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Volatile Anesthetic-Induced Cardiac Protection: Molecular Mechanisms, Clinical Aspects, and Interactions With Nonvolatile Agents

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Volatile Anesthetic-Induced Cardioprotection

A number of cardioprotective interventions using volatile anesthetics were identified since the original description of anesthetic-induced preconditioning (APC) in 1997.4 In this regard, actions during myocardial ischemia (state of low cellular pO2) and those happening during myocardial reperfusion (state of high cellular pO2) can be distinguished. Powerful protection via APC can be expected when administering volatile anesthetics before myocardial ischemia, with infarct size reductions of up

Cytosolic Signaling Pathways

Molecular pathways start at receptors of the cell membrane acting on inhibitory G-protein signaling,9 sarcolemmal ATP-dependent potassium channels (sarcKATP),10 β1- and β2-adrenergic receptors,11, 12, 13 and the adenosine-A1 receptor.14 Signal transmission is ensured through survival kinases, in particular phosphatidylinositol-3-kinase (PI3K) with subsequent Akt phosphorylation.15 Both interact with extracellular signal-regulated kinase 1 and 2 (Erk1/2) to form the reperfusion injury salvage

Mitochondrial Mechanisms

The mitochondrion represents a molecular center of cardioprotective signaling. All major mitochondrial functions are pivotal elements of cell survival. Most recently, a proteomics approach revealed that isoflurane-induced cardioprotection altered 98 mitochondrial proteins, emphasizing the importance of the mitochondrial respiratory chain as well as mitochondrial bioenergetics.33

Translocation of survival signaling to the organelle is accomplished mainly through the activation of different PKC

Clinical Studies

Although the use of volatile anesthetics has been identified as an important intervention that might reduce perioperative mortality,59 clinical data provide conflicting results. High concentrations of isoflurane and sevoflurane alleviate cardiac as well as renal damage after coronary artery bypass graft (CABG) surgery,60, 61 and a 1-year follow-up study by Zaugg et al62 suggested improved cardiovascular outcomes. DeHert et al63 corroborated these results while concomitantly challenging the need

Co-Factors Interacting with Volatile Anesthetic-Induced Cardioprotection

The biggest unresolved mystery limiting the clinical translation of any cardioprotective strategy relates to the interactions of age, co-medications, and co-diseases with the molecular pathways of survival signaling (Fig 3). The identification and restoration of the responsible molecular mechanisms represent an urgent goal to facilitate clinical translation. Multiple drugs and co-morbidities affecting volatile anesthetic-induced cardioprotection have been identified, including frequently used

Anesthetic Gases: Nitrous Oxide and Xenon

So far, nitrous oxide has proved to be the only negative exception among inhalation anesthetics with respect to its preconditioning abilities. Studies involving nitrous oxide failed to protect the rat heart in-vivo79 and demonstrated an increased mortality after I/R injury because of impaired recovery of stunned myocardium.80 However, the negative effect of this classic anesthetic is limited, because its mono-use is not feasible in clinical practice and concomitant use does not affect the

Beta-Adrenergic-Receptor Blockers

Beta-adrenergic-receptor blockers are well-known therapeutics in the treatment of coronary artery disease.96 Nevertheless, their beneficial effects often are scrutinized. Therapeutic efficacy in non-heart failure patients remains unclear and a recent observational study even suggested salutary effects might only exist after a prior history of myocardial infarction≤1 year. Patients with risk factors for CAD, those with known prior myocardial infarction>1 year, or CAD without myocardial

Alpha2-Adrenoceptor Agonists

Clonidine and dexmedetomidine long have been shown to protect the heart against ischemic damage, with clonidine’s hemodynamic effects benefiting myocardial oxygen supply and demand.99, 100 Perioperative clonidine administration over 4 days was found to be safe while reducing the risk of perioperative myocardial ischemia in patients undergoing elective noncardiac surgery. Furthermore, 30-day and 2-year survival significantly were improved.101 A meta-analysis including clonidine, mivazerol, and

Propofol

Alterations of the available molecular pathways not only concern long-term medication, but also intravenous anesthetics, most notably propofol. Propofol is a potential mitochondrion toxin, interfering with multiple mitochondrial signaling pathways including the respiratory chain. The propofol infusion syndrome, for example, mimics mitochondrial myopathies. It is caused by impaired entry of long-chain fatty acids, disruption of fatty-acid oxidation and failure of the respiratory chain at complex

Opioids

A number of opioids have been shown to protect the heart against I/R injury if administered before the ischemic insult or myocardial reperfusion. These include remifentanil,139 sufentanil,140 and fentanyl,141 as well as morphine.142, 143 The recruited molecular pathways feature kappa, mu, or delta opioid receptors,144, 145, 146 as well as common pathways of anesthetic or ischemic-induced cardioprotection. Increased Erk1/2 signaling, enhanced antiapoptotic mechanisms, inhibition of proapoptotic

Benzodiazepines

Benzodiazepines do not have cardioprotective effects, but still play an interesting and, to some extent, nebulous role within the paradigms of myocardial I/R damage. A prospective randomized study in pediatric patients did not show a significant difference in cardiac troponin postsurgery when comparing midazolam, propofol, or sevoflurane as the mainstay of anesthesia. However, troponin levels were nearly twice as high in patients receiving midazolam and propofol, suggesting a lack of power.152

Advanced Age

Aging is a dynamic process that alters the availability of numerous signaling pathways and increases the vulnerability to I/R injury. This includes a diminished responsiveness to volatile anesthetic-induced cardioprotection. Sevoflurane alleviated an intracellular pH decrease, Na+ and Ca2+ accumulation, as well as adenosine triphosphate recovery in young adult and middle-aged hearts. In the aged myocardium, these hallmarks of ischemic injury could not be improved.160 Similar results were found

Hyperglycemia and Diabetes Mellitus

Impaired glucose metabolism is one of the hallmarks of the metabolic syndrome and has a significant impact on the ability to condition the heart against I/R injury. Hyperglycemia with blood glucose concentrations of 300 or 600 mg/dL attenuates anesthetic-induced cardioprotection in a dose-dependent manner. Moderate hyperglycemia blocked the protective effects of 0.5 MAC of isoflurane and severe hyperglycemia prevented infarct size reductions while using up to 1.0 MAC.167 The same findings

Perspectives

Volatile anesthetic-induced cardioprotection is a fascinating and proliferative research area, providing a wealth of information on the molecular mechanisms targeted by volatile anesthetics. However, a number of major challenges remain. Clinical practice largely differs from the laboratory setting. The optimal treatment protocol is unknown and molecular interactions interfering with volatile anesthetic-induced cardioprotection are frequent. Advanced age or co-morbidities such as hyperglycemia

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