Miomir Jovic

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.

Anesthetics and cerebral protection in patients undergoing carotid endarterectomy.

EREBRAL ISCHEMIA/HYPOXIA may occur in a vari-ety of perioperative circumstances. The main pathophy-siologic aspects involved in cerebral ischemia/reperfusion arecaused by adenosine triphosphate (ATP) consumption, theexcitotoxic actions of glutamate, changes in ionic homeostasis,and formation of free radicals (Fig 1). Outcomes from suchevents range from subclinical neurocognitive deficits to cata-strophic neurologic morbidity or death.

Mitral valve replacement with posterior transposition of the anterior mitral leaflet which covers and buttresses partially decalcified posterior mitral annular bed.

Mitral valve replacement (MVR) in the presence of the extensive calcification of the mitral annulus is a technical challenge. The heavily calcified annulus can cause great difficulty in the insertion of a prosthetic valve and periprosthetic leakage later on. Vigorous annular decalcification may cause circumflex coronary artery injury, atrioventricular rupture and thromboembolic events. We herein describe a surgical technique for MVR in such cases while focusing on partial decalcification of the posterior mitral annulus and its reinforcement and buttressing with the transferred anterior mitral leaflet (AML). At the same time, the transferred AML supports the posterior annular region and maintains ventricular-annular continuity, thus preserving the left ventricular function.

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.

A refined flanged Bentall technique using Valsalva tube graft: does it really wrap all of the proximal anastomosis line?

We read with great interest the article by Koshiyama et al. [1] regarding reinforcement of the proximal anastomosis during composite graft replacement of the aortic root, using one of the modifications of the Bentall and DeBono technique [2]. Modified Bentall procedures have many beneficial effects such as prevention of excessive bleeding and development of false aneurysm, avoidance of the kinking of coronary arteries, as well as reduced tension on ‘button’ coronary anastomoses. However, a major weakness in the composite graft replacement of the ascending aorta is haemostasis at the proximal suture line. A refined, flanged Bentall technique using Vasalva tube graft reported by Koshiyama et al. [1] is similar to the flanged technique reported by Yakut [3], previously. The Valsalva sinus portion of the graft is resected, leaving 10 mm in length as the flange and is everted outwards using Koshiyama’s technique [1], whether a segment (several millimetres in a length) of the proximal end of vascular graft is everted outwards to form the flange of the graft using Yakut’s technique [3]. The polypropylene running suture (3–0 or 4–0) is used to anastomose the cuff of the prosthetic valve to the bottom border of the chosen conduit. Subsequently, the flange is returned to its original position. In both techniques, the homemade composite conduit is seated on the aortic annulus, using continuous 3–0 polypropylene suture [3], or everting pledgeted 2–0 polyester sutures [1], which are passed through the flange below the sewing cuff of the prosthetic valve. Koshiyama et al. [1] stated that using 3–0 polyprolene suture to sew the flange and the margin of the residual proximal aortic wall enabled them to wrap tightly all of the proximal anastomosis line. However, as it can be easily seen on figure 1D of their manuscript [1], only the pledgets of the tied everting pledgeted 2–0 polyester sutures are covered, while the knots of these sutures are still ‘naked’, outside, on the flange, between the flange and prosthetic tube, thus leaving pinholes of the everting mattress sutures as the potential sites of bleeding. On the contrary, Chen et al. [4] modified the composite graft by adding a short skirt (which was made of a part of the distal end of the prosthetic tube) to a standard composite graft root. After the proximal end of the modified composite conduit was secured in the aortic annulus, the short skirt was sewn to the remaining native proximal aortic wall to really wrap all of the proximal anastomosis line. However, we have to point out that Copeland et al. [5] reported an elegant, easily reproducible, and efficient technique to reduce bleeding from the proximal anastomosis after the Bentall procedure. After the composite conduit is seated into the aortic annulus and the sutures are tied, an additional 3–0 polypropylene suture is used to sew the cut edge of the proximal aortic wall and the prosthetic sewing cuff or the prosthetic tube, thus reinforcing and really completely covering all of the proximal anastomosis line.

Copeptin Levels Do Not Correlate With Cross-Clamping Time in Patients Undergoing Carotid Endarterectomy Under General Anesthesia.

Copeptin is a sensitive and more stable surrogate marker for arginine vasopressin. In this study, we evaluated copeptin levels in carotid endarterectomy (CEA) patients, perioperatively, to determine whether copeptin levels can be related to carotid artery cross clamping (CC) time and to postoperative neurological outcomes. Copeptin, interleukin 6, C-reactive protein, cortisol, and brain natriuretic peptide were measured preoperatively (T1) and 3 hours postoperatively (T3) as well as intraoperatively (T2). We recruited 77 patients. Values of copeptin rose gradually over the observed times: T1 = 7.9 (6.4-9.6), T2 = 12.6 (9.3-16.8), and T3 = 72.3 (49.1-111.2) pmol/L. There was a significant difference for repeated measurement (P = .000, P = .000, and P = .000). Duration of carotid artery CC during CEA does not affect postoperative copeptin level (CC ≤ 13 minutes: 106.8 ± 93.6 pmol/L, CC > 13 minutes: 96.7 ± 89.1 pmol/L; P = .634). Preoperative copeptin level was significantly higher in patients with ulcerated plaque morphology. Activation of the stress axis in patients undergoing CEA results in copeptin elevation. Duration of CC during CEA does not affect postoperative copeptin levels.

Experience with IgM-enriched immunoglobulins as adjuvant therapy in septic patient after redo cardiac surgery

Infective endocarditis after combined mitral valve repair and coronary artery bypass surgery, multi-organ failure and sepsis, were treated with mitral valve replacement, antibiotics and adjunctive therapy. Sepsis caused by Gramnegative bacteria, was identified based on the grave clinical status, hemodynamic findings and high levels of proinflammatory cytokines. On the day of the redo surgery, the APACHE II and SOFA scores were 26 and 14, respectively. The IgM-enriched immunoglobulin Pentaglobin® was administered on the first postoperative day after redo procedure. The cardiac index improved from 1.9 L/m2 to 3.7 L/m2 on the 1st postoperative day, accompanied with increasing values of mixed venous oxygen saturation from 59.3% to 77%, while systemic vascular resistance 887 dyn·s/cm5 was maintained by vasopressor agent. On the 4th postoperative day the inotropes and pressors ceased. The acute physiology and chronic health evaluation (APACHE II) score and sequential organ failure assessment (SOFA) score decreased to 10 and 2, respectively. The prompt improvement in patient’s general clinical condition, stabilised hemodynamic parameters, balanced perfusion and oxygen pattern, accompanied by notable reduction of pro-inflammatory cytokine expression, were the outcome of the presented therapeutic approach.

The EuroSCORE: are we contributing to its overprediction of mortality in cardiac surgery nowadays?

We read with great interest the article by Akar et al. [1] regarding validation of the EuroSCORE risk models in the Turkish adult cardiac surgical population. This manuscript is in agreement with previous reports [2–4] that additive and logistic EuroSCORE models overpredict mortality in cardiac surgery nowadays. However, in our opinion there are a few issues that should be clarified. The first one is a definition of mortality. The original EuroSCORE model [5] defined operative mortality as death within 30 days from operation or even later than 30 days if still in hospital (not 30-day mortality as the authors stated in Discussion section of their manuscript [1]). On the other side, their calculation and statistical observations were based only on in-hospital mortality. It is possible that, with the inclusion of all patients who should be included as perioperative deaths (30-day mortality plus in-hospital mortality), the findings of the study [1] would no longer be statistically significant. When we validate a risk stratification model on a population out of its original database, we have to check its discriminatory power and calibration. Model discrimination was analysed by determining the area under the receiver operating characteristic (ROC) curve [1– 5]. However, several statistical procedures have been used to determine calibration. The Hosmer–Lemeshow (H-L) test has been used in >90% of all manuscripts to test the EuroSCORE calibration in different patient population (the H–L test confirms good calibration if the P-value is >0.05), including the EuroSCORE working group [5]. In a few manuscripts calibration plots, unpaired t-test [1], chisquare test [4] or observed to expected (O/E) ratios were used to prove that calibration of the EuroSCORE models was inadequate. Thus, we are curious as to what would be the results of the EuroSCORE calibration checking in these articles if the H–L test was used. On the contrary, Yap et al. [2] wrote an excellent manuscript with intention of validating the EuroSCORE model in Australia. Mortality definition was correct (in-hospital mortality plus 30-day mortality), areas under the ROC curves (0.82) confirmed an excellent discrimination for both additive and logistic EuroSCORE models, but calibration using the H–L test was poor (P 0.05) of the logistic EuroSCORE model. Finally, our question is—should we use the H–L test any more, or we are looking for a statistical procedure that will confirm poor calibration of the EuroSCORE models?

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.