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In 2021, progress in clinical science related to Cardiac Anesthesiology continued, but at a slower rate due to the ongoing pandemic and disruptions to clinical research. Most progress was incremental and addressed persistent questions related to our field. To identify articles for this review, we completed a structured review using our previously reported methods (1). Specifically, we used the search terms: “cardiac anesthesiology and outcomes” (n = 177), “cardiothoracic anesthesiology” (n = 34), “cardiac anesthesia,” and “clinical outcomes” (n = 42) filtered on clinical trials and the year 2021 in PubMed. We also reviewed clinical trials from the most prominent clinical journals to identify additional studies for a narrative review. We then selected the most noteworthy publications for inclusion in this review and identified key themes.

INTRODUCTION: Pathological flows in patients with severe aortic stenosis are associated with acquired von Willebrand syndrome. This syndrome is characterized by excessive cleavage of von Willebrand factor by its main protease, A Disintegrin and Metalloproteinase with a Thrombospondin Type 1 Motif, Member 13 (ADAMTS13) leading to decreased VWF function and mucocutaneous bleeding. Aortic valve replacement and correction of the flow behavior to physiological levels reverses the syndrome, supporting the association between pathological flow and acquired von Willebrand syndrome. We investigated the effects of shear and elongational rates on von Willebrand factor cleavage in the presence of ADAMTS13. METHODS: We identified acquired von Willebrand syndrome in five patients with severe aortic stenosis. Doppler echography values from these patients were used to develop three computational fluid dynamic (CFD) aortic valve models (normal, mild and severe stenosis). Shear, elongational rates and exposure times identified in the CFD simulations were used as parameters for the design of microfluidic devices to test the effects of pathologic shear and elongational rates on the structure and function of von Willebrand factor. RESULTS: The shear rates (0–10,000s(−1)), elongational rates (0–1000 s(−1)) and exposure times (1–180 ms) tested in our microfluidic designs mimicked the flow features identified in patients with aortic stenosis. The shear and elongational rates tested in vitro did not lead to excessive cleavage or decreased function of von Willebrand factor in the presence of the protease. CONCLUSIONS: High shear and elongational rates in the presence of ADAMTS13 are not sufficient for excessive cleavage of von Willebrand Factor. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12195-020-00631-2) contains supplementary material, which is available to authorized users.

Aging and chronic inflammation are independent risk factors for the development of atherothrombosis and cardiovascular disease. We hypothesized that aging-associated inflammation promotes the development of platelet hyperreactivity and increases thrombotic risk during aging. Functional platelet studies in aged-frail adults and old mice demonstrated that their platelets are hyperreactive and form larger thrombi. We identified tumor necrosis factor α (TNF-α) as the key aging-associated proinflammatory cytokine responsible for platelet hyperreactivity. We further showed that platelet hyperreactivity is neutralized by abrogating signaling through TNF-α receptors in vivo in a mouse model of aging. Analysis of the bone marrow compartments showed significant platelet-biased hematopoiesis in old mice reflected by increased megakaryocyte-committed progenitor cells, megakaryocyte ploidy status, and thrombocytosis. Single-cell RNA-sequencing analysis of native mouse megakaryocytes showed significant reprogramming of inflammatory, metabolic, and mitochondrial gene pathways in old mice that appeared to play a significant role in determining platelet hyperreactivity. Platelets from old mice (where TNF-α was endogenously increased) and from young mice exposed to exogenous TNF-α exhibited significant mitochondrial changes characterized by elevated mitochondrial mass and increased oxygen consumption during activation. These mitochondrial changes were mitigated upon TNF-α blockade. Similar increases in platelet mitochondrial mass were seen in platelets from patients with myeloproliferative neoplasms, where TNF-α levels are also increased. Furthermore, metabolomics studies of platelets from young and old mice demonstrated age-dependent metabolic profiles that may differentially poise platelets for activation. Altogether, we present previously unrecognized evidence that TNF-α critically regulates megakaryocytes resident in the bone marrow niche and aging-associated platelet hyperreactivity and thrombosis.

The roles of factor XIIIa–specific cross-links in thrombus formation, regression, or probability for embolization are largely unknown. A molecular understanding of fibrin architecture at the level of these cross-links could inform the development of therapeutic strategies to prevent the sequelae of thromboembolism. Here, we present an MS-based method to map native factor XIIIa cross-links in the insoluble matrix component of whole-blood or plasma-fibrin clots and in in vivo thrombi. Using a chaotrope-insoluble digestion method and quantitative cross-linking MS, we identified the previously mapped fibrinogen peptides that are responsible for covalent D-dimer association, as well as dozens of novel cross-links in the αC region of fibrinogen α. Our findings expand the known native cross-linked species from one to over 100 and suggest distinct antiparallel registries for interprotofibril association and covalent attachment of serpins that regulate clot dissolution.

The year 2020 was marred by the emergence of a deadly pandemic that disrupted every aspect of life. Despite the disruption, notable research accomplishments in the practice of cardiothoracic anesthesiology occurred in 2020 with an emphasis on optimizing care, improving outcomes, and expanding what is possible for patients undergoing cardiac surgery. This year’s edition of Noteworthy Literature Review will focus on specific themes in cardiac anesthesiology that include preoperative anemia, predictors of acute kidney injury following cardiac surgery, pain management modalities, anticoagulation strategies after transcatheter aortic valve replacement, mechanical circulatory support, and future directions in research.

Blood coagulation is central to myocardial ischemia and reperfusion (IR) injury. Studies on the light elicited circadian rhythm protein Period 2 (PER2) using whole bodyPer2-/-mice found deficient platelet function and reduced clotting which would be expected to protect from myocardial IR-injury. In contrast, intense light induction of PER2 protected from myocardial IR-injury whilePer2deficiency was detrimental. Based on these conflicting data, we sought to evaluate the role of platelet specific PER2 in coagulation and myocardial ischemia and reperfusion injury. We demonstrated that platelets from mice with tissue-specific deletion ofPer2in the megakaryocyte lineage (Per2loxP/loxP-PF4-CRE) significantly clot faster than platelets from control mice. We further found increases in infarct sizes or plasma troponin levels inPer2loxP/loxP-PF4-CRE mice when compared to controls. As intense light increases PER2 protein in human tissues, we also performed translational studies and tested the effects of intense light therapy on coagulation in healthy human subjects. Our human studies revealed that intense light therapy repressed procoagulant pathways in human plasma samples and significantly reduced the clot rate. Based on these results we conclude that intense light elicited PER2 has an inhibitory function on platelet aggregation in mice. Further, we suggest intense light as a novel therapy to prevent or treat clotting in a clinical setting.

This article represents a selective review of literature published in 2019. Initial results from PubMed searching for a combination of terms, including cardiac anesthesiology and anesthesiology outcomes, yielded more than 1400 publications. From there, we manually screened the results and identified 5 major themes for the year of 2019, including transcatheter techniques, delirium and anesthesiology, coagulation management following cardiopulmonary bypass, perfusion management with del Nido cardioplegia, and applied clinical research. The following research accomplishments have expanded what is possible and set ambitious goals for the future.

Consistent daylight oscillations and abundant oxygen availability are fundamental to human health. While both are connected from an evolutionary and cellular perspective, only oxygen is an established therapy in cardiovascular medicine. Here, we probe the mechanistic intersection between light-(Period 2, PER2) and oxygen-(hypoxia inducible factor, HIF1A) sensing pathways in cellular adaptation to low oxygen conditions with respect to myocardial ischemia.Using a whole genome array from daylight exposed wildtype orPer2−/−mice, an affinity purification-mass spectrometry-based proteomics screen for PER2 targets in hypoxic human endothelial cells, and targeted metabolomics from human healthy volunteers after daylight therapy, we investigated the intersection of light and hypoxia elicited pathways. Housing mice under daylight conditions prior to myocardial ischemia and reperfusion (IR)-injury, uncovered circadian PER2 amplitude enhancement as novel cardioprotective strategy, mimicking HIF1A metabolic adaptation to myocardial ischemia in a PER2 regulated manner. Whole genome array analysis from daylight exposed wildtype andPer2−/−mice or myocardial IR-injury in endothelial specific PER2 deficient mice (Per2loxP/loxP-VE-Cadherin -Cre) revealed a critical role for light elicited PER2 in maintaining the endothelial barrier function during myocardial ischemia. Mechanistic studies in human endothelia pointed towards a master transcriptional regulatory role for endothelial PER2 in metabolic reprograming to hypoxia via HIF1A, which was mimicked during normoxic PER2 stabilization. Translational investigation of light elicited pathways in human healthy volunteers found similar increases of PER2 or mimicking of HIF1A dependent metabolism. These studies identify light elicited circadian amplitude enhancement of endothelial PER2 as a novel cardioprotective strategy. Furthermore, these studies identify PER2 as critical control point of endothelial metabolic reprograming to maintain vascular integrity during myocardial IR-injury and implicate the use of daylight therapy to increase endothelial PER2 signaling as a strategy for the treatment of coronary artery disease.

BACKGROUND: Understanding the molecular mechanisms in perturbation of the metabolome following ischaemia and reperfusion is critical in developing novel therapeutic strategies to prevent the sequelae of post-injury shock. While the metabolic substrates fueling these alterations have been defined, the relative contribution of specific organs to the systemic metabolic reprogramming secondary to ischaemic or haemorrhagic hypoxia remains unclear. MATERIALS AND METHODS: A porcine model of selected organ ischaemia was employed to investigate the relative contribution of liver, kidney, spleen and small bowel ischaemia/reperfusion to the plasma metabolic phenotype, as gleaned through ultra-high performance liquid chromatography-mass spectrometry-based metabolomics. RESULTS: Liver ischaemia/reperfusion promotes glycaemia, with increases in circulating carboxylic acid anions and purine oxidation metabolites, suggesting that this organ is the dominant contributor to the accumulation of these metabolites in response to ischaemic hypoxia. Succinate, in particular, accumulates selectively in response to the hepatic ischemia, with levels 6.5 times spleen, 8.2 times small bowel, and 6 times renal levels. Similar trends, but lower fold-change increase in comparison to baseline values, were observed upon ischaemia/reperfusion of kidney, spleen and small bowel. DISCUSSION: These observations suggest that the liver may play a critical role in mediating the accumulation of the same metabolites in response to haemorrhagic hypoxia, especially with respect to succinate, a metabolite that has been increasingly implicated in the coagulopathy and pro-inflammatory sequelae of ischaemic and haemorrhagic shock.

Metabolomic analysis has made substantial contributions to the understanding of diverse pathological processes and has the potential to improve diagnosis and identify novel therapeutic targets. As early success in perinatal medicine, nutrition, chronic diseases, cancer and trauma demonstrates, metabolomics is approaching feasibility in terms of guiding improvement in population-level diagnosis and treatment. A key barrier to implementing metabolomics as a routine diagnostic tool is rapid sample extraction and data analysis along with the establishment of normal values for novel metabolic markers. This review covers key advancements in clinical metabolomics and applies a high throughput metabolomics method as a proof of principle to identify novel metabolites associated with remote ischemic preconditioning.

Acute kidney injury (AKI) is a systemic disease associated with widespread effects on distant organs, including the heart. Normal cardiac function is dependent on constant ATP generation, and the preferred method of energy production is via oxidative phosphorylation. Following direct ischemic cardiac injury, the cardiac metabolome is characterized by inadequate oxidative phosphorylation, increased oxidative stress, and increased alternate energy utilization. We assessed the impact of ischemic AKI on the metabolomics profile in the heart. Ischemic AKI was induced by 22 minutes of renal pedicle clamping, and 124 metabolites were measured in the heart at 4 hours, 24 hours, and 7 days post-procedure. Forty-one percent of measured metabolites were affected, with the most prominent changes observed 24 hours post-AKI. The post-AKI cardiac metabolome was characterized by amino acid depletion, increased oxidative stress, and evidence of alternative energy production, including a shift to anaerobic forms of energy production. These metabolomic effects were associated with significant cardiac ATP depletion and with echocardiographic evidence of diastolic dysfunction. In the kidney, metabolomics analysis revealed shifts suggestive of energy depletion and oxidative stress, which were reflected systemically in the plasma. This is the first study to examine the cardiac metabolome after AKI, and demonstrates that effects of ischemic AKI on the heart are akin to the effects of direct ischemic cardiac injury.

Tissue injury and hemorrhagic shock induce significant systemic metabolic reprogramming in animal models and critically injured patients. Recent expansions of the classic concepts of metabolomic aberrations in tissue injury and hemorrhage opened the way for novel resuscitative interventions based on the observed abnormal metabolic demands. We hypothesize that metabolic demands and resulting metabolic signatures in pig plasma will vary in response to isolated or combined tissue injury and hemorrhagic shock.A total of 20 pigs underwent either isolated tissue injury, hemorrhagic shock, or combined tissue injury and hemorrhagic shock referenced to a sham protocol (n = 5/group). Plasma samples were analyzed by UHPLC-MS.Hemorrhagic shock promoted a hypermetabolic state. Tissue injury alone dampened metabolic responses in comparison to sham and hemorrhagic shock, and attenuated the hypermetabolic state triggered by shock with respect to energy metabolism (glycolysis, glutaminolysis, and Krebs cycle). Tissue injury and hemorrhagic shock had a more pronounced effect on nitrogen metabolism (arginine, polyamines, and purine metabolism) than hemorrhagic shock alone.Isolated or combined tissue injury and hemorrhagic shock result in distinct plasma metabolic signatures. These findings indicate that optimized resuscitative interventions in critically ill patients are possible based on identifying the severity of tissue injury and hemorrhage.

SUMMARY Consistent daylight oscillations and abundant oxygen availability are fundamental to human health. Here, we investigate the intersection between light-sensing (Period 2 [PER2]) and oxygen-sensing (hypoxia-inducible factor [HIF1A]) pathways in cellular adaptation to myocardial ischemia. We demonstrate that intense light is cardioprotective via circadian PER2 amplitude enhancement, mimicking hypoxia-elicited adenosine- and HIF1A-metabolic adaptation to myocardial ischemia under normoxic conditions. Whole-genome array from intense light-exposed wild-type or Per2−/− mice and myocardial ischemia in endothelial-specific PER2-deficient mice uncover a critical role for intense light in maintaining endothelial barrier function via light-enhanced HIF1A transcription. A proteomics screen in human endothelia reveals a dominant role for PER2 in metabolic reprogramming to hypoxia via mitochondrial translocation, tricarboxylic acid (TCA) cycle enzyme activity regulation, and HIF1A transcriptional adaption to hypoxia. Translational investigation of intense light in human subjects identifies similar PER2 mechanisms, implicating the use of intense light for the treatment of cardiovascular disease., Graphical Abstract, In Brief Oyama et al. investigate the mechanisms that underlie intense light-mediated protection from myocardial ischemia and find that intense light increases the circadian amplitude of PER2, which preconditions the myocardium via adenosine and HIF1A transcriptional reprogramming of the endothelium before an ischemic event.

Purpose Despite recent advancements in the use of thrombelastography (TEG) in the surgical setting, adequate technology to accurately predict bleeding phenotypes for patients undergoing cardiopulmonary bypass on the basis of non-mechanical parameters is lacking. While basic science and translational studies have provided key mechanistic insights about the protein components of coagulation cascades and regulatory mediators of hemostasis and fibrinolysis, targeted protein assays are still missing and the association of protein profiles to bleeding phenotypes and TEG readouts have yet to be discovered. Objective To identify protein biomarkers of bleeding phenotypes of cardiopulmonary bypass patients in pre-operative plasma. Experimental design We applied a targeted proteomics approach to quantify 123 plasma proteins from 23 patients undergoing cardiopulmonary bypass (CPB) and sternotomy. We then correlated these measurements to bleeding outcomes and TEG parameters, associated with speed of clot formation and strength. Results In this pilot study, we demonstrate the feasibility of protein quantitation as a viable strategy to predict low versus high bleeding phenotypes (loss of than 20% of estimated blood volume, calculated as 70 mL/kg for BMI 40. Statistical elaborations highlighted a core set of proteins showing significant correlations to either total blood loss or TEG R/MA parameters. Conclusion and clinical relevance Though prospective verification and validation in larger cohorts will be necessary, this report suggests a potential for targeted quantitative proteomics of pre-operative plasma protein concentrations in the prediction of estimated blood loss following CPB.

Local anesthetics (LA) work by blocking sodium conductance through voltage-gated sodium channels. Complete local anesthetic resistance is infrequent, and the cause is unknown. Genetic variation in sodium channels is a potential mechanism for local anesthetic resistance. A patient with a history of inadequate loss of sensation following LA administration underwent an ultrasound-guided brachial plexus nerve block with a complete failure of the block. We hypothesized that LA resistance is due to a variant form of voltage-gated sodium channel.Whole-Exome Sequencing. The patient and her immediate family provided consent for exome sequencing, and they were screened with a questionnaire to identify family members with a history of LA resistance. Exome sequencing results for four individuals were referenced to the 1000 Genomes Project and the NHLBI ESP to identify variants associated with local anesthetic resistance present in less than 1% of the general population and located in functional regions of the genome.Exome sequencing of the four family members identified one genetic variant in the voltage-gated sodium channel shared by the three individuals with LA resistance but not present in the unaffected family member. Specifically, we noted the A572D mutation in the SCN5A gene encoding for Nav1.5.We identified a genetic variant that is associated with LA resistance in the gene encoding for Nav1.5. We also demonstrate that Nav1.5 is present in human peripheral nerves to support the plausibility that an abnormal form of the Nav1.5 protein could be responsible for the observed local anesthetic resistance.

We present a standardized method for using four-dimensional ultrasound (4D US) guidance for peripheral nerve blocks. 4D US allows for needle tracking in multiple planes simultaneously and accurate measurement of the local anesthetic volume surrounding the nerve following injection. Additionally, the morphology and proximity of local anesthetic spread around the target nerve is clearly seen with the described technique. This method provides additional spatial information in real time compared to standard two-dimensional ultrasound.

Background. There are a variety of techniques for targeting placement of an infraclavicular blockade; these include eliciting paresthesias, nerve stimulation, and 2-dimensional (2D) ultrasound (US) guidance. Current 2D US allows direct visualization of a “flat” image of the advancing needle and neurovascular structures but without the ability to extensively analyze multidimensional data and allow for real-time manipulation. Three-dimensional (3D) ultrasonography has gained popularity and usefulness in many clinical specialties such as obstetrics and cardiology. We describe some of the potential clinical applications of 3D US in regional anesthesia.Methods. This case represents an infraclavicular catheter placement facilitated by 3D US, which demonstrates 360-degree spatial relationships of the entire anatomic region.Results. The block needle, peripheral nerve catheter, and local anesthetic diffusion were observed in multiple planes of view without manipulation of the US probe.Conclusion. Advantages of 3D US may include the ability to confirm correct needle and catheter placement prior to the injection of local anesthetic. The spread of local anesthetic along the length of the nerve can be easily observed while manipulating the 3D images in real-time by simply rotating the trackball on the US machine to provide additional information that cannot be identified with 2D US alone.