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Biomedical subjects

M Zaugg

Publications and source records attributed to M Zaugg.

At least 19 recordsLinked to original sources
PubMed2005

Anaesthetic preconditioning but not postconditioning prevents early activation of the deleterious cardiac remodelling programme: evidence of opposing genomic responses in cardioprotection by pre- and postconditioning.

BACKGROUND: Anaesthetic preconditioning (A_PreC) and postconditioning (A_PostC) both provide protection against ischaemia-reperfusion in the heart. However, post-ischaemic gene responses may differ between the two therapeutic strategies. METHODS: Isolated perfused rat hearts were exposed to 40 min test ischaemia followed by 3 h reperfusion and used to determine transcriptional changes in response to A_PreC and A_PostC. A_PreC was induced by 15 min of isoflurane 2.1 vol% followed by 10 min of washout, and A_PostC was induced by 15 min of isoflurane 2.1 vol% administered at the onset of reperfusion. Untreated hearts served as ischaemic control (ISCH). Coupled-two way clustering (CTWC) and principal component analysis (PCA) were used to identify gene expression patterns. RESULTS: A_PreC (7[sd 1]%) and A_PostC (6[2]%) produced a similar decrease in infarct size (ISCH 36[1]%, P<0.05). However, post-ischaemic genomic reprogramming was completely different. Few genes were jointly regulated (2.1 per thousand of upregulated genes and 1.3% of downregulated genes). Eight stable gene clusters including three subclusters emerged from CTWC and were related to inflammation, signalling, ion channels, transcription factors, long interspersed repetitive DNA, heat shock response and remodelling. Two stable sample clusters were identified for postconditioned hearts (first cluster) and for all other protocols (second cluster), emphasizing the unique cardiac phenotype elicited by A_PostC. PCA revealed a close genomic relationship between A_PreC and non-ischaemic healthy myocardium. CONCLUSIONS: A_PreC, but not A_PostC, induces a post-ischaemic gene expression profile similar to virgin myocardium and prevents activation of the deleterious cardiac remodelling programme. Hence A_PreC and A_PostC are not interchangeable with respect to their molecular outcome in the heart.

Anesthetics↗
PubMed2005

[Strategies for perioperative sympatho-modulation].

Despite the growing evidence for the efficacy of different sympatho-modulatory therapies to lower perioperative cardiac morbidity and mortality, such therapeutic strategies are rather infrequently used in daily clinical practice. Most physicians involved in perioperative medicine are aware of the increasing literature related to this topic, but only few comply with current clinical practice guidelines even in the absence of contraindications. This review discusses possible explanations for this reluctance and again summarizes the basic and clinical principles of current sympatho-modulatory therapies including alpha(2)-agonism, beta-adrenergic antagonism, and regional anesthetic techniques in modern anesthetic practice. In addition, the emerging perioperative concept of a patient-tailored individualized pharmacotherapy based on "gene profiling", particularly the adrenergic polymorphisms, is discussed.

Adrenergic alpha-Agonists↗
PubMed2004

Preconditioning with sevoflurane decreases PECAM-1 expression and improves one-year cardiovascular outcome in coronary artery bypass graft surgery.

BACKGROUND: Cardiac preconditioning is thought to be involved in the observed decreased coronary artery reocclusion rate in patients with angina preceding myocardial infarction. We prospectively examined whether preconditioning by sevoflurane would decrease late cardiac events in patients undergoing coronary artery bypass graft (CABG) surgery. METHODS: Seventy-two patients scheduled for elective CABG surgery were randomized to preconditioning by sevoflurane (10 min at 4 vol%) or placebo. For all patients, follow-up of adverse cardiac events was obtained 6 and 12 months after surgery. Transcript levels for platelet-endothelial cell adhesion molecule-1 (PECAM-1/CD31), catalase and heat shock protein 70 (Hsp70) were determined in atrial biopsies after sevoflurane preconditioning. RESULTS: Pharmacological preconditioning by sevoflurane reduced the incidence of late cardiac events during the first year after CABG surgery (sevoflurane 3% vs 17% in the placebo group, log-rank test, P=0.038). One patient in the sevoflurane group and three patients in the placebo group experienced new episodes of congestive heart failure and three additional patients had coronary artery reocclusion. Perioperative peak concentrations for myocardial injury markers were higher in patients with subsequent late cardiac events [NTproBNP, 9031 (4125) vs 3049 (1906) ng litre(-1), P<0.001; cTnT, 1.31 (0.88) vs 0.46 (0.29) microg litre(-1), P<0.001]. Transcript levels were reduced for PECAM-1 and increased for catalase but unchanged for Hsp70 in atrial biopsies after sevoflurane preconditioning. CONCLUSIONS: This prospective randomized clinical study provides evidence of a protective role for pharmacological preconditioning by sevoflurane in late cardiac events in CABG patients, which may be related to favourable transcriptional changes in pro- and antiprotective proteins.

Adult↗
PubMed2004

Cellular mechanisms in sympatho-modulation of the heart.

Cardiovascular function relies on complex servo-controlled regulation mechanisms that involve both fast-acting feedback responses and long-lasting adaptations affecting the gene expression. The adrenergic system, with its specific receptor subtypes and intracellular signalling cascades provides the major regulatory system, while the parasympathetic system plays a minor role. At the molecular level, Ca(2+) acts as the general signal trigger for the majority of cell activities including contraction, metabolism and growth. During recent years, important new results have emerged allowing an integrated view of how the multifarious Ca(2+)-signalling mechanisms transmit adrenergic impulses to intracellular target sites. These insights into cellular and molecular mechanisms are pivotal in improving pharmacological control of the sympathetic responses to surgical trauma and perioperative stress. They are examined in detail in this review, with particular emphasis being given to the differences in intracellular signalling between cardiomyocytes and vascular smooth muscle cells.

Calcium↗
PubMed2004

Off-pump coronary artery bypass surgery: physiology and anaesthetic management.

Increasing interest is being shown in beating heart (off-pump) coronary artery surgery (OPCAB) because, compared with operations performed with cardiopulmonary bypass, OPCAB surgery may be associated with decreased postoperative morbidity and reduced total costs. Its appears to produce better results than conventional surgery in high-risk patient populations, elderly patients, and those with compromised cardiac function or coagulation disorders. Recent improvements in the technique have resulted in the possibility of multiple-vessel grafting in all coronary territories, with a graft patency comparable with conventional surgery. During beating-heart surgery, anaesthetists face two problems: first, the maintenance of haemodynamic stability during heart enucleation necessary for accessing each coronary artery; and second, the management of intraoperative myocardial ischaemia when coronary flow must be interrupted during grafting. The anaesthetic technique is less important than adequate management of these two major constraints. However, experimental and recent clinical data suggest that volatile anaesthetics have a marked cardioprotective effect against ischaemia, and might be specifically indicated. OPCAB surgery requires team work between anaesthetists and surgeons, who must be aware of each other's constraints. Some surgical aspects of the operation are reviewed along with physiological and anaesthetic data.

Anesthesia, General↗
PubMed2003

Anaesthetics and cardiac preconditioning. Part I. Signalling and cytoprotective mechanisms.

Cardiac preconditioning represents the most potent and consistently reproducible method of rescuing heart tissue from undergoing irreversible ischaemic damage. Major milestones regarding the elucidation of this phenomenon have been passed in the last two decades. The signalling and amplification cascades from the preconditioning stimulus, be it ischaemic or pharmacological, to the putative end-effectors, including the mechanisms involved in cellular protection, are discussed in this review. Volatile anaesthetics and opioids effectively elicit pharmacological preconditioning. Anaesthetic-induced preconditioning and ischaemic preconditioning share many fundamental steps, including activation of G-protein-coupled receptors, multiple protein kinases and ATP-sensitive potassium channels (K(ATP) channels). Volatile anaesthetics prime the activation of the sarcolemmal and mitochondrial K(ATP) channels, the putative end-effectors of preconditioning, by stimulation of adenosine receptors and subsequent activation of protein kinase C (PKC) and by increased formation of nitric oxide and free oxygen radicals. In the case of desflurane, stimulation of alpha- and beta-adrenergic receptors may also be of importance. Similarly, opioids activate delta- and kappa-opioid receptors, and this also leads to PKC activation. Activated PKC acts as an amplifier of the preconditioning stimulus and stabilizes, by phosphorylation, the open state of the mitochondrial K(ATP) channel (the main end-effector in anaesthetic preconditioning) and the sarcolemmal K(ATP) channel. The opening of K(ATP) channels ultimately elicits cytoprotection by decreasing cytosolic and mitochondrial Ca(2+) overload.

Adaptation, Physiological↗
PubMed2003

Anaesthetics and cardiac preconditioning. Part II. Clinical implications.

There is compelling evidence that preconditioning occurs in humans. Experimental studies with potential clinical implications as well as clinical studies evaluating ischaemic, pharmacological and anaesthetic cardiac preconditioning in the perioperative setting are reviewed. These studies reveal promising results. However, there are conflicting reports on the efficacy of preconditioning in the diseased and aged myocardium. In addition, many anaesthetics and a significant number of perioperatively administered drugs affect the activity of cardiac sarcolemmal and mitochondrial K(ATP) channels, the end-effectors of cardiac preconditioning, and thereby markedly modulate preconditioning effects in myocardial tissue. Although these modulatory effects on K(ATP) channels have been investigated almost exclusively in laboratory investigations, they may have potential implications in clinical medicine. Important questions regarding the clinical utility and applicability of perioperative cardiac preconditioning remain unresolved and need more experimental work and randomized controlled clinical trials.

Adaptation, Physiological↗
PubMed2002

Modulation of beta-adrenergic receptor subtype activities in perioperative medicine: mechanisms and sites of action.

This review focuses on the mechanisms and sites of action underlying beta-adrenergic antagonism in perioperative medicine. A large body of knowledge has recently emerged from basic and clinical research concerning the mechanisms of the life-saving effects of beta-adrenergic antagonists (beta-AAs) in high-risk cardiac patients. This article re-emphasizes the mechanisms underlying beta-adrenergic antagonism and also illuminates novel rationales behind the use of perioperative beta-AAs from a biological point of view. Particularly, it delineates new concepts of beta-adrenergic signal transduction emerging from transgenic animal models. The role of the different characteristics of various beta-AAs is discussed, and evidence will be presented for the selection of one specific agent over another on the basis of individual drug profiles in defined clinical situations. The salutary effects of beta-AAs on the cardiovascular system will be described at the cellular and molecular levels. Beta-AAs exhibit many effects beyond a reduction in heart rate, which are less known by perioperative physicians but equally desirable in the perioperative care of high-risk cardiac patients. These include effects on core components of an anaesthetic regimen, such as analgesia, hypnosis, and memory function. Despite overwhelming evidence of benefit, beta-AAs are currently under-utilized in the perioperative period because of concerns of potential adverse effects and toxicity. The effects of acute administration of beta-AAs on cardiac function in the compromised patient and strategies to counteract potential adverse effects will be discussed in detail. This may help to overcome barriers to the initiation of perioperative treatment with beta-AAs in a larger number of high-risk cardiac patients undergoing surgery.

Adrenergic beta-Antagonists↗
PubMed2001

Anabolic-androgenic steroids induce apoptotic cell death in adult rat ventricular myocytes.

We tested whether exposure to anabolic-androgenic steroids (AASs) would induce apoptosis in adult rat ventricular myocytes in vitro. Myocytes were exposed to stanozolol (STZ), testosterone enanthate (TE) and testosterone (T) (0.1 micromol/L, 1 micromol/L, 10 micromol/L, and 100 micromol/L) for 20 h. The percentage of myocytes undergoing apoptosis was determined by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) and was found to be increased when compared to control myocytes at STZ 10 micromol/L 12 +/- 2% (mean +/- SD), STZ 100 micromol/L 42 +/- 3%; TE 1 micromol/L 11 +/- 2%, TE 10 micromol/L 21 +/- 3%, TE 100 micromol/L 62 +/- 2%; T 10 micromol/L 11 +/- 2%, T 100 micromol/L 40 +/- 3% (P < 0.001 vs. CTL 2 +/- 2%). The STZ-, TE- and T-induced dose-dependent apoptotic cell death was corroborated by a significantly increased DNA laddering in myocytes exposed to STZ and T > or = 10 micromol/L and TE > or = 1 micromol/L. Notably, STZ, TE, and T exposure markedly increased the expression of the pro-apoptotic oncogene Bax-alpha, as assessed by reverse transcription-polymerase chain reaction. Taken together, these results clearly show for the first time that AASs induce apoptotic cell death in a dose-dependent manner. This finding may have important implications in understanding the pathogenesis of ventricular remodeling, cardiomyopathy, and sudden cardiac death associated with AAS abuse.

Anabolic Agents↗
PubMed2000

Beta-adrenergic receptor subtypes differentially affect apoptosis in adult rat ventricular myocytes.

BACKGROUND-Catecholamine-induced apoptosis is mediated by activation of the beta-adrenergic signaling pathway. We tested the hypothesis that beta(1)- and beta(2)-adrenergic receptor (AR) subtypes differentially affect apoptosis in adult rat ventricular myocytes in vitro. METHODS AND RESULTS-Myocytes were first exposed to norepinephrine (NE) alone (10 mcmol/L) or NE+atenolol (AT) (10 mcmol/L) for 12 hours. AT, a beta(1)-selective AR antagonist, abolished the NE-induced increase in nick end-labeling (TUNEL)-positive cells compared with control (NE, 33+/-3% versus control, 3+/-1%, P<0.0001; NE+AT, 4+/-2% versus control, 3+/-1%, P=0. 98). Annexin V staining, DNA laddering, and caspase activity determinations corroborated these results. Subsequent experiments under prazosin treatment established the apoptosis dose-response curves for the increasingly beta(2)-selective AR agonists isoproterenol (ISO) (beta(1) approximately beta(2)) and albuterol (ALB) (beta(2)>beta(1)). ISO and ALB induced significantly less apoptosis than NE (beta(1)>beta(2)) at equimolar concentrations as assessed by TUNEL staining [1 mcmol/L: NE (8+/-2%) approximately ISO (7+/-1%)>ALB (2+/-1%); 10 mcmol/L: NE (35+/-2%)>ISO (23+/-1%)>ALB (3+/-1%); 100 mcmol/L: NE (50+/-2%)>ISO (29+/-2%)>ALB (14+/-1%), P<0.0001 except for NE versus ISO at 1 mcmol/L with P=0.62]. ALB-induced apoptosis at 100 mcmol/L was abolished by AT (10 mcmol/L), indicating a beta(1)AR-mediated effect. Importantly, ICI 118551 (0.1 mcmol/L), a highly selective beta(2)AR antagonist, did not decrease the percentage of NE-, ISO-, and ALB-induced apoptosis. Reverse transcription-polymerase chain reaction studies revealed that AT completely reversed the beta-adrenergic signaling-induced changes in the Bcl-2-to-Bax ratio. CONCLUSIONS-These observations provide evidence that beta AR-mediated apoptotic death signaling is largely dissociated from beta(2)ARs and selectively mediated by beta(1)ARs in adult rat ventricular myocytes.

Adrenergic beta-Antagonists↗
PubMed2000

Respiratory function in the elderly.

Aging reduces the reserve capacity of virtually all pulmonary functions. Age-related alterations in the respiratory system are based on structural changes that lead to functional impairment of gas exchange. Pulmonary complications during anesthesia and the postoperative period are significantly increased in elderly patients with pre-existing diseases. The physiologic changes in the aged respiratory system and their anesthetic implications are reviewed in this article.

Aged↗
PubMed2000

Norepinephrine-induced apoptosis is inhibited in adult rat ventricular myocytes exposed to volatile anesthetics.

BACKGROUND: Volatile anesthetics are used to provide anesthesia to patients with heart disease under heightened adrenergic drive. The purpose of this study was to test whether volatile anesthetics can inhibit norepinephrine (NE)-induced apoptosis in cardiomyocytes. METHODS: Rat ventricular cardiomyocytes were exposed to NE (10 microm) alone or in the presence of increasing concentrations of isoflurane and halothane. RESULTS: Isoflurane at 1.6 minimum alveolar concentration (MAC) (4 +/- 2% [SD]) and halothane at 1.2 MAC (3 +/- 2%) abolished the percentage of cardiomyocytes undergoing NE-induced apoptosis (34 +/- 8%), as assessed by terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) (P < 0.0001). Lower concentrations of isoflurane and halothane markedly decreased the number of TUNEL-positive cells. Similarly, isoflurane at 1.6 MAC (5 +/- 3%) and halothane at 1.2 MAC (6 +/- 3%) prevented the increase in annexinV-staining cardiomyocytes (38 +/- 7%; P < 0. 0001). These findings were corroborated with a decreased quantity of NE-induced DNA laddering by volatile anesthetics. Halothane at 1.2 MAC abolished the increase in TUNEL-positive cardiomyocytes exposed to the dihydropyridine Ca2+-channel agonist BAY K-8644 (1 microm) (BAY K-8644 + halothane: 3 +/- 2% vsBAY K-8644: 34 +/- 6%; P < 0. 0001) and the Ca2+-ionophore 4-bromo-A23187 (1 microm) (4-bromo-A23187 + halothane: 2 +/- 2% vs4-bromo-A23187: 13 +/- 4%; P = 0.03). NE treatment increased caspase-9 activity to 197 +/- 62% over control myocytes (P < 0.0001), whereas no caspase-8 activation was detectable. This increase in caspase-9 activity was blocked by isoflurane at 1.6 MAC and halothane at 1.2 MAC. CONCLUSIONS: Volatile anesthetics offer significant protection against beta-adrenergic apoptotic death signaling in ventricular cardiomyocytes. The authors present evidence that this protection is mainly mediated through modulation of cellular Ca2+ homeostasis and inhibition of the apoptosis initiator caspase-9.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1999

Beneficial effects from beta-adrenergic blockade in elderly patients undergoing noncardiac surgery.

BACKGROUND: Perioperative beta-blockade has been shown to improve long-term cardiac outcome in noncardiac surgical patients. A possible mechanism for the reduced risk of perioperative myocardial infarction is the attenuation of the excitotoxic effects of catecholamine surges by beta-blockade. It was hypothesized that beta-blocker-induced alteration of the stress response was responsible for the reported improvements in cardiovascular outcome. Several variables associated with the perioperative use of beta-blockade were also evaluated. METHODS: Sixty-three patients were randomly assigned to one of three groups: group I, no atenolol; group II, pre- and postoperative atenolol; group III, intraoperative atenolol. Hormonal markers of the stress response (neuropeptide Y, epinephrine, norepinephrine, cortisol, and adrenocorticotropic hormone) were evaluated preoperatively and for 72 h after surgery. RESULTS: Perioperative beta-blockade did not significantly alter the hormonal stress response. However, the beta-blocked patients showed improved hemodynamic stability during emergence and postoperatively. They also received less fentanyl intraoperatively (27.7%, P < 0.0001), experienced faster early recovery, had lower pain scores, and required less analgesia in the postanesthesia care unit. Cardiac troponin I release was detected in 8 of 19, 4 of 20, and 5 of 20 patients in groups I, II, and III, respectively (not significant). Three patients in group I had cardiac troponin I levels consistent with myocardial infarction. CONCLUSION: Beta-blockade does not reduce the neuroendocrine stress response, suggesting that this mechanism is not responsible for the previously reported improved cardiovascular outcome. However, it confers several advantages, including decreased analgesic requirements, faster recovery from anesthesia, and improved hemodynamic stability. The release of cardiac troponin I suggests the occurrence of perioperative myocardial damage in this elderly population, which appears to be independent of the neuroendocrine stress response.

Adrenergic beta-Antagonists↗