Hemodynamic effects in dogs anesthetized with isoflurane and remifentanil-isoflurane

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Hemodynamic Performance of Edwards Intuity Valve in a Compliant Aortic Root Model

Numerous designs of bioprosthetic valves exist. The sutureless surgical valve is a newer design concept which combines elements of the transcatheter valve technology with surgical valves. This design aims at shorter and easier implantation. It was the aim of this study to perform hemodynamic and kinematic measurements for this type of valves to serve as a baseline for following studies which investigate the effect of the aortic root on the valve performance. To this end, the Edwards Intuity aortic valve was investigated in a new in vitro flow loop mimicking the left heart. The valve was implanted in a transparent, compliant aortic root model, and the valve kinematics was investigated using a high speed camera together with synchronized hemodynamic measurements of pressures and flows. The valve closure was asynchronous (one by one leaflet), and the valve started to close before the deceleration of the fluid. The aortic root model showed a dilation of the sinuses which was different to the ascending aorta, and the annulus was found to move towards the left ventricle during diastole and towards the aorta during systole.

Postoperative Volume Therapy in Cardiac Surgery : Effects on Hemostatic and Circulatory Variables

Background: Patients may need massive volume-replacement therapy after cardiac surgery because of large fluid transfer perioperatively, and the use of cardiopulmonary bypass. Hemodynamic stability is better maintained with colloids than crystalloids but colloids have more adverse effects such as coagulation disturbances and impairment of renal function than do crystalloids. The present study examined the effects of modern hydroxyethyl starch (HES) and gelatin solutions on blood coagulation and hemodynamics. The mechanism by which colloids disturb blood coagulation was investigated by thromboelastometry (TEM) after cardiac surgery and in vitro by use of experimental hemodilution. Materials and methods: Ninety patients scheduled for elective primary cardiac surgery (Studies I, II, IV, V), and twelve healthy volunteers (Study III) were included in this study. After admission to the cardiac surgical intensive care unit (ICU), patients were randomized to receive different doses of HES 130/0.4, HES 200/0.5, or 4% albumin solutions. Ringer’s acetate or albumin solutions served as controls. Coagulation was assessed by TEM, and hemodynamic measurements were based on thermodilutionally measured cardiac index (CI). Results: HES and gelatin solutions impaired whole blood coagulation similarly as measured by TEM even at a small dose of 7 mL/kg. These solutions reduced clot strength and prolonged clot formation time. These effects were more pronounced with increasing doses of colloids. Neither albumin nor Ringer’s acetate solution disturbed blood coagulation significantly. Coagulation disturbances after infusion of HES or gelatin solutions were clinically slight, and postoperative blood loss was comparable with that of Ringer’s acetate or albumin solutions. Both single and multiple doses of all the colloids increased CI postoperatively, and this effect was dose-dependent. Ringer’s acetate had no effect on CI. At a small dose (7 mL/kg), the effect of gelatin on CI was comparable with that of Ringer’s acetate and significantly less than that of HES 130/0.4 (Study V). However, when the dose was increased to 14 and 21 mL/kg, the hemodynamic effect of gelatin rose and became comparable with that of HES 130/0.4. Conclusions: After cardiac surgery, HES and gelatin solutions impaired clot strength in a dose-dependent manner. The potential mechanisms were interaction with fibrinogen and fibrin formation, resulting in decreased clot strength, and hemodilution. Although the use of HES and gelatin inhibited coagulation, postoperative bleeding on the first postoperative morning in all the study groups was similar. A single dose of HES solutions improved CI postoperatively more than did gelatin, albumin, or Ringer’s acetate. However, when administered in a repeated fashion, (cumulative dose of 14 mL/kg or more), no differences were evident between HES 130/0.4 and gelatin.

Augmentation of cardiac contractility mediated by the human beta(3)-adrenergic receptor overexpressed in the hearts of transgenic mice.

BACKGROUND: Stimulation of beta(1)- and beta(2)-adrenergic receptors (ARs) in the heart results in positive inotropy. In contrast, it has been reported that the beta(3)AR is also expressed in the human heart and that its stimulation leads to negative inotropic effects. METHODS AND RESULTS: To better understand the role of beta(3)ARs in cardiac function, we generated transgenic mice with cardiac-specific overexpression of 330 fmol/mg protein of the human beta(3)AR (TGbeta(3) mice). Hemodynamic characterization was performed by cardiac catheterization in closed-chest anesthetized mice, by pressure-volume-loop analysis, and by echocardiography in conscious mice. After propranolol blockade of endogenous beta(1)- and beta(2)ARs, isoproterenol resulted in an increase in contractility in the TGbeta(3) mice (30%), with no effect in wild-type mice. Similarly, stimulation with the selective human beta(3)AR agonist L-755,507 significantly increased contractility in the TGbeta(3) mice (160%), with no effect in wild-type mice, as determined by hemodynamic measurements and by end-systolic pressure-volume relations. The underlying mechanism of the positive inotropy incurred with L-755,507 in the TGbeta(3) mice was investigated in terms of beta(3)AR-G-protein coupling and adenylyl cyclase activation. Stimulation of cardiac membranes from TGbeta(3) mice with L-755,507 resulted in a pertussis toxin-insensitive 1.33-fold increase in [(35)S]GTPgammaS loading and a 1.6-fold increase in adenylyl cyclase activity. CONCLUSIONS: Cardiac overexpression of human beta(3)ARs results in positive inotropy only on stimulation with a beta(3)AR agonist. Overexpressed beta(3)ARs couple to G(s) and activate adenylyl cyclase on agonist stimulation.

A dynamic causal model of the coupling between pulse stimulation and neural activity

We present a dynamic causal model that can explain context-dependent changes in neural responses, in the rat barrel cortex, to an electrical whisker stimulation at different frequencies. Neural responses were measured in terms of local field potentials. These were converted into current source density (CSD) data, and the time series of the CSD sink was extracted to provide a time series response train. The model structure consists of three layers (approximating the responses from the brain stem to the thalamus and then the barrel cortex), and the latter two layers contain nonlinearly coupled modules of linear second-order dynamic systems. The interaction of these modules forms a nonlinear regulatory system that determines the temporal structure of the neural response amplitude for the thalamic and cortical layers. The model is based on the measured population dynamics of neurons rather than the dynamics of a single neuron and was evaluated against CSD data from experiments with varying stimulation frequency (1–40 Hz), random pulse trains, and awake and anesthetized animals. The model parameters obtained by optimization for different physiological conditions (anesthetized or awake) were significantly different. Following Friston, Mechelli, Turner, and Price (2000), this work is part of a formal mathematical system currently being developed (Zheng et al., 2005) that links stimulation to the blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal through neural activity and hemodynamic variables. The importance of the model described here is that it can be used to invert the hemodynamic measurements of changes in blood flow to estimate the underlying neural activity.

Tyrosine hydroxylase immunoreactivity as indicator of sympathetic activity: simultaneous evaluation in different tissues of hypertensive rats

Burgi K, Cavalleri MT, Alves AS, Britto LRG, Antunes VR, Michelini LC. Tyrosine hydroxylase immunoreactivity as indicator of sympathetic activity: simultaneous evaluation in different tissues of hypertensive rats. Am J Physiol Regul Integr Comp Physiol 300: R264-R271, 2011. First published December 9, 2010; doi: 10.1152/ajpregu.00687.2009.-Vasomotor control by the sympathetic nervous system presents substantial heterogeneity within different tissues, providing appropriate homeostatic responses to maintain basal/stimulated cardiovascular function both at normal and pathological conditions. The availability of a reproducible technique for simultaneous measurement of sympathetic drive to different tissues is of great interest to uncover regional patterns of sympathetic nerve activity (SNA). We propose the association of tyrosine hydroxylase immunoreactivity (THir) with image analysis to quantify norepinephrine (NE) content within nerve terminals in arteries/arterioles as a good index for regional sympathetic outflow. THir was measured in fixed arterioles of kidney, heart, and skeletal muscle of WistarKyoto rats (WKY) and spontaneously hypertensive rats (SHR) (123 +/- 2 and 181 +/- 4 mmHg, 300 +/- 8 and 352 +/- 8 beats/min, respectively). There was a differential THir distribution in both groups: higher THir was observed in the kidney and skeletal muscle (similar to 3-4-fold vs. heart arterioles) of WKY; in SHR, THir was increased in the kidney and heart (2.4- and 5.3-fold vs. WKY, respectively) with no change in the skeletal muscle arterioles. Observed THir changes were confirmed by either: 1) determination of NE content (high-performance liquid chromatography) in fresh tissues (SHR vs. WKY): +34% and +17% in kidney and heart, respectively, with no change in the skeletal muscle; 2) direct recording of renal (RSNA) and lumbar SNA (LSNA) in anesthetized rats, showing increased RSNA but unchanged LSNA in SHR vs. WKY. THir in skeletal muscle arterioles, NE content in femoral artery, and LSNA were simultaneously reduced by exercise training in the WKY group. Results indicate that THir is a valuable technique to simultaneously evaluate regional patterns of sympathetic activity.

Aspectos metodológicos relacionados aos sistemas manométricos utilizados em estudos hemodinâmicos

Atualmente, diante das técnicas atuais, a manometria tem sido relegada a plano secundário durante a cateterização cardíaca. No entanto, ainda fornece importantes informações para identificação e avaliação das doenças cardiovasculares. Os dados coletados durante os exames possibilitam a obtenção de variáveis quantitativas e qualitativas, as quais podem ser comparadas aos padrões normais. Os sistemas manométricos são compostos por transdutor, amplificador e registrador, que, em conjunto, devem espelhar com fidelidade a morfologia e os valores das variáveis analisadas. Para atingir esse objetivo, é necessário desempenho adequado de todos os componentes. Se uma determinada informação é de extrema relevância, o operador deve gastar tempo suficiente para obtê-la de maneira inequívoca. Assim, o operador deve estar familiarizado com os sistemas manométricos e com as fontes de erro relacionadas com as técnicas de registro, cateteres, conectores e fluidos. Com os fundamentos analisados neste manuscrito, salientamos que deve ser dispensada atenção às ondas de pressão usadas nas interpretações da fisiopatologia das doenças cardiovasculares.

Elevated Plasma Hemoglobin Levels Increase Nitric Oxide Consumption in Experimental and Clinical Acute Pulmonary Thromboembolism

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Antioxidant treatment protects against matrix metalloproteinase activation and cardiomyocyte injury during acute pulmonary thromboembolism

Increased reactive oxygen species (ROS) promote matrix metalloproteinase (MMP) activities and may underlie cardiomyocyte injury and the degradation of cardiac troponin I (cTI) during acute pulmonary thromboembolism (APT). We examined whether pretreatment or therapy with tempol (a ROS scavenger) prevents MMP activation and cardiomyocyte injury of APT. Anesthetized sheep received tempol infusion (1.0 mg kg(-1) min(-1), i.v.) or saline starting 30 min before or 30 min after APT (autologous blood clots). Control animals received saline. Hemodynamic measurements were performed. MMPs were studied in the right ventricle (RV) by gelatin zymography, fluorimetric activity assay, and in situ zymography. The ROS levels were determined in the RV and cTI were measured in serum samples. APT increased the pulmonary arterial pressure and pulmonary vascular resistance by 146 and 164 %, respectively. Pretreatment or therapy with tempol attenuated these increases. While APT increased RV + dP/dt (max), tempol infusions had no effects. APT increased RV MMP-9 (but not MMP-2) levels. In line with these findings, APT increased RV MMP activities, and this finding was confirmed by in situ zymography. APT increased the RV ROS levels and tempol infusion, before or after APT, and blunted APT-induced increases in MMP-9 levels, MMP activities, in situ MMP activities, and ROS levels in the RV. cTI concentrations increased after APT, and tempol attenuated these increases. RV oxidative stress after APT increases the RV MMP activities, leading to the degradation of sarcomeric proteins, including cTI. Antioxidant treatment may prevent MMP activation and protect against cardiomyocyte injury after APT.

Transjugular intravascular ultrasound for the evaluation of hepatic vasculature and parenchyma in patients with chronic liver disease

Background The evaluation of the hepatic parenchyma in patients with chronic liver disease is important to assess the extension, localization and relationship with adjacent anatomical structures of possible lesions. This is usually performed with conventional abdominal ultrasound, CT-scan or magnetic resonance imaging. In this context, the feasibility and the safety of intravascular ultrasound in the liver have not been assessed yet. Methods We tested the safety and performance of an intracardiac echography (ICE) catheter applied by a transjugular approach into the hepatic veins in patients with chronic liver disease undergoing hepatic hemodynamic measurements. Results Five patients were enrolled in this pilot study. The insertion of the ICE catheter was possible into the right and middle, but not into the left hepatic vein. The position of the ICE was followed using fluoroscopy and external conventional ultrasound. Accurate imaging of focal hepatic parenchymal lesions, Doppler ultrasound of surrounding blood vessels and assessment of liver surface and ascites were achieved without complications. Conclusions This study demonstrated that a diagnostic approach using an ICE device inserted in the hepatic veins is feasible, safe and well tolerated. However, it remains for the moment only an experimental investigative tool. Whether ICE adds further information regarding parenchymal lesions and associated vascular alterations as compared to other techniques, needs additional investigation.

Practical sources of error in measuring pulmonary artery occlusion pressure: a study in participants of a special intensivist training program of The Scandinavian Society of Anaesthesiology and Intensive Care Medicine (SSAI)

BACKGROUND: Physiological data obtained with the pulmonary artery catheter (PAC) are susceptible to errors in measurement and interpretation. Little attention has been paid to the relevance of errors in hemodynamic measurements performed in the intensive care unit (ICU). The aim of this study was to assess the errors related to the technical aspects (zeroing and reference level) and actual measurement (curve interpretation) of the pulmonary artery occlusion pressure (PAOP). METHODS: Forty-seven participants in a special ICU training program and 22 ICU nurses were tested without pre-announcement. All participants had previously been exposed to the clinical use of the method. The first task was to set up a pressure measurement system for PAC (zeroing and reference level) and the second to measure the PAOP. RESULTS: The median difference from the reference mid-axillary zero level was - 3 cm (-8 to + 9 cm) for physicians and -1 cm (-5 to + 1 cm) for nurses. The median difference from the reference PAOP was 0 mmHg (-3 to 5 mmHg) for physicians and 1 mmHg (-1 to 15 mmHg) for nurses. When PAOP values were adjusted for the differences from the reference transducer level, the median differences from the reference PAOP values were 2 mmHg (-6 to 9 mmHg) for physicians and 2 mmHg (-6 to 16 mmHg) for nurses. CONCLUSIONS: Measurement of the PAOP is susceptible to substantial error as a result of practical mistakes. Comparison of results between ICUs or practitioners is therefore not possible.

Myocardial Ablation of G Protein-Coupled Receptor Kinase 2 (GRK2) Decreases Ischemia/Reperfusion Injury through an Anti-Intrinsic Apoptotic Pathway

Studies from our lab have shown that decreasing myocardial G protein-coupled receptor kinase 2 (GRK2) activity and expression can prevent heart failure progression after myocardial infarction. Since GRK2 appears to also act as a pro-death kinase in myocytes, we investigated the effect of cardiomyocyte-specific GRK2 ablation on the acute response to cardiac ischemia/reperfusion (I/R) injury. To do this we utilized two independent lines of GRK2 knockout (KO) mice where the GRK2 gene was deleted in only cardiomyocytes either constitutively at birth or in an inducible manner that occurred in adult mice prior to I/R. These GRK2 KO mice and appropriate control mice were subjected to a sham procedure or 30 min of myocardial ischemia via coronary artery ligation followed by 24 hrs reperfusion. Echocardiography and hemodynamic measurements showed significantly improved post-I/R cardiac function in both GRK2 KO lines, which correlated with smaller infarct sizes in GRK2 KO mice compared to controls. Moreover, there was significantly less TUNEL positive myocytes, less caspase-3, and -9 but not caspase-8 activities in GRK2 KO mice compared to control mice after I/R injury. Of note, we found that lowering cardiac GRK2 expression was associated with significantly lower cytosolic cytochrome C levels in both lines of GRK2 KO mice after I/R compared to corresponding control animals. Mechanistically, the anti-apoptotic effects of lowering GRK2 expression were accompanied by increased levels of Bcl-2, Bcl-xl, and increased activation of Akt after I/R injury. These findings were reproduced in vitro in cultured cardiomyocytes and GRK2 mRNA silencing. Therefore, lowering GRK2 expression in cardiomyocytes limits I/R-induced injury and improves post-ischemia recovery by decreasing myocyte apoptosis at least partially via Akt/Bcl-2 mediated mitochondrial protection and implicates mitochondrial-dependent actions, solidifying GRK2 as a pro-death kinase in the heart.

Attenuated portal hypertension in germ-free mice: Function of bacterial flora on the development of mesenteric lymphatic and blood vessels

Intestinal bacterial flora may induce splanchnic hemodynamic and histological alterations that are associated with portal hypertension (PH). We hypothesized that experimental PH would be attenuated in the complete absence of intestinal bacteria. We induced prehepatic PH by partial portal vein ligation (PPVL) in germ-free (GF) or mice colonized with altered Schaedler's flora (ASF). After 2 or 7 days, we performed hemodynamic measurements, including portal pressure (PP) and portosystemic shunts (PSS), and collected tissues for histomorphology, microbiology, and gene expression studies. Mice colonized with intestinal microbiota presented significantly higher PP levels after PPVL, compared to GF, mice. Presence of bacterial flora was also associated with significantly increased PSS and spleen weight. However, there were no hemodynamic differences between sham-operated mice in the presence or absence of intestinal flora. Bacterial translocation to the spleen was demonstrated 2 days, but not 7 days, after PPVL. Intestinal lymphatic and blood vessels were more abundant in colonized and in portal hypertensive mice, as compared to GF and sham-operated mice. Expression of the intestinal antimicrobial peptide, angiogenin-4, was suppressed in GF mice, but increased significantly after PPVL, whereas other angiogenic factors remained unchanged. Moreover, colonization of GF mice with ASF 2 days after PPVL led to a significant increase in intestinal blood vessels, compared to controls. The relative increase in PP after PPVL in ASF and specific pathogen-free mice was not significantly different. CONCLUSION In the complete absence of gut microbial flora PP is normal, but experimental PH is significantly attenuated. Intestinal mucosal lymphatic and blood vessels induced by bacterial colonization may contribute to development of PH.

Genome wide search for genetic determinants of habitual alcohol, tobacco and coffee use, obesity-related traits, response to mental and physical stress and hemodynamic traits

Les habitudes de consommation de substances psychoactives, le stress, l’obésité et les traits cardiovasculaires associés seraient en partie reliés aux mêmes facteurs génétiques. Afin d’explorer cette hypothèse, nous avons effectué, chez 119 familles multi-générationnelles québécoises de la région du Saguenay-Lac-St-Jean, des études d’association et de liaison pangénomiques pour les composantes génétiques : de la consommation usuelle d’alcool, de tabac et de café, de la réponse au stress physique et psychologique, des traits anthropométriques reliés à l’obésité, ainsi que des mesures du rythme cardiaque (RC) et de la pression artérielle (PA). 58000 SNPs et 437 marqueurs microsatellites ont été utilisés et l’annotation fonctionnelle des gènes candidats identifiés a ensuite été réalisée. Nous avons détecté des corrélations phénotypiques significatives entre les substances psychoactives, le stress, l’obésité et les traits hémodynamiques. Par exemple, les consommateurs d’alcool et de tabac ont montré un RC significativement diminué en réponse au stress psychologique. De plus, les consommateurs de tabac avaient des PA plus basses que les non-consommateurs. Aussi, les hypertendus présentaient des RC et PA systoliques accrus en réponse au stress psychologique et un indice de masse corporelle (IMC) élevé, comparativement aux normotendus. D’autre part, l’utilisation de tabac augmenterait les taux corporels d’épinéphrine, et des niveaux élevés d’épinéphrine ont été associés à des IMC diminués. Ainsi, en accord avec les corrélations inter-phénotypiques, nous avons identifié plusieurs gènes associés/liés à la consommation de substances psychoactives, à la réponse au stress physique et psychologique, aux traits reliés à l’obésité et aux traits hémodynamiques incluant CAMK4, CNTN4, DLG2, DAG1, FHIT, GRID2, ITPR2, NOVA1, NRG3 et PRKCE. Ces gènes codent pour des protéines constituant un réseau d’interactions, impliquées dans la plasticité synaptique, et hautement exprimées dans le cerveau et ses tissus associés. De plus, l’analyse des sentiers de signalisation pour les gènes identifiés (P = 0,03) a révélé une induction de mécanismes de Potentialisation à Long Terme. Les variations des traits étudiés seraient en grande partie liées au sexe et au statut d’hypertension. Pour la consommation de tabac, nous avons noté que le degré et le sens des corrélations avec l’obésité, les traits hémodynamiques et le stress sont spécifiques au sexe et à la pression artérielle. Par exemple, si des variations ont été détectées entre les hommes fumeurs et non-fumeurs (anciens et jamais), aucune différence n’a été observée chez les femmes. Nous avons aussi identifié de nombreux traits reliés à l’obésité dont la corrélation avec la consommation de tabac apparaît essentiellement plus liée à des facteurs génétiques qu’au fait de fumer en lui-même. Pour le sexe et l’hypertension, des différences dans l’héritabilité de nombreux traits ont également été observées. En effet, des analyses génétiques sur des sous-groupes spécifiques ont révélé des gènes additionnels partageant des fonctions synaptiques : CAMK4, CNTN5, DNM3, KCNAB1 (spécifique à l’hypertension), CNTN4, DNM3, FHIT, ITPR1 and NRXN3 (spécifique au sexe). Ces gènes codent pour des protéines interagissant avec les protéines de gènes détectés dans l’analyse générale. De plus, pour les gènes des sous-groupes, les résultats des analyses des sentiers de signalisation et des profils d’expression des gènes ont montré des caractéristiques similaires à celles de l’analyse générale. La convergence substantielle entre les déterminants génétiques des substances psychoactives, du stress, de l’obésité et des traits hémodynamiques soutiennent la notion selon laquelle les variations génétiques des voies de plasticité synaptique constitueraient une interface commune avec les différences génétiques liées au sexe et à l’hypertension. Nous pensons, également, que la plasticité synaptique interviendrait dans de nombreux phénotypes complexes influencés par le mode de vie. En définitive, ces résultats indiquent que des approches basées sur des sous-groupes et des réseaux amélioreraient la compréhension de la nature polygénique des phénotypes complexes, et des processus moléculaires communs qui les définissent.

Long-latency reductions in gamma power predict hemodynamic changes that underlie the negative BOLD signal

Studiesthat use prolonged periods of sensory stimulation report associations between regional reductions in neural activity and negative blood oxygenation level-dependent (BOLD) signaling. However, the neural generators of the negative BOLD response remain to be characterized. Here, we use single-impulse electrical stimulation of the whisker pad in the anesthetized rat to identify components of the neural response that are related to “negative” hemodynamic changes in the brain. Laminar multiunit activity and local field potential recordings of neural activity were performed concurrently withtwo-dimensional optical imaging spectroscopy measuring hemodynamic changes. Repeated measurements over multiple stimulation trials revealed significant variations in neural responses across session and animal datasets. Within this variation, we found robust long-latency decreases (300 and 2000 ms after stimulus presentation) in gammaband power (30 – 80 Hz) in the middle-superficial cortical layers in regions surrounding the activated whisker barrel cortex. This reduction in gamma frequency activity was associated with corresponding decreases in the hemodynamic responses that drive the negative BOLD signal. These findings suggest a close relationship between BOLD responses and neural events that operate over time scales that outlast the initiating sensory stimulus, and provide important insights into the neurophysiological basis of negative neuroimaging signals.