. These results suggest that (-)-epicatechin induces strong endothelium-independent relaxation of HIMA pre-contracted by phenylephrine whilst 4-AP- and margatoxin-sensitive KV channels, as well as BKCa and KATP channels, located in vascular smooth muscle, mediate this relaxation. In addition, it seems that (-)-epicatechin could inhibit influx of extracellular Ca(2+), interfere with intracellular Ca(2+) release and re-uptake by the sarcoplasmic reticulum.

Nicorandil directly and cyclic GMP-dependently opens K+ channels in human bypass grafts.

As we previously demonstrated the role of different K(+) channels in the action of nicorandil on human saphenous vein (HSV) and human internal mammary artery (HIMA), this study aimed to analyse the contribution of the cGMP pathway in nicorandil-induced vasorelaxation and to determine the involvement of cGMP in the K(+) channel-activating effect of nicorandil. An inhibitor of soluble guanylate cyclase (GC), ODQ, significantly inhibited nicorandil-induced relaxation, while ODQ plus glibenclamide, a selective ATP-sensitive K(+) (KATP) channel inhibitor, produced a further inhibition of both vessels. In HSV, ODQ in combination with 4-aminopyridine, a blocker of voltage-gated K(+) (KV) channels, did not modify the concentration-response to nicorandil compared with ODQ, whereas in HIMA, ODQ plus iberiotoxin, a selective blocker of large-conductance Ca(2+)-activated K(+) (BKCa) channels, produced greater inhibition than ODQ alone. We showed that the cGMP pathway plays a significant role in the vasorelaxant effect of nicorandil on HSV and HIMA. It seems that nicorandil directly opens KATP channels in both vessels and BKCa channels in HIMA, although it is possible that stimulation of GC contributes to KATP channels activation in HIMA. Contrary, the activation of KV channels in HSV is probably due to GC activation and increased levels of cGMP.

Preoperative Insight Into the Quality of Radial Artery Grafts.

We investigated the impact of preoperative ultrasonography of the forearm circulation on radial artery conduit selection. Preoperative ultrasound of the forearm circulation was performed routinely in 536 patients planned for radial artery harvesting. The safety assessment of the harvest included the following algorithm of tests: the ultrasound, the Allen test, and pulse oximetry. The quality criteria that were used to exclude a radial artery from harvesting were small size of the artery, diffuse atherosclerosis, calcifications, and severe neointimal hyperplasia. The overall rejection rate due to safety reasons was 16.4%. Seventy-one (13.2%) radial arteries did not fulfill the conduit quality criteria and consequently these arteries were not harvested. In 13.4% of radial arteries, localized arterial wall disease was found in the distal third of the artery. The distal part of the artery was discarded and the rest was used as a conduit. Our results indicate that the ultrasound provides an accurate preoperative insight into the radial artery morphology, enabling selection of the arteries with favorable morphological features.

Endothelium-dependent vasorelaxant effect of procyanidin B2 on human internal mammary artery

Abstract The aim of the present study was to investigate and characterize vasorelaxant effect of procyanidin B2 on human internal mammary artery (HIMA) as one of the mechanisms of its protective effect against vascular risk. Procyanidin B2 induced strong concentration‐dependent relaxation of HIMA rings pre‐contracted by phenylephrine. Pretreatment with L‐NAME, a NO synthase inhibitor, hydroxocobalamin, a NO scavenger, and ODQ, an inhibitor of soluble guanylate cyclase, significantly inhibited procyanidin B2‐induced relaxation of HIMA, while indomethacin, a cyclooxygenase inhibitor, considerably reduced effects of low concentrations. Among K+ channel blockers, iberiotoxin, a selective blocker of large conductance Ca2+‐activated K+ channels (BKCa), abolished procyanidin B2‐induced relaxation, glibenclamide, a selective ATP‐sensitive K+(KATP) channels blocker, induced partial inhibition, while 4‐aminopyridine, a blocker of voltage‐gated K+(KV) channels, and TRAM‐34, an inhibitor of intermediate‐conductance Ca2+‐activated K+(IKCa) channels, slightly reduced maximal relaxation of HIMA. Further, procyanidin B2 relaxed contraction induced by phenylephrine in Ca2+‐free Krebs solution, but had no effect on contraction induced by caffeine. Finally, thapsigargin, a sarcoplasmic reticulum Ca2+‐ATPase inhibitor, significantly reduced relaxation of HIMA produced by procyanidin B2. These results demonstrate that procyanidin B2 produces endothelium‐dependent relaxation of HIMA pre‐contracted by phenylephrine. This effect is primarily the result of an increased NO synthesis and secretion by endothelial cells and partially of prostacyclin, although it involves activation of BKCa and KATP, as well as KV and IKCa channels in high concentrations of procyanidin B2.

Effect of Elective Bentall Procedure on Left Ventricular Systolic Function and Functional Status: Long-Term Follow-Up in 90 patients

Because there are so few data on the long-term effects on left ventricular systolic function and functional status in patients who electively undergo Bentall procedures, we established a retrospective study group of 90 consecutive patients. This group consisted of 71 male and 19 female patients (mean age, 54 ± 10 yr) who had undergone the Bentall procedure to correct aortic valve disease and aneurysm of the ascending aorta, from 1997 through 2003 in a single tertiary-care center. We monitored these patients for a mean period of 117 ± 41 months for death, left ventricular ejection fraction and volume indices, and functional capacity as determined by New York Heart Association (NYHA) class. There were no operative deaths. The survival rate was 73.3% during follow-up. There were 10 cardiac and 13 noncardiac deaths, and 1 death of unknown cause. Echocardiography was performed before the index procedure and again after 117 ± 41 months. In surviving patients, statistically significant improvement in left ventricular ejection fraction, in comparison with preoperative values (0.49 ± 0.11 vs 0.41 ± 0.11; P <0.0001), was noted at follow-up. Similarly, we observed statistically significant reductions in left ventricular end-systolic (39.24 ± 28.7 vs 48.77 ± 28.62 mL/m(2)) and end-diastolic volumes (54.63 ± 6.97 vs 59.17 ± 8.92 mL/m(2); both P <0.0001). Most patients (53/66 [80.3%]) progressed from a higher to a lower NYHA class during the follow-up period. The Bentall procedure significantly improved long-term left ventricular systolic function and functional status in surviving patients who underwent operation on a nonemergency basis.

Different Potassium Channels are Involved in Relaxation of Rat Renal Artery Induced by P1075

The ATP‐sensitive K+ channels opener (KATPCO), P1075 [N‐cyano‐N′‐(1,1‐dimethylpropyl)‐N″‐3‐pyridylguanidine], has been shown to cause relaxation of various isolated animal and human blood vessels by opening of vascular smooth muscle ATP‐sensitive K+ (KATP) channels. In addition to the well‐known effect on the opening of KATP channels, it has been reported that vasorelaxation induced by some of the KATPCOs includes some other K+ channel subtypes. Given that there is still no information on other types of K+ channels possibly involved in the mechanism of relaxation induced by P1075, this study was designed to examine the effects of P1075 on the rat renal artery with endothelium and with denuded endothelium and to define the contribution of different K+ channel subtypes in the P1075 action on this blood vessel. Our results show that P1075 induced a concentration‐dependent relaxation of rat renal artery rings pre‐contracted by phenylephrine. Glibenclamide, a selective KATP channels inhibitor, partly antagonized the relaxation of rat renal artery induced by P1075. Tetraethylammonium (TEA), a non‐selective inhibitor of Ca2+‐activated K+ channels, as well as iberiotoxin, a most selective blocker of large‐conductance Ca2+‐activated K+ (BKCa) channels, did not abolish the effect of P1075 on rat renal artery. In contrast, a non‐selective blocker of voltage‐gated K+ (KV) channels, 4‐aminopyridine (4‐AP), as well as margatoxin, a potent inhibitor of KV1.3 channels, caused partial inhibition of the P1075‐induced relaxation of rat renal artery. In addition, in this study, P1075 relaxed contractions induced by 20 mM K+, but had no effect on contractions induced by 80 mM K+. Our results showed that P1075 induced strong endothelium‐independent relaxation of rat renal artery. It seems that KATP, 4‐AP‐ and margatoxin‐sensitive K+ channels located in vascular smooth muscle mediated the relaxation of rat renal artery induced by P1075.

(−)-Epicatechin-induced relaxation of isolated human saphenous vein: Roles of K+ and Ca2+ channels

In this study, we aimed to investigate relaxant effect of flavanol (−)‐epicatechin on the isolated human saphenous vein (HSV), as a part of its cardioprotective action, and to define the mechanisms underlying this vasorelaxation. (−)‐Epicatechin induced a concentration‐dependent relaxation of HSV pre‐contracted by phenylephrine. Among K+ channel blockers, 4‐aminopyridine, margatoxin, and iberiotoxin significantly inhibited relaxation of HSV, while glibenclamide considerably reduced effects of the high concentrations of (−)‐epicatechin. Additionally, (−)‐epicatechin relaxed contraction induced by 80 mM K+, whereas in the presence of nifedipine produced partial relaxation of HSV rings pre‐contracted by phenylephrine. In Ca2+‐free solution, (−)‐epicatechin relaxed contraction induced by phenylephrine, but had no effect on contraction induced by caffeine. A sarcoplasmic reticulum Ca2+‐ATPase inhibitor, thapsigargin, significantly reduced relaxation of HSV produced by (−)‐epicatechin. These results demonstrate that (−)‐epicatechin produces endothelium‐independent relaxation of isolated HSV rings. Vasorelaxation to (−)‐epicatechin probably involves activation of 4‐aminopyridine‐ and margatoxin‐sensitive KV channels, BKCa channels, and at least partly, KATP channels. In addition, not only the inhibition of extracellular Ca2+ influx, but regulation of the intracellular Ca2+ release, via inositol‐trisphosphate receptors and reuptake into sarcoplasmic reticulum, via stimulation of Ca2+‐ATPase, as well, most likely participate in (−)‐epicatechin‐induced relaxation of HSV.

Postoperative Complications and Patient’s Satisfaction after Harvesting of the Radial Artery for Coronary Artery Bypass

Objectives: There is a paucity of data regarding wound-site complications and patient’s satisfaction after harvesting of a radial artery. This study is conducted to evaluate the frequency complications and the level of patient’s satisfaction after myocardial revascularization in our setting. Methods: From April 2009 to October 2013, 97 patients had radial artery (RA) used as a graft in myocardial revascularization. The graft was harvested using open technique. This was retrospective study. Telephone questionnaire was used to evaluate: arm pain, swelling, mobility, sensory changes, patient’s contentment with a cosmetic result and the general health state. Results: Pain of limited duration was reported by 24 patients (24.7%), none of them reported permanent pain. Some problems in performing everyday’s activities were reported by 8 pts (8.2%). Sensory changes were permanently present in 5 pts (5.2%), and frequent arm fatigue was reported by 4 pts (4.1%). Positive opinion regarding the cosmetic result was reported by 95 pts (97.9%). State of the health after surgery, 81 pts (83.5%) described as excellent or good. Patients who had more mobility problems, also had more sensory and neurological discomfort respectively. Patients with better self-reported general health state were also more satisfied with the esthetic effect of the intervention. Conclusions: Using the open technique resulted in excellent cosmetic effect. This gives us credit to point out that exclusive need of the endoscopic as a supreme method might be under the question mark. Our study suggests that individual attitude of the particular patient plays extremely important role in his/her overall satisfaction with the end effect of the procedure.