Publications by authors named "Jochen Steppan"

68 Publications

Author Correction: An in situ activity assay for lysyl oxidases.

Commun Biol 2021 Sep 16;4(1):1110. Epub 2021 Sep 16.

Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.

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http://dx.doi.org/10.1038/s42003-021-02655-4DOI Listing
September 2021

Probing tissue transglutaminase mediated vascular smooth muscle cell aging using a novel transamidation-deficient Tgm2-C277S mouse model.

Cell Death Discov 2021 Jul 29;7(1):197. Epub 2021 Jul 29.

Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.

Tissue transglutaminase (TG2), a multifunctional protein of the transglutaminase family, has putative transamidation-independent functions in aging-associated vascular stiffening and dysfunction. Developing preclinical models will be critical to fully understand the physiologic relevance of TG2's transamidation-independent activity and to identify the specific function of TG2 for therapeutic targeting. Therefore, in this study, we harnessed CRISPR-Cas9 gene editing technology to introduce a mutation at cysteine 277 in the active site of the mouse Tgm2 gene. Heterozygous and homozygous Tgm2-C277S mice were phenotypically normal and were born at the expected Mendelian frequency. TG2 protein was ubiquitously expressed in the Tgm2-C277S mice at levels similar to those of wild-type (WT) mice. In the Tgm2-C277S mice, TG2 transglutaminase function was successfully obliterated, but the transamidation-independent functions ascribed to GTP, fibronectin, and integrin binding were preserved. In vitro, a remodeling stimulus led to the significant loss of vascular compliance in WT mice, but not in the Tgm2-C277S or TG2 mice. Vascular stiffness increased with age in WT mice, as measured by pulse-wave velocity and tensile testing. Tgm2-C277S mice were protected from age-associated vascular stiffening, and TG2 knockout yielded further protection. Together, these studies show that TG2 contributes significantly to overall vascular modulus and vasoreactivity independent of its transamidation function, but that transamidation activity is a significant cause of vascular matrix stiffening during aging. Finally, the Tgm2-C277S mice can be used for in vivo studies to explore the transamidation-independent roles of TG2 in physiology and pathophysiology.
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http://dx.doi.org/10.1038/s41420-021-00543-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322091PMC
July 2021

A novel approach to perioperative risk assessment for patients with pulmonary hypertension.

ERJ Open Res 2021 Jul 19;7(3). Epub 2021 Jul 19.

Dept of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.

Rationale: Pulmonary hypertension (PH) is associated with significant perioperative morbidity and mortality. We hypothesised that pulmonary arterial hypertension (PAH) composite risk assessment scores could estimate perioperative risk for PH patients when adjusted for inherent procedural risk.

Methods: We identified patients in the Johns Hopkins PH Center Registry that had noncardiac surgery (including endoscopies) between September 2015 and January 2020. We collected information on preoperative patient-level and procedural variables and used logistic regression to evaluate associations with a composite outcome of death within 30 days or serious postoperative complication. We generated composite patient-level risk assessment scores for each subject and used logistic regression to estimate the association with adverse surgical outcomes. We adjusted multivariable models for inherent procedural risk of major cardiovascular events and used these models to generate a numerical PH perioperative risk (PHPR) score.

Results: Among 150 subjects, 19 (12.7%) reached the primary outcome, including 7 deaths (4.7%). Individual patient-level and procedural variables were associated with the primary outcome (all p<0.05). A composite patient-level risk assessment score built on three noninvasive parameters was strongly associated with reduced risk for poor outcomes (OR=0.4, p=0.03). This association was strengthened after adjusting the model for procedural risk. A PHPR score derived from the multivariable model stratified patients into low (0%), intermediate (≤10%), or high (>10%) risk of reaching the primary outcome.

Conclusion: Composite PAH risk assessment scores can predict perioperative risk for PH patients after accounting for inherent procedural risk. Validation of the PHPR score in a multicentre, prospective cohort is warranted.
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http://dx.doi.org/10.1183/23120541.00257-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287131PMC
July 2021

Pressure-based estimation of right ventricular ejection fraction: Validation as a clinically relevant target for drug development in a rodent model of pulmonary hypertension.

J Pharmacol Toxicol Methods 2021 Jul 7;112:107102. Epub 2021 Jul 7.

Dept. of Anesthesiology, Division of Applied Hemodynamics, Yale University School of Medicine, USA. Electronic address:

Depressed right ventricular ejection fraction (RVEF) has clear prognostic significance in patients with pulmonary arterial hypertension (PAH). Accordingly, improvements in RVEF represent a desirable end-point in the development of PAH therapies. However, current methods for determination of RVEF require measurement of RV volume and are relatively complex and costly. Here, we validate a novel method for quantitative estimation of RVEF in rats based entirely upon analysis of readily available RV pressure waveforms that eliminates the need for simultaneous volume measurement and can be rapidly applied. Right ventricular pressure and volume (conductance catheter) measurements acquired from 15 rats (7 controls, 8 sugen/hypoxia PAH; 220-250 g) were used for the study. Over the same 10 beat interval, RVEF was directly measured from the volume signal and estimated from the pressure signal. Simultaneous measures were compared by linear regression and Bland-Altman analysis to define bias (accuracy) and precision. Measured RVEF ranged from 0.19 to 0.60 (mean 0.44 ± 0.10) and estimated from 0.19 to 0.52 (mean 0.42 ± 0.09). Across the dataset there was strong correlation (r = 0.813), with minimal bias (0.01) and an overall error of 20% consistent with acceptable accuracy and precision. Study results support the potential utility of a method based entirely upon analysis of the RV pressure waveform for assessing drug effects on RVEF in rat models of PAH.
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http://dx.doi.org/10.1016/j.vascn.2021.107102DOI Listing
July 2021

An in situ activity assay for lysyl oxidases.

Commun Biol 2021 07 5;4(1):840. Epub 2021 Jul 5.

Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.

The lysyl oxidase family of enzymes (LOXs) catalyze oxidative deamination of lysine side chains on collagen and elastin to initialize cross-linking that is essential for the formation of the extracellular matrix (ECM). Elevated expression of LOXs is highly associated with diverse disease processes. To date, the inability to detect total LOX catalytic function in situ has limited the ability to fully elucidate the role of LOXs in pathobiological mechanisms. Using LOXL2 as a representative member of the LOX family, we developed an in situ activity assay by utilizing the strong reaction between hydrazide and aldehyde to label the LOX-catalyzed allysine (-CHO) residues with biotin-hydrazide. The biotinylated ECM proteins are then labeled via biotin-streptavidin interaction and detected by fluorescence microscopy. This assay detects the total LOX activity in situ for both overexpressed and endogenous LOXs in cells and tissue samples and can be used for studies of LOXs as therapeutic targets.
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http://dx.doi.org/10.1038/s42003-021-02354-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257687PMC
July 2021

Update on Perioperative Pediatric Pulmonary Hypertension Management.

J Cardiothorac Vasc Anesth 2021 Feb 28. Epub 2021 Feb 28.

Department of Anesthesiology and Critical Care Medicine, Division of Pediatric Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; Department of Anesthesiology and Critical Care Medicine, Division of Adult Cardiothoracic Anesthesia, Division of Adult Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

Pediatric pulmonary hypertension is a disease that has many etiologies and can present anytime during childhood. Its newly revised hemodynamic definition follows that of adult pulmonary hypertension: a mean pulmonary artery pressure >20 mmHg. However, the pediatric definition stipulates that the elevated pressure must be present after the age of three months. The definition encompasses many different etiologies, and diagnosis often involves a combination of noninvasive and invasive testing. Treatment often is extrapolated from adult studies or based on expert opinion. Moreover, although general anesthesia may be required for pediatric patients with pulmonary hypertension, it poses certain risks. A thoughtful, multidisciplinary approach is needed to deliver excellent perioperative care.
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http://dx.doi.org/10.1053/j.jvca.2021.02.055DOI Listing
February 2021

Red blood cell storage duration and peri-operative outcomes in paediatric cardiac surgery.

Vox Sang 2021 Mar 24. Epub 2021 Mar 24.

Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Prior research on red blood cell (RBC) storage duration and clinical outcomes in paediatric cardiac surgery has shown conflicting results. The purpose of this study was to evaluate whether blood stored for a longer duration is harmful in these patients.

Methods: We performed a retrospective cohort study of paediatric patients undergoing cardiac surgery at our institution between January 2011 and June 2015. Patients were stratified based on whether they were transfused RBCs stored for ≤15 days (fresher blood) or >15 days (older blood). The primary outcome was composite morbidity, with prolonged length of stay (LOS) as a secondary outcome. Subgroup analyses were performed after stratification by RBC transfusion volume (≤2 vs. >2 RBC units). Multivariable logistic regression models were used to assess the impact of RBC storage duration on composite morbidity and prolonged LOS.

Results: Of 461 patients, 122 (26·5%) received fresher blood and 339 (73·5%) received older blood. The overall rate of composite morbidity was 18·0% (n = 22) for patients receiving fresher blood and 13·6% (n = 46) for patients receiving older blood (P = 0·24). In the risk-adjusted model, patients receiving older blood did not exhibit an increased risk of composite morbidity (OR: 0·74, 95% CI: 0·37-1·47, P = 0·40) or prolonged LOS (OR: 0·72, 95% CI: 0·38-1·35, P = 0·30) compared to patients receiving fresher blood. Similar results were seen after stratification by RBC transfusion volume.

Conclusions: Transfusing RBCs stored for a longer duration was not associated with an increased risk of morbidity or prolonged LOS in paediatric cardiac surgery patients.
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http://dx.doi.org/10.1111/vox.13098DOI Listing
March 2021

Anesthetic techniques for patients with pulmonary hypertension undergoing ophthalmologic procedures: A case series.

J Clin Anesth 2021 Aug 2;71:110220. Epub 2021 Mar 2.

Department of Anesthesiology and Critical Care Medicine, Division of Adult Cardiothoracic Anesthesia, Division of Pediatric Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America.

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http://dx.doi.org/10.1016/j.jclinane.2021.110220DOI Listing
August 2021

Fast-degrading TEVGs Lead to Increased ECM Cross-linking Enzymes Expression.

Tissue Eng Part A 2021 Feb 18. Epub 2021 Feb 18.

University of Chicago, 2462, Surgery, Chicago, Illinois, United States;

Tissue-engineered vascular grafts (TEVGs) require adequate extracellular matrix (ECM) to withstand arterial pressure. Tissue transglutaminase (TG2) and lysyl oxidase (LOX) are enzymes that cross-link ECM proteins and play a pivotal role in the development of vascular stiffness associated with aging. The purpose of this study is to investigate the expression of ECM cross-linking enzymes and mechanisms of scaffold degeneration leading to vascular stiffness in TEVG remodeling. Fast- and slow-degrading electrospun TEVGs were fabricated using polydioxanone (PDO) and poly(L-lactide-co-caprolactone) (PLCL) copolymer, with a PDO/PLCL ratio of 9:1 for fast-degrading and 1:1 for slow-degrading graft. These grafts were implanted in rats (n=5/group) as abdominal aortic interposition conduits. The grafts were harvested at one month to evaluate patency, mechanical properties, vascular neotissue formation and the expression of ECM cross-linking enzymes. All TEVGs were patent without any aneurysmal formation at one month. ECM area, TG2 positive area and LOX positive area were significantly greater in fast-degrading TEVGs compared to slow-degrading TEVGs, with significantly less remaining scaffold. The mechanical properties of fast-degrading TEVGs were similar to that of native aorta, as demonstrated by strain-stress curve. In conclusion, at one month, fast-degrading TEVGs had rapid and well-organized ECM with greater TG2 and LOX expression and native-like mechanical properties, compared to slow-degrading TEVGs.
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http://dx.doi.org/10.1089/ten.TEA.2020.0266DOI Listing
February 2021

Preoperative Assessment and Perioperative Management of the Patient with Pulmonary Vascular Disease.

Clin Chest Med 2021 03 8;42(1):133-141. Epub 2021 Jan 8.

Department of Anesthesiology Yale School of Medicine, Division of Applied Hemodynamics, New Haven, CT, USA.

The incidence of pulmonary hypertension (PH) in patients undergoing noncardiac surgery has increased steadily over the past decade. Patients with known PH have significantly higher perioperative morbidity and mortality than those without PH. Moreover, a substantial number of patients may have occult disease. It, therefore, is of paramount importance for perioperative providers to recognize high-risk patients and treat them appropriately. This review first provides an overview of PH pathophysiology, then estimates the perioperative incidence of PH and its impact on surgical outcomes, and finally outlines a perioperative management strategy.
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http://dx.doi.org/10.1016/j.ccm.2020.11.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870014PMC
March 2021

Restoring Blood Pressure in Hypertensive Mice Fails to Fully Reverse Vascular Stiffness.

Front Physiol 2020 21;11:824. Epub 2020 Jul 21.

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States.

Background: Hypertension is a well-established driver of vascular remodeling and stiffening. The goal of this study was to evaluate whether restoring normal blood pressure (BP) fully restores vascular stiffness toward that of normotensive controls.

Methods: C57Bl6/J male mice received angiotensin II (angII; 1 μg/kg/min) via infusion pump for 8 weeks (hypertension group: HH), angII for 4 weeks (hypertension group: H4), angII for 4 weeks followed by 4 weeks of recovery (reversal group: HN), or sham treatment (normotensive group: NN). BP, heart rate, and pulse wave velocity (PWV) were measured longitudinally. At the end of the study period, aortas were harvested for testing of vasoreactivity, passive mechanical properties, and vessel structure.

Results: The HH group exhibited a sustained increase in BP and PWV over the 8-week period ( < 0.01). In the HN group, BP and PWV increased during the 4-week angII infusion, and, though BP was restored during the 4-week recovery, PWV exhibited only partial restoration ( 0.05). Heart rate was similar in all cohorts. Compared to NN controls, both HH and HN groups had significantly increased wall thickness ( 0.05 HH vs. NN, 0.01 HN vs. NN), mucosal extracellular matrix accumulation ( 0.0001 HH vs. NN, 0.05 HN vs. NN), and intralamellar distance ( 0.001 HH vs. NN, 0.01 HN vs. NN). Both intact and decellularized vessels were noted to have significantly higher passive stiffness in the HH and H4 cohorts than in NN controls ( 0.0001). However, in the HN cohort, intact vessels were only modestly stiffer than those of NN controls, and decellularized HN vessels were identical to those from the NN controls. Compared to NN controls, the HH and HN cohorts exhibited significantly diminished phenylephrine-induced contraction ( 0.0001) and endothelium-dependent vasodilation ( 0.05).

Conclusion: Hypertension causes a significant increase in aortic stiffness that is only partially reversible after BP normalization. Although hypertension does lead to matrix stiffening, restoration of BP restores matrix mechanics to levels similar to those of normotensive controls. Nevertheless, endothelial and vascular smooth muscle cell dysfunction persist after restoration of normotension. This dysfunction is, in part, responsible for augmented PWV after restoration of BP.
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http://dx.doi.org/10.3389/fphys.2020.00824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385310PMC
July 2020

Commonly used mouse strains have distinct vascular properties.

Hypertens Res 2020 11 14;43(11):1175-1181. Epub 2020 May 14.

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD, USA.

Mice are the most common animal model to investigate human disease and explore physiology. Mice are practical, cost efficient, and easily used for genetic manipulations. Although variability in cardiac structure and function among mouse strains is well noted, the effect of mouse strain on vascular stiffness indices is not known. Here, we compared mouse strain-dependent differences in key vascular stiffness indices among frequently used inbred mouse strains-C57Bl/6J, 129S, and Bl6/129S. In young healthy animals, baseline blood pressure and heart rate were identical in all strains, and independent of gender. However, both active in vivo and passive ex vivo vascular stiffness indices exhibited distinct differences. Specifically, both male and female 129S animals demonstrated the highest tensile stiffness, were least responsive to acetylcholine-induced vasorelaxation, and showed the lowest pulse wave velocity (PWV), an index of in vivo stiffness. C57Bl/6J mice demonstrated the highest PWV, lowest tensile stiffness, and the highest response to acetylcholine-induced vasorelaxation. Interestingly, within each strain, female mice had more compliant aortas. C57Bl/6J mice had thinner vessel walls with fewer layers, whereas 129S mice had the thickest walls with the most layers. Values in the Bl6/129S mixed background mice fell between C57Bl/6J and 129S mice. In conclusion, we show that underlying vascular properties of different inbred wild-type mouse strains are distinct, despite superficial similarities in blood pressure. For each genetic modification, care should be taken to identify proper controls, and conclusions might need to be verified in more than one strain to minimize the risk of false positive studies.
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http://dx.doi.org/10.1038/s41440-020-0467-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7926191PMC
November 2020

The Use of Bivalirudin in Pediatric Cardiac Surgery and in the Interventional Cardiology Suite.

J Cardiothorac Vasc Anesth 2020 Aug 21;34(8):2215-2223. Epub 2020 Jan 21.

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, School of Medicine, Baltimore, MD. Electronic address:

Anticoagulation is an essential component for patients undergoing cardiopulmonary bypass or extracorporeal membrane oxygenation and for those with ventricular assist devices. However, thrombosis and bleeding are common complications. Heparin continues to be the agent of choice for most patients, likely owing to practitioners' comfort and experience and the ease with which the drug's effects can be reversed. However, especially in pediatric cardiac surgery, there is increasing interest in using bivalirudin as the primary anticoagulant. This drug circumvents certain problems with heparin administration, such as heparin resistance and heparin-induced thrombocytopenia, but it comes with additional challenges. In this manuscript, the authors review the literature on the emerging role of bivalirudin in pediatric cardiac surgery, including its use with cardiopulmonary bypass surgery, extracorporeal membrane oxygenation, ventricular assist devices, and interventional cardiology. Moreover, they provide an overview of bivalirudin's pharmacodynamics and monitoring methods.
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http://dx.doi.org/10.1053/j.jvca.2020.01.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7321892PMC
August 2020

Perioperative Lung Ultrasound in the Pediatric Intensive Care Unit-Beyond the Vasculature and Parenchyma.

J Cardiothorac Vasc Anesth 2020 04 20;34(4):956-958. Epub 2020 Jan 20.

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.

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http://dx.doi.org/10.1053/j.jvca.2020.01.031DOI Listing
April 2020

Lysyl oxidase-like 2 depletion is protective in age-associated vascular stiffening.

Am J Physiol Heart Circ Physiol 2019 07 19;317(1):H49-H59. Epub 2019 Apr 19.

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University , Baltimore, Maryland.

Vascular stiffening and its sequelae are major causes of morbidity and mortality in the elderly. The increasingly accepted concept of "smooth muscle cell (SMC) stiffness syndrome" along with matrix deposition has emerged in vascular biology to account for the mechanical phenotype of arterial aging, but the molecular targets remain elusive. In this study, using an unbiased proteomic analysis, we identified lysyl oxidase-like 2 (LOXL2) as a critical SMC mediator for age-associated vascular stiffening. We tested the hypothesis that loss of LOXL2 function is protective in aging-associated vascular stiffening. We determined that exogenous and endogenous nitric oxide markedly decreased LOXL2 abundance and activity in the extracellular matrix of isolated SMCs and LOXL2 endothelial cells suppress LOXL2 abundance in the aorta. In a longitudinal study, LOXL2 mice were protected from age-associated increase in pulse-wave velocity, an index of vascular stiffening, as occurred in littermate wild-type mice. Using isolated aortic segments, we found that LOXL2 mediates vascular stiffening in aging by promoting SMC stiffness, augmented SMC contractility, and vascular matrix deposition. Together, these studies establish LOXL2 as a nodal point for a new therapeutic approach to treat age-associated vascular stiffening. Increased central vascular stiffness augments risk of major adverse cardiovascular events. Despite significant advances in understanding the genetic and molecular underpinnings of vascular stiffening, targeted therapy has remained elusive. Here, we show that lysyl oxidase-like 2 (LOXL2) drives vascular stiffening during aging by promoting matrix remodeling and vascular smooth muscle cell stiffening. Reduced LOXL2 expression protects mice from age-associated vascular stiffening and delays the onset of isolated systolic hypertension, a major consequence of stiffening.
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http://dx.doi.org/10.1152/ajpheart.00670.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692735PMC
July 2019

Trends and Updates on Cardiopulmonary Bypass Setup in Pediatric Cardiac Surgery.

J Cardiothorac Vasc Anesth 2019 Oct 9;33(10):2804-2813. Epub 2019 Jan 9.

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD. Electronic address:

Perfusion strategies for cardiopulmonary bypass have direct consequences on pediatric cardiac surgery outcomes. However, inconsistent study results and a lack of uniform evidence-based guidelines for pediatric cardiopulmonary bypass management have led to considerable variability in perfusion practices among, and even within, institutions. Important aspects of cardiopulmonary bypass that can be optimized to improve clinical outcomes of pediatric patients undergoing cardiac surgery include extracorporeal circuit components, priming solutions, and additives. This review summarizes the current literature on circuit components and priming solution composition with an emphasis on crystalloid, colloid, and blood-based primes, as well as mannitol, bicarbonate, and calcium.
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http://dx.doi.org/10.1053/j.jvca.2019.01.025DOI Listing
October 2019

When Your 35-Year-Old Patient has a Sternotomy Scar: Anesthesia for Adult Patients with Congenital Heart Disease Presenting for Noncardiac Surgery.

Int Anesthesiol Clin 2018 ;56(4):3-20

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

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http://dx.doi.org/10.1097/AIA.0000000000000204DOI Listing
June 2019

A Review of Goal-Directed Cardiopulmonary Bypass Management in Pediatric Cardiac Surgery.

World J Pediatr Congenit Heart Surg 2018 09;9(5):565-572

3 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA.

Cardiopulmonary bypass perfusion management significantly affects postoperative outcomes. In recent years, the principles of goal-directed therapy have been applied to the field of cardiothoracic surgery to improve patient outcomes. Goal-directed therapy involves continuous peri- and postoperative monitoring of vital clinical parameters to tailor perfusion to each patient's specific needs. Closely measured parameters include fibrinogen, platelet count, lactate, venous oxygen saturation, central venous oxygen saturation, mean arterial pressure, perfusion flow rate, and perfusion pulsatility. These parameters have been shown to influence postoperative fresh frozen plasma transfusion rate, coagulation state, end-organ perfusion, and mortality. In this review, we discuss the recent paradigm shift in pediatric perfusion management toward goal-directed perfusion.
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http://dx.doi.org/10.1177/2150135118775964DOI Listing
September 2018

Continuous Versus Bolus Furosemide in the Critically Ill: More Questions than Answers.

J Cardiothorac Vasc Anesth 2018 10 22;32(5):2311-2312. Epub 2018 Feb 22.

Department of Anesthesiology and Critical Care Medicine, Divisions of Cardiac Anesthesia and Adult Critical Care, The Johns Hopkins Medical Institutions, Baltimore, MD.

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http://dx.doi.org/10.1053/j.jvca.2018.02.029DOI Listing
October 2018

Focused Review of Perioperative Care of Patients with Pulmonary Hypertension and Proposal of a Perioperative Pathway.

Cureus 2018 Jan 15;10(1):e2072. Epub 2018 Jan 15.

Division of Pulmonary and Critical Care Medicine, The Johns Hopkins University School of Medicine.

Morbidity and mortality risk increase considerably for patients with pulmonary hypertension (PH) undergoing non-cardiac surgery. Unfortunately, there are no comprehensive, evidence-based guidelines for perioperative evaluation and management of these patients. We present a brief review of the literature on perioperative outcomes for patients with PH and describe the implementation of a collaborative perioperative management program for these high-risk patients at a tertiary academic center.
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http://dx.doi.org/10.7759/cureus.2072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854330PMC
January 2018

Ischemic Postconditioning and Milrinone.

J Cardiothorac Vasc Anesth 2018 10 2;32(5):2149-2151. Epub 2018 Feb 2.

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD.

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http://dx.doi.org/10.1053/j.jvca.2018.01.047DOI Listing
October 2018

Anesthetic Management of Pheochromocytoma Resection in Adults with Single Ventricle Physiology.

Cureus 2017 Dec 8;9(12):e1928. Epub 2017 Dec 8.

Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine.

Survival rates for patients with palliated congenital heart disease are increasing, and an increasing number of adults with cyanotic congenital heart disease (CCHD) might require surgical resection of pheochromocytoma-paraganglioma (PHEO-PGL). A recent study supports the idea that patients with a history of CCHD and current or historical cyanosis might be at increased risk for developing PHEO-PGL. We review the anesthetic management of two adults with single-ventricle physiology following Fontan palliation presenting for PHEO-PGL resection and review prior published case reports. We found the use of epidural analgesia to be safe and effective in the operative and postoperative management of our patients.
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http://dx.doi.org/10.7759/cureus.1928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806932PMC
December 2017

Blood Transfusions in Cardiac Surgery: Balancing Science and Art.

J Cardiothorac Vasc Anesth 2018 06 31;32(3):1233-1235. Epub 2018 Jan 31.

Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD.

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http://dx.doi.org/10.1053/j.jvca.2018.01.019DOI Listing
June 2018

Relationship Between the Ambulatory Arterial Stiffness Index and the Lower Limit of Cerebral Autoregulation During Cardiac Surgery.

J Am Heart Assoc 2018 02 8;7(4). Epub 2018 Feb 8.

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD

Background: Pulse pressure, the ambulatory arterial stiffness index (AASI), and the symmetric AASI are established predictors of adverse cardiovascular outcomes. However, little is known about their relationship to cerebral autoregulation. This study evaluated whether these markers of vascular properties relate to the lower limit of cerebral autoregulation (LLA).

Methods And Results: The LLA was determined during cardiac surgery with transcranial Doppler ultrasonography in 181 patients. All other variables were calculated from continuous intraoperative readings obtained before cardiopulmonary bypass. The LLA varied directly with the AASI (β=3.12 per 0.1 change in AASI, <0.001) and to a lesser extent the symmetric AASI (β=2.02 per 0.1 change in symmetric AASI, ≤0.022), while peripheral pulse pressure was not significantly related (β=0.0, >0.99). Logistic regression revealed that the likelihood of LLA being >65 mm Hg increased by 50% (95% confidence interval, 11%-102%, =0.008) for every 0.1 increase in the AASI. The AASI was able to predict a LLA above certain thresholds (area under the curve receiver operating characteristic for AASI predicting an LLA >65 mm Hg: 0.60; 95% confidence interval, 0.51%-0.68%, =0.043). Incorporating additional variables improved the model's predictive ability (area under the curve for AASI predicting a LLA >65 mm Hg: 0.75; 95% confidence interval, 0.68-0.82, =0.036).

Conclusions: These data indicate that the LLA is related to the mechanical properties of the vasculature as represented by the AASI. The AASI can be used to predict LLA threshold levels during cardiac surgery. It is now possible to link elevations in the LLA with an increased AASI as determined from readily accessible intraoperative variables.
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http://dx.doi.org/10.1161/JAHA.117.007816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850197PMC
February 2018

Difference between ejection times measured at two different peripheral locations as a novel marker of vascular stiffness.

PLoS One 2017 29;12(11):e0187781. Epub 2017 Nov 29.

Division of Cardiac Anesthesia, Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

Pulse wave velocity (PWV) has been recommended as an arterial damage assessment tool and a surrogate of arterial stiffness. However, the current technology does not allow to measure PWV both continuously and in real-time. We reported previously that peripherally measured ejection time (ET) overestimates ET measured centrally. This difference in ET is associated with the inherent vascular properties of the vessel. In the current study we examined ETs derived from plethysmography simultaneously at different peripheral locations and examined the influence of the underlying arterial properties on ET prolongation by changing the subject's position. We calculated the ET difference between two peripheral locations (ΔET) and its corresponding PWV for the same heartbeat. The ΔET increased with a corresponding decrease in PWV. The difference between ΔET in the supine and standing (which we call ET index) was higher in young subjects with low mean arterial pressure and low PWV. These results suggest that the difference in ET between two peripheral locations in the supine vs standing positions represents the underlying vascular properties. We propose ΔET in the supine position as a potential novel real-time continuous and non-invasive parameter of vascular properties, and the ET index as a potential non-invasive parameter of vascular reactivity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187781PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5706705PMC
December 2017

A Pulse Wave Velocity Based Method to Assess the Mean Arterial Blood Pressure Limits of Autoregulation in Peripheral Arteries.

Front Physiol 2017 2;8:855. Epub 2017 Nov 2.

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Constant blood flow despite changes in blood pressure, a phenomenon called autoregulation, has been demonstrated for various organ systems. We hypothesized that by changing hydrostatic pressures in peripheral arteries, we can establish these limits of autoregulation in peripheral arteries based on local pulse wave velocity (PWV). Electrocardiogram and plethysmograph waveforms were recorded at the left and right index fingers in 18 healthy volunteers. Each subject changed their left arm position, keeping the right arm stationary. Pulse arrival times (PAT) at both fingers were measured and used to calculate PWV. We calculated ΔPAT (ΔPWV), the differences between the left and right PATs (PWVs), and compared them to the respective calculated blood pressure at the left index fingertip to derive the limits of autoregulation. : ΔPAT decreased and ΔPWV increased exponentially at low blood pressures in the fingertip up to a blood pressure of 70 mmHg, after which changes in ΔPAT and ΔPWV were minimal. The empirically chosen 20 mmHg window (75-95 mmHg) was confirmed to be within the autoregulatory limit (slope = 0.097, = 0.56). ΔPAT and ΔPWV within a 20 mmHg moving window were not significantly different from the respective data points within the control 75-95 mmHg window when the pressure at the fingertip was between 56 and 110 mmHg for ΔPAT and between 57 and 112 mmHg for ΔPWV. : Changes in hydrostatic pressure due to changes in arm position significantly affect peripheral arterial stiffness as assessed by ΔPAT and ΔPWV, allowing us to estimate peripheral autoregulation limits based on PWV.
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http://dx.doi.org/10.3389/fphys.2017.00855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681752PMC
November 2017

Pulse wave travel distance as a novel marker of ventricular-arterial coupling.

Heart Vessels 2018 Mar 3;33(3):279-290. Epub 2017 Oct 3.

Division of Cardiac Anesthesia, Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Zayed Tower 6208C, 1800 Orleans Street, Baltimore, MD, 21287, USA.

Each stroke volume ejected by the heart is distributed along the arterial system as a pressure waveform. How far the front of the pressure waveform travels within the arterial system depends both on the pulse wave velocity (PWV) and the ejection time (ET). We tested the hypothesis that ET and PWV are coupled together, in order to produce a pulse wave travel distance (PWTD = PWV × ET) which would match the distance from the heart to the most distant site in the arterial system. The study was conducted in 11 healthy volunteers. We recorded lead II of the ECG along with pulse plethysmography at ear, finger and toe. The ET at the ear and pulse arrival time to each peripheral site were extracted. We then calculated PWV followed by PWTD for each location. Taken into account the individual subject variability PWTD in the supine position was 153 cm (95% CI 146-160 cm). It was not different from arterial pathway distance from the heart to the toe (D 153 cm). The PWTD and PWTD were longer than the distance from the heart to the finger and ear irrespective of body position. ET and PWV appear to be coupled in healthy subjects to produce a PWTD that is roughly equivalent to the arterial pathway distance to the toe. We propose that PWTD should be evaluated further to test its potential as a noninvasive parameter of ventricular-arterial coupling in subjects with cardiovascular diseases.
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http://dx.doi.org/10.1007/s00380-017-1058-4DOI Listing
March 2018

Opsin 3 and 4 mediate light-induced pulmonary vasorelaxation that is potentiated by G protein-coupled receptor kinase 2 inhibition.

Am J Physiol Lung Cell Mol Physiol 2018 01 7;314(1):L93-L106. Epub 2017 Sep 7.

Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University , Baltimore, Maryland.

We recently demonstrated that blue light induces vasorelaxation in the systemic mouse circulation, a phenomenon mediated by the nonvisual G protein-coupled receptor melanopsin (Opsin 4; Opn4). Here we tested the hypothesis that nonvisual opsins mediate photorelaxation in the pulmonary circulation. We discovered Opsin 3 (Opn3), Opn4, and G protein-coupled receptor kinase 2 (GRK2) in rat pulmonary arteries (PAs) and in pulmonary arterial smooth muscle cells (PASMCs), where the opsins interact directly with GRK2, as demonstrated with a proximity ligation assay. Light elicited an intensity-dependent relaxation of PAs preconstricted with phenylephrine (PE), with a maximum response between 400 and 460 nm (blue light). Wavelength-specific photorelaxation was attenuated in PAs from Opn4 mice and further reduced following shRNA-mediated knockdown of Opn3. Inhibition of GRK2 amplified the response and prevented physiological desensitization to repeated light exposure. Blue light also prevented PE-induced constriction in isolated PAs, decreased basal tone, ablated PE-induced single-cell contraction of PASMCs, and reversed PE-induced depolarization in PASMCs when GRK2 was inhibited. The photorelaxation response was modulated by soluble guanylyl cyclase but not by protein kinase G or nitric oxide. Most importantly, blue light induced significant vasorelaxation of PAs from rats with chronic pulmonary hypertension and effectively lowered pulmonary arterial pressure in isolated intact perfused rat lungs subjected to acute hypoxia. These findings show that functional Opn3 and Opn4 in PAs represent an endogenous "optogenetic system" that mediates photorelaxation in the pulmonary vasculature. Phototherapy in conjunction with GRK2 inhibition could therefore provide an alternative treatment strategy for pulmonary vasoconstrictive disorders.
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http://dx.doi.org/10.1152/ajplung.00091.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335007PMC
January 2018

Ejection time: influence of hemodynamics and site of measurement in the arterial tree.

Hypertens Res 2017 Sep 30;40(9):811-818. Epub 2017 Mar 30.

Division of Cardiac Anesthesia, Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

The left ventricular ejection time is routinely measured from a peripheral arterial waveform. However, the arterial waveform undergoes constant transformation as the pulse wave propagates along the arterial tree. Our goal was to determine if the left ventricular ejection time measured peripherally in the arterial tree accurately reflected the ejection time measured through the aortic valve. Moreover, we examined/accessed the modulating influence of hemodynamics on ejection time measurements. Continuous wave Doppler waveform images through the aortic valve and the simultaneously obtained radial artery pressure waveforms were analyzed to determine central and peripheral ejection times, respectively. The peripheral ejection time was significantly longer than the simultaneously measured central ejection time (174.5±25.2 ms vs. 120.7±14.4 ms; P<0.0001; 17.4±8.7% increase). Moreover, the ejection time prolongation was accentuated at lower blood pressures, lower heart rate and lower pulse wave velocity. The time difference between centrally and peripherally measured ejection times likely reflects intrinsic vascular characteristics. Moreover, given that the ejection time also depends on blood pressure, heart rate and pulse wave velocity, peripherally measured ejection times might need to be adjusted to account for changes in these variables.
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http://dx.doi.org/10.1038/hr.2017.43DOI Listing
September 2017

The impact of posture on the cardiac depolarization and repolarization phases of the QT interval in healthy subjects.

J Electrocardiol 2017 Sep - Oct;50(5):640-645. Epub 2017 Mar 12.

Division of Cardiac Anesthesia, Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address:

Background: Postural changes affect both heart rate and the QT interval.

Objective: To investigate the effects of postural changes on the depolarization and repolarization phases of the QT interval.

Methods: A three lead ECG from 12 healthy young volunteers was recorded in the standing, sitting and in the supine positions. For the purpose of this study, we defined the depolarization phase as the QRS complex plus the ST segment and the repolarization phase as the duration of the T wave.

Results: QTc did not change with changes in position. The ratio of the duration of the depolarization phase to the repolarization phase was higher in the supine position (0.98±0.13) compared to the standing position (0.83±0.17).

Conclusions: The origin of the T wave moves closer to the QRS complex during standing compared to the supine position. The observed changes are mainly due to shortening of the ST segment during standing compared to supine position.
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http://dx.doi.org/10.1016/j.jelectrocard.2017.03.001DOI Listing
June 2018
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