Mauricio Ibacache

Cardiomyocyte death: mechanisms and translational implications

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Although treatments have improved, development of novel therapies for patients with CVD remains a major research goal. Apoptosis, necrosis, and autophagy occur in cardiac myocytes, and both gradual and acute cell death are hallmarks of cardiac pathology, including heart failure, myocardial infarction, and ischemia/reperfusion. Pharmacological and genetic inhibition of autophagy, apoptosis, or necrosis diminishes infarct size and improves cardiac function in these disorders. Here, we review recent progress in the fields of autophagy, apoptosis, and necrosis. In addition, we highlight the involvement of these mechanisms in cardiac pathology and discuss potential translational implications.

Estimation of the plasma effect site equilibration rate constant (ke0) of propofol in children using the time to peak effect: comparison with adults.

Background:Targeting the effect site concentration may offer advantages over the traditional forms of administrating intravenous anesthetics. Because the lack of the plasma effect site equilibration rate constant (ke0) for propofol in children precludes the use of this technique in this population, the authors estimated the value of ke0 for propofol in children using the time to peak effect (tpeak) method and two pharmacokinetic models of propofol for children. Methods:The tpeak after a submaximal bolus dose of propofol was measured by means of the Alaris A-Line auditory evoked potential monitor (Danmeter A/S, Odense, Denmark) in 25 children (aged 3–11 yr) and 25 adults (aged 35–48 yr). Using tpeak and two previously validated sets of pharmacokinetic parameters for propofol in children, Kataria’s and that used in the Paedfusor (Graseby Medical Ltd., Hertfordshire, United Kingdom), the ke0 was estimated according to a method recently published. Results:The mean tpeak was 80 ± 20 s in adults and 132 ± 49 s in children (P < 0.001). The median ke0 in children was 0.41 min−1 with the model of Kataria and 0.91 min−1 with the Paedfusor model (P < 0.01). The corresponding t1/2 ke0 values, in minutes, were 1.7 and 0.8, respectively (P < 0.01). Conclusions:Children have a significantly longer tpeak of propofol than adults. The values of ke0 of propofol calculated for children depend on the pharmacokinetic model used and also can only be used with the appropriate set of pharmacokinetic parameters to target effect site in this population.

Dexmedetomidine preconditioning activates pro-survival kinases and attenuates regional ischemia/reperfusion injury in rat heart

Pharmacological preconditioning limits myocardial infarct size after ischemia/reperfusion. Dexmedetomidine is an α(2)-adrenergic receptor agonist used in anesthesia that may have cardioprotective properties against ischemia/reperfusion injury. We investigate whether dexmedetomidine administration activates cardiac survival kinases and induces cardioprotection against regional ischemia/reperfusion injury. In in vivo and ex vivo models, rat hearts were subjected to 30 min of regional ischemia followed by 120 min of reperfusion with dexmedetomidine before ischemia. The α(2)-adrenergic receptor antagonist yohimbine was also given before ischemia, alone or with dexmedetomidine. Erk1/2, Akt and eNOS phosphorylations were determined before ischemia/reperfusion. Cardioprotection after regional ischemia/reperfusion was assessed from infarct size measurement and ventricular function recovery. Localization of α(2)-adrenergic receptors in cardiac tissue was also assessed. Dexmedetomidine preconditioning increased levels of phosphorylated Erk1/2, Akt and eNOS forms before ischemia/reperfusion; being significantly reversed by yohimbine in both models. Dexmedetomidine preconditioning (in vivo model) and peri-insult protection (ex vivo model) significantly reduced myocardial infarction size, improved functional recovery and yohimbine abolished dexmedetomidine-induced cardioprotection in both models. The phosphatidylinositol 3-kinase inhibitor LY-294002 reversed myocardial infarction size reduction induced by dexmedetomidine preconditioning. The three isotypes of α(2)-adrenergic receptors were detected in the whole cardiac tissue whereas only the subtypes 2A and 2C were observed in isolated rat adult cardiomyocytes. These results show that dexmedetomidine preconditioning and dexmedetomidine peri-insult administration produce cardioprotection against regional ischemia/reperfusion injury, which is mediated by the activation of pro-survival kinases after cardiac α(2)-adrenergic receptor stimulation.

Effect site concentrations of propofol producing hypnosis in children and adults: comparison using the bispectral index.

Background:  No study has determined the concentration of propofol producing a degree of hypnosis compatible with anaesthesia in children. As a result, concentrations determined in adults are recommended for children. As this can result in an inadequate depth of anaesthesia, we determined the predicted effect site concentration (Ce) of propofol necessary to obtain a bispectral index (BIS) of 50 in 50% (ECe50) of children and adults.

Performance of Propofol Target-Controlled Infusion Models in the Obese: Pharmacokinetic and Pharmacodynamic Analysis

BACKGROUND:Obesity is associated with important physiologic changes that can potentially affect the pharmacokinetic (PK) and pharmacodynamic (PD) profile of anesthetic drugs. We designed this study to assess the predictive performance of 5 currently available propofol PK models in morbidly obese patients and to characterize the Bispectral Index (BIS) response in this population. METHODS:Twenty obese patients (body mass index >35 kg/m2), aged 20 to 60 years, scheduled for laparoscopic bariatric surgery, were studied. Anesthesia was administered using propofol by target-controlled infusion and remifentanil by manually controlled infusion. BIS data and propofol infusion schemes were recorded. Arterial blood samples to measure propofol were collected during induction, maintenance, and the first 2 postoperative hours. Median performance errors (MDPEs) and median absolute performance errors (MDAPEs) were calculated to measure model performance. A PKPD model was developed using NONMEM to characterize the propofol concentration–BIS dynamic relationship in the presence of remifentanil. RESULTS:We studied 20 obese adults (mean weight: 106 kg, range: 85–141 kg; mean age: 33.7 years, range: 21–53 years; mean body mass index: 41.4 kg/m2, range: 35–52 kg/m2). We obtained 294 arterial samples and analyzed 1431 measured BIS values. When total body weight (TBW) was used as input of patient weight, the Eleveld allometric model showed the best (P < 0.0001) performance with MDPE = 18.2% and MDAPE = 27.5%. The 5 tested PK models, however, showed a tendency to underestimate propofol concentrations. The use of an adjusted body weight with the Schnider and Marsh models improved the performance of both models achieving the lowest predictive errors (MDPE = <10% and MDAPE = <25%; all P < 0.0001). A 3-compartment PK model linked to a sigmoidal inhibitory Emax PD model by a first-order rate constant (ke0) adequately described the propofol concentration–BIS data. A lag time parameter of 0.44 minutes (SE = 0.04 minutes) to account for the delay in BIS response improved the fit. A simulated effect-site target of 3.2 &mgr;g/mL (SE = 0.17 &mgr;g/mL) was estimated to obtain BIS of 50, in the presence of remifentanil, for a typical patient in our study. CONCLUSIONS:The Eleveld allometric PK model proved to be superior to all other tested models using TBW. All models, however, showed a trend to underestimate propofol concentrations. The use of adjusted body weight instead of TBW with the traditional Schnider and Marsh models markedly improved their performance achieving the lowest predictive errors of all tested models. Our results suggest no relevant effect of obesity on both the time profile of BIS response and the propofol concentration–BIS relationship.

Remifentanil requirements during propofol administration to block the somatic response to skin incision in children and adults.

BACKGROUND:During sevoflurane administration, children require a remifentanil infusion rate twofold higher than adults to block responses to skin incision. Similar data concerning remifentanil requirements are unavailable during total IV anesthesia. METHODS:We prospectively determined the infusion rate (IR) of remifentanil necessary to block the somatic response to skin incision in 50% (IR50) of adults (n = 20, aged 20–60 yr) and children (n = 20, aged 3–11 yr) during propofol anesthesia. In each patient undergoing lower abdominal surgery, a remifentanil infusion was initiated, followed by target-controlled infusion of propofol set at a plasma concentration of 6 &mgr;g/mL. After tracheal intubation, propofol was reduced to 3 &mgr;g/mL until the end of the study. Remifentanil IR was determined according to Dixons up-and-down method, with the first patient in each group receiving 0.2 &mgr;g · kg−1 · min−1 followed by the consecutive patient receiving 0.02 &mgr;g · kg−1 · min−1 modifications according to the response of the previous patient. The remifentanil IR was kept unchanged for at least 20 min before surgery. At the beginning of surgery, only the skin incision was performed, and the somatic response was observed. If there was any gross movement of extremity the response was considered positive. RESULTS:The IR50 (CI95%) was 0.08 (0.06–0.12) &mgr;g · kg−1 · min−1 in adults and 0.15 (0.13–0.17) &mgr;g · kg−1 · min−1 in children (P < 0.001). CONCLUSION:These results demonstrate that, similar to sevoflurane anesthesia, during total IV anesthesia with propofol, children require a remifentanil IR almost twofold higher than adults to block the somatic response to skin incision.

Influence of glucose metabolism on vascular smooth muscle cell proliferation.

Differentiation of vascular smooth muscle cells (VSMC) is an essential process of vascular development. VSMC have biosynthetic, proliferative, and contractile roles in the vessel wall. Alterations in the differentiated state of the VSMC play a critical role in the pathogenesis of atherosclerosis and intimal hyperplasia, as well as in a variety of other human diseases, including hypertension, asthma, atherosclerosis and vascular aneurysm. This review provides an overview of the current state of knowledge of molecular mechanisms involved in controlling VSMC proliferation, with particular focus on glucose metabolism and its relationship with mitochondrial bioenergetics. Increased levels of glucose transporter 1 (GLUT1) are observed in VSMC after endothelial injury, suggesting a relationship between glucose uptake and VSMC proliferation. Mitochondrial dysfunction is a common feature in VSMC during atherosclerosis. Alterations in mitochondrial function can be produced by dysregulation of mitofusin-2, a small GTPase associated with mitochondrial fusion. Moreover, exacerbated proliferation was observed in VSMC from pulmonary arteries with hyperpolarized mitochondria and enhanced glycolysis/glucose oxidation ratio. Several lines of evidence highlight the relevance of glucose metabolism in the control of VSMC proliferation, indicating a new area to be explored in the control of vascular pathogenesis.

Defective insulin signaling and mitochondrial dynamics in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM) is a common consequence of longstanding type 2 diabetes mellitus (T2DM) and encompasses structural, morphological, functional, and metabolic abnormalities in the heart. Myocardial energy metabolism depends on mitochondria, which must generate sufficient ATP to meet the high energy demands of the myocardium. Dysfunctional mitochondria are involved in the pathophysiology of diabetic heart disease. A large body of evidence implicates myocardial insulin resistance in the pathogenesis of DCM. Recent studies show that insulin signaling influences myocardial energy metabolism by impacting cardiomyocyte mitochondrial dynamics and function under physiological conditions. However, comprehensive understanding of molecular mechanisms linking insulin signaling and changes in the architecture of the mitochondrial network in diabetic cardiomyopathy is lacking. This review summarizes our current understanding of how defective insulin signaling impacts cardiac function in diabetic cardiomyopathy and discusses the potential role of mitochondrial dynamics.

Dexmedetomidine protects the heart against ischemia-reperfusion injury by an endothelial eNOS/NO dependent mechanism.

The alpha2-adrenergic receptor agonist Dexmedetomidine (Dex) is a sedative medication used by anesthesiologists. Dex protects the heart against ischemia-reperfusion (IR) and can also act as a preconditioning mimetic. The mechanisms involved in Dex-dependent cardiac preconditioning, and whether this action occurs directly or indirectly on cardiomyocytes, still remain unclear. The endothelial nitric oxide synthase (eNOS)/nitric oxide (NO) signaling pathway and endothelial cells are known to play key roles in cardioprotection against IR injury. Therefore, the aims of this work were to evaluate whether the eNOS/NO pathway mediates the pharmacological cardiac effect of Dex, and whether endothelial cells are required in this cardioprotective action. Isolated adult rat hearts were treated with Dex (10nM) for 25min and the dimerization of eNOS and production of NO were measured. Hearts were then subjected to global IR (30/120min) and the role of the eNOS/NO pathway was evaluated. Dex promoted the activation of eNOS and production of NO. Dex reduced the infarct size and improved the left ventricle function recovery, but this effect was reversed when Dex was co-administered with inhibitors of the eNOS/NO/PKG pathway. In addition, Dex was unable to reduce cell death in isolated adult rat cardiomyocytes subjected to simulated IR. Cardiomyocyte death was attenuated by co-culturing them with endothelial cells pre-treated with Dex. In summary, our results show that Dex triggers cardiac protection by activating the eNOS/NO signaling pathway. This pharmacological effect of Dex requires its interaction with the endothelium.

Propofol concentration to induce general anesthesia in children aged 3–11 years with the Kataria effect-site model

The propofol pharmacokinetic model derived by Kataria et al. was recently modified to perform effect‐site target‐controlled infusion (TCI). Effect‐site concentration (Ce) targets to induce general anesthesia with this model in children have not been described. The aim of this study was to identify propofol Ce targets associated with success rates of 50% (Ce50) and 95% (Ce95) among children 3–11 years of age.