Publications by authors named "Bryan A Whitson"

189 Publications

Continuous renal replacement therapy and extracorporeal membrane oxygenation: implications in the COVID-19 era.

Perfusion 2021 Sep 8:2676591211042561. Epub 2021 Sep 8.

Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

The novel severe acute respiratory syndrome coronavirus 2, SARS-CoV-2 (coronavirus Disease 19 (COVID-19)) was identified as the causative agent of viral pneumonias in Wuhan, China in December 2019, and has emerged as a pandemic causing acute respiratory distress syndrome (ARDS) and multiple organ dysfunction. Interim guidance by the World Health Organization states that extracorporeal membrane oxygenation (ECMO) should be considered as a rescue therapy in COVID-19-related ARDS. International registries tracking ECMO in COVID-19 patients reveal a 21%-70% incidence of acute renal injury requiring renal replacement therapy (RRT) during ECMO support. The indications for initiating RRT in patients on ECMO are similar to those for patients not requiring ECMO. RRT can be administered during ECMO via a temporary dialysis catheter, placement of a circuit in-line hemofilter, or direct connection of continuous RRT in-line with the ECMO circuit. Here we review methods for RRT during ECMO, RRT initiation and timing during ECMO, anticoagulation strategies, and novel cytokine filtration approaches to minimize COVID-19's pathophysiological impact.
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http://dx.doi.org/10.1177/02676591211042561DOI Listing
September 2021

Temporary extracorporeal left ventricular support with transapical ProtekDuo cannula.

JTCVS Tech 2021 Feb 20;5:76-79. Epub 2020 Nov 20.

Division of Cardiac Surgery, Department of Surgery, The Ohio State University, Columbus, Ohio.

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http://dx.doi.org/10.1016/j.xjtc.2020.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8300020PMC
February 2021

MG53 suppresses NF-κB activation to mitigate age-related heart failure.

JCI Insight 2021 Sep 8;6(17). Epub 2021 Sep 8.

Department of Surgery, Division of Cardiac Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.

Aging is associated with chronic oxidative stress and inflammation that affect tissue repair and regeneration capacity. MG53 is a TRIM family protein that facilitates repair of cell membrane injury in a redox-dependent manner. Here, we demonstrate that the expression of MG53 was reduced in failing human hearts and aged mouse hearts, concomitant with elevated NF-κB activation. We evaluated the safety and efficacy of longitudinal, systemic administration of recombinant human MG53 (rhMG53) protein in aged mice. Echocardiography and pressure-volume loop measurements revealed beneficial effects of rhMG53 treatment in improving heart function of aged mice. Biochemical and histological studies demonstrated that the cardioprotective effects of rhMG53 are linked to suppression of NF-κB-mediated inflammation, reducing apoptotic cell death and oxidative stress in the aged heart. Repetitive administration of rhMG53 in aged mice did not have adverse effects on major vital organ functions. These findings support the therapeutic value of rhMG53 in treating age-related decline in cardiac function.
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http://dx.doi.org/10.1172/jci.insight.148375DOI Listing
September 2021

Impact of thoracotomy approach on right ventricular failure and length of stay in left ventricular assist device implants: an intermacs registry analysis.

J Heart Lung Transplant 2021 Sep 12;40(9):981-989. Epub 2021 Jun 12.

Division of Cardiac Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio.

Introduction: Traditionally, implantation of Left Ventricular Assist Devices (LVADs) is performed via median sternotomy. Recently, less invasive thoracotomy approaches are growing in popularity as they involve less surgical trauma, potentially less bleeding, and may preserve right ventricular function. We hypothesized implantation of LVADs via thoracotomy has less perioperative right ventricular failure (RVF) and shorter postoperative length of stay (LOS).

Methods: Continuous flow LVAD implants from Intermacs between February 6, 2014 - December 31, 2018 were identified. Patients implanted via thoracotomy were propensity matched in a 1:1 ratio with patients implanted via sternotomy. Outcomes were compared between sternotomy and thoracotomy approach and by device type (axial, centrifugal-flow with hybrid levitation (CF-HL), centrifugal-flow with full magnetic levitation devices (CF-FML)). The primary outcome was time to first moderate or severe RVF. Secondary outcomes included survival and LOS.

Results: Overall 978 thoracotomy patients were matched with 978 sternotomy patients. Over the study period, 242 thoracotomy patients and 219 sternotomy patients developed RVF with no significant difference in time to first moderate to severe RVF by surgical approach overall (p = 0.27) or within CF-HL (p = 0.36) or CF-FML devices (p = 0.25). Survival did not differ by implant technique (150 deaths in thoracotomy group, 154 deaths in sternotomy group; p = 0.58). However, sternotomy approach was associated with a significantly shorter LOS (17 Vs 18 days, p = 0.009).

Conclusion: As compared to sternotomy, implantation of continuous flow LVADs via thoracotomy approach does not reduce moderate to severe RVF or improve survival but does reduce post-operative LOS. Device type did not influence outcomes and most centers did a small volume of thoracotomy implants.
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http://dx.doi.org/10.1016/j.healun.2021.05.022DOI Listing
September 2021

Muscle multiorgan crosstalk with MG53 as a myokine for tissue repair and regeneration.

Curr Opin Pharmacol 2021 08 27;59:26-32. Epub 2021 May 27.

Department of Surgery Division of Cardiac Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA. Electronic address:

Through stress and injury to tissues, the cell membrane is damaged and can lead to cell death and a cascade of inflammatory events. Soluble factors that mitigate and repair membrane injury are important to normal homeostasis and are a potential therapeutic intervention for regenerative medicine. A myokine is a type of naturally occurring factors that come from muscle and have impact on remote organs. MG53, a tripartite motif-containing family protein, is such a myokine which has protective effects on lungs, kidneys, liver, heart, eye, and brain. Three mechanisms of action for the beneficial regenerative medicine potential of MG53 have been identified and consist of 1) repair of acute injury to the cellular membrane, 2) anti-inflammatory effects associated with chronic injuries, and 3) rejuvenation of stem cells for tissue regeneration. As such, MG53 has the potential to be a novel and effective regeneration medicine therapeutic.
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http://dx.doi.org/10.1016/j.coph.2021.04.005DOI Listing
August 2021

2020 in review.

J Thorac Cardiovasc Surg 2021 Aug 24;162(2):628-632. Epub 2021 Apr 24.

Section of Cardiac Surgery, Department of Surgery, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.

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http://dx.doi.org/10.1016/j.jtcvs.2021.04.049DOI Listing
August 2021

Allocation changes in heart transplantation: What has really changed?

J Thorac Cardiovasc Surg 2021 Mar 16. Epub 2021 Mar 16.

Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio.

Objective: In 2018, the heart allocation system changed status classifications and broadened geographic distribution. We examined this change at a national level based on the immediate pre- and postchange periods.

Methods: Using the Scientific Registry of Transplant Recipients database, we identified all adult primary, isolated heart transplants from October 18, 2017, to October 17, 2019. Two time periods were compared: (1) October 18, 2017, to October 17, 2018 (pre); and (2) October 18, 2018, to October 17, 2019 (post). Comparisons were made between groups, and a multivariable logistic regression model was created to identify factors associated with pretransplant temporary mechanical circulatory support. Volume analysis at the regional, state, and center level was also conducted as the primary focus.

Results: A total of 5381 independent heart transplants were identified within the time frame. On unadjusted analysis, there was a significant increase in temporary mechanical circulatory support (pre, 11.1%; post, 36.2%, P < .01) and decrease in waitlist days (pre, 93 days; post, 41 days; P < .01). Distance traveled (nautical miles) (pre, 83; post, 225; P < .01) and ischemic time (hours) (pre, 3.0; post, 3.4; P < .01) were significantly increased. On multivariable analysis, the postallocation time period was independently associated with temporary MCS (odds ratio, 4.463; 95% confidence interval, 3.844-5.183; P < .001). Transplant volumes did not significantly change after the allocation change at a regional, state, and center level.

Conclusions: Since the planned alteration to the allocation system, there have been changes in the use of temporary mechanical circulatory support as well as distance and ischemic time associated with transplant, but no significant volume changes were observed. Continued observation of outcomes and volume under the new allocation system will be necessary in the upcoming years.
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http://dx.doi.org/10.1016/j.jtcvs.2021.03.031DOI Listing
March 2021

Fibroblast-Specific Proteotranscriptomes Reveal Distinct Fibrotic Signatures of Human Sinoatrial Node in Nonfailing and Failing Hearts.

Circulation 2021 Jul 20;144(2):126-143. Epub 2021 Apr 20.

Department of Physiology & Cell Biology (A.K., N.L., E.J.A., B.J.H., P.M.L.J., P.J.M., V.V.F.), The Ohio State University Wexner Medical Center, Columbus.

Background: Up to 50% of the adult human sinoatrial node (SAN) is composed of dense connective tissue. Cardiac diseases including heart failure (HF) may increase fibrosis within the SAN pacemaker complex, leading to impaired automaticity and conduction of electric activity to the atria. Unlike the role of cardiac fibroblasts in pathologic fibrotic remodeling and tissue repair, nothing is known about fibroblasts that maintain the inherently fibrotic SAN environment.

Methods: Intact SAN pacemaker complex was dissected from cardioplegically arrested explanted nonfailing hearts (non-HF; n=22; 48.7±3.1 years of age) and human failing hearts (n=16; 54.9±2.6 years of age). Connective tissue content was quantified from Masson trichrome-stained head-center and center-tail SAN sections. Expression of extracellular matrix proteins, including collagens 1 and 3A1, CILP1 (cartilage intermediate layer protein 1), and POSTN (periostin), and fibroblast and myofibroblast numbers were quantified by in situ and in vitro immunolabeling. Fibroblasts from the central intramural SAN pacemaker compartment (≈10×5×2 mm) and right atria were isolated, cultured, passaged once, and treated ± transforming growth factor β1 and subjected to comprehensive high-throughput next-generation sequencing of whole transcriptome, microRNA, and proteomic analyses.

Results: Intranodal fibrotic content was significantly higher in SAN pacemaker complex from HF versus non-HF hearts (57.7±2.6% versus 44.0±1.2%; <0.0001). Proliferating phosphorylated histone 3/vimentin/CD31 (cluster of differentiation 31) fibroblasts were higher in HF SAN. Vimentin/α-smooth muscle actin/CD31 myofibroblasts along with increased interstitial POSTN expression were found only in HF SAN. RNA sequencing and proteomic analyses identified unique differences in mRNA, long noncoding RNA, microRNA, and proteomic profiles between non-HF and HF SAN and right atria fibroblasts and transforming growth factor β1-induced myofibroblasts. Specifically, proteins and signaling pathways associated with extracellular matrix flexibility, stiffness, focal adhesion, and metabolism were altered in HF SAN fibroblasts compared with non-HF SAN.

Conclusions: This study revealed increased SAN-specific fibrosis with presence of myofibroblasts, CILP1, and POSTN-positive interstitial fibrosis only in HF versus non-HF human hearts. Comprehensive proteotranscriptomic profiles of SAN fibroblasts identified upregulation of genes and proteins promoting stiffer SAN extracellular matrix in HF hearts. Fibroblast-specific profiles generated by our proteotranscriptomic analyses of the human SAN provide a comprehensive framework for future studies to investigate the role of SAN-specific fibrosis in cardiac rhythm regulation and arrhythmias.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8277727PMC
July 2021

Donor Aorta as Conduit for Ex Vivo Lung Perfusion.

ASAIO J 2021 Mar 24. Epub 2021 Mar 24.

From the Minneapolis Heart Institute, Abbott Northwestern Hospital, Minneapolis, Minnesota Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio.

For ex vivo lung perfusion (EVLP), there is often inadequate pulmonary artery for effective EVLP. Creation of a neopulmonary artery conduit with donor aorta alleviates this shortcoming. This technique will become of more importance and need as there are more donation after circulatory death donor (DCD) heart procurements as this is a common source of EVLP. With the time constraints associated with the DCD recovery approach, there is a high likelihood of having a short native pulmonary artery with the lung block necessitating this approach.
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http://dx.doi.org/10.1097/MAT.0000000000001361DOI Listing
March 2021

Impact of etiology on force and kinetics of left ventricular end-stage failing human myocardium.

J Mol Cell Cardiol 2021 07 22;156:7-19. Epub 2021 Mar 22.

Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, United States; Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, United States; Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, United States. Electronic address:

Background: Heart failure (HF) is associated with highly significant morbidity, mortality, and health care costs. Despite the significant advances in therapies and prevention, HF remains associated with poor clinical outcomes. Understanding the contractile force and kinetic changes at the level of cardiac muscle during end-stage HF in consideration of underlying etiology would be beneficial in developing targeted therapies that can help improve cardiac performance.

Objective: Investigate the impact of the primary etiology of HF (ischemic or non-ischemic) on left ventricular (LV) human myocardium force and kinetics of contraction and relaxation under near-physiological conditions.

Methods And Results: Contractile and kinetic parameters were assessed in LV intact trabeculae isolated from control non-failing (NF; n = 58) and end-stage failing ischemic (FI; n = 16) and non-ischemic (FNI; n = 38) human myocardium under baseline conditions, length-dependent activation, frequency-dependent activation, and response to the β-adrenergic stimulation. At baseline, there were no significant differences in contractile force between the three groups; however, kinetics were impaired in failing myocardium with significant slowing down of relaxation kinetics in FNI compared to NF myocardium. Length-dependent activation was preserved and virtually identical in all groups. Frequency-dependent activation was clearly seen in NF myocardium (positive force frequency relationship [FFR]), while significantly impaired in both FI and FNI myocardium (negative FFR). Likewise, β-adrenergic regulation of contraction was significantly impaired in both HF groups.

Conclusions: End-stage failing myocardium exhibited impaired kinetics under baseline conditions as well as with the three contractile regulatory mechanisms. The pattern of these kinetic impairments in relation to NF myocardium was mainly impacted by etiology with a marked slowing down of kinetics in FNI myocardium. These findings suggest that not only force development, but also kinetics should be considered as a therapeutic target for improving cardiac performance and thus treatment of HF.
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http://dx.doi.org/10.1016/j.yjmcc.2021.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217133PMC
July 2021

Evaluating the Impact of Pulmonary Artery Obstruction After Lung Transplant Surgery: A Systematic Review and Meta-analysis.

Transplantation 2021 04;105(4):711-722

Department of Anesthesiology, Wexner Medical Center, The Ohio State University, Columbus, OH.

Background: Pulmonary artery obstruction is an uncommon but significant complication after lung transplantation. Although numerous reports have documented its occurrence, the hemodynamic parameters associated with its presentation and diagnostic considerations remain ill-defined. This systematic review summarizes evidence in the literature surrounding pulmonary artery obstruction after lung transplantation surgery.

Methods: Databases were searched for all articles and abstracts reporting on pulmonary artery obstruction. Data collected included the number of patients studied, patient characteristics, incidences of pulmonary artery obstruction, and timing and imaging modality used for diagnosis.

Results: Thirty-four full-text citations were included in this review. The point prevalence of pulmonary artery obstruction was 3.66%. The peak pulmonary artery velocity associated with obstruction was found to be 2.60 ± 0.58 m/s. The diameter of the obstructed pulmonary artery predictive of poor outcomes was noted to be 0.78 ± 0.40 cm. The majority of diagnoses were made in the late postoperative period using pulmonary angiogram and transesophageal echocardiography. Overall, 76% of patients (47 of 62) required emergent procedural reintervention, and 23% of patients (14 of 62) diagnosed with pulmonary artery obstruction died during their hospital stay.

Conclusions: This systematic review underscores the importance of identifying pulmonary artery obstruction immediately after lung transplant surgery. The clinical implications of these results warrant the development of identification and management strategies for early detection of irregularities in pulmonary artery anastomosis in lung transplant patients.
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http://dx.doi.org/10.1097/TP.0000000000003407DOI Listing
April 2021

Attributes of Successful Thoracic Surgery Residency Matriculants: Could It Be Mentorship?

Authors:
Bryan A Whitson

Ann Thorac Surg 2021 Mar 3. Epub 2021 Mar 3.

Department of Surgery, Division of Cardiac Surgery, Ohio State University Medical Center, N-816 Doan Hall, 410 W. 10(th) Ave, Columbus, OH 43210. Electronic address:

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http://dx.doi.org/10.1016/j.athoracsur.2021.01.069DOI Listing
March 2021

One to Ten…What's in a Number?

Semin Thorac Cardiovasc Surg 2021 Autumn;33(3):848-849. Epub 2021 Feb 15.

Department of Surgery Division of Cardiac Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio. Electronic address:

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http://dx.doi.org/10.1053/j.semtcvs.2020.12.023DOI Listing
February 2021

Microfibrillar-Associated Protein 4 Regulates Stress-Induced Cardiac Remodeling.

Circ Res 2021 Mar 3;128(6):723-737. Epub 2021 Feb 3.

Physiology and Cell Biology (L.E.D., W.L., J.M.P., M.S.S., P.M.L.J., P.J.M., F.A.), The Ohio State University Wexner Medical Center, Columbus.

[Figure: see text].
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188624PMC
March 2021

MG53 as a Novel Therapeutic Protein to Treat Acute Lung Injury.

Mil Med 2021 01;186(Suppl 1):339-345

Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.

Introduction: Lung injury has several inciting etiologies ranging from trauma (contusion and hemorrhage) to ischemia reperfusion injury. Reflective of the injury, tissue and cellular injury increases proportionally with the injury stress and is an area of potential intervention to mitigate the injury. This study aims to evaluate the therapeutic benefits of recombinant human MG53 (rhMG53) protein in porcine models of acute lung injury (ALI).

Materials And Methods: We utilized live cell imaging to monitor the movement of MG53 in cultured human bronchial epithelial cells following mechanical injury. The in vivo efficacy of rhMG53 was evaluated in a porcine model of hemorrhagic shock/contusive lung injury. Varying doses of rhMG53 (0, 0.2, or 1 mg/kg) were administered intravenously to pigs after induction of hemorrhagic shock/contusive induced ALI. Ex vivo lung perfusion system enabled assessment of the isolated porcine lung after a warm ischemic induced injury with rhMG53 supplementation in the perfusate (1 mg/mL).

Results: MG53-mediated cell membrane repair is preserved in human bronchial epithelial cells. rhMG53 mitigates lung injury in the porcine model of combined hemorrhagic shock/contusive lung injury. Ex vivo lung perfusion administration of rhMG53 reduces warm ischemia-induced injury to the isolated porcine lung.

Conclusions: MG53 is an endogenous protein that circulates in the bloodstream. Therapeutic treatment with exogenous rhMG53 may be part of a strategy to restore (partially or completely) structural morphology and/or functional lung integrity. Systemic administration of rhMG53 constitutes a potential effective therapeutic means to combat ALI.
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http://dx.doi.org/10.1093/milmed/usaa313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980479PMC
January 2021

MG53, A Tissue Repair Protein with Broad Applications in Regenerative Medicine.

Cells 2021 01 11;10(1). Epub 2021 Jan 11.

Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.

Under natural conditions, injured cells can be repaired rapidly through inherent biological processes. However, in the case of diabetes, cardiovascular disease, muscular dystrophy, and other degenerative conditions, the natural repair process is impaired. Repair of injury to the cell membrane is an important aspect of physiology. Inadequate membrane repair function is implicated in the pathophysiology of many human disorders. Recent studies show that Mitsugumin 53 (MG53), a TRIM family protein, plays a key role in repairing cell membrane damage and facilitating tissue regeneration. Clarifying the role of MG53 and its molecular mechanism are important for the application of MG53 in regenerative medicine. In this review, we analyze current research dissecting MG53's function in cell membrane repair and tissue regeneration, and highlight the development of recombinant human MG53 protein as a potential therapeutic agent to repair multiple-organ injuries.
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http://dx.doi.org/10.3390/cells10010122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827922PMC
January 2021

Aggressive treatment of afterload mismatch to address left ventricular dysfunction after mitral valve repair: A case report.

Int J Crit Illn Inj Sci 2020 Jul-Sep;10(3):148-151. Epub 2020 Sep 22.

Department of Anesthesiology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

Mitral regurgitation (MR), one of the most common valvulopathies, occurs in at least 10% of the individuals older than 75 years. The long-standing volume overload occurring in severe MR inevitably leads to left ventricular (LV) enlargement and dysfunction; untreated, severe MR can progress to heart failure and death. Hypotension following separation from cardiopulmonary bypass after mitral valve intervention should alert an anesthesiologist to consider a myriad of differential diagnoses. This includes, but is not limited to, afterload mismatch, which can contribute to severe LV dysfunction, even in patients with seemingly normal preoperative ejection fraction. We present a case of acute on chronic biventricular failure after mitral valve repair due to afterload mismatch and discuss its management intraoperatively. Admittedly, identifying the causes of hypotension to guide treatment after mitral valve surgery in patients with severe MR is challenging. High index of suspicion and transesophageal echocardiogram guidance are important for prompt diagnosis, increasing the likelihood of successful outcomes with appropriate clinical management.
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http://dx.doi.org/10.4103/IJCIIS.IJCIIS_101_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771624PMC
September 2020

New or Worsened Mitral Regurgitation After Surgical Aortic Valve Replacement: A Systematic Review.

Semin Cardiothorac Vasc Anesth 2021 Sep 24;25(3):173-184. Epub 2020 Dec 24.

Department of Anesthesiology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

Background: New or worsened mitral regurgitation (MR) is an uncommon yet serious complication after surgical aortic valve replacement (SAVR). While there have been numerous reports of its occurrence, there is little consensus regarding its presentation and management. This systematic review summarizes the evidence in the current literature surrounding new or worsened MR after SAVR and analyzes its potential implications.

Methods: Databases were examined for all articles and abstracts reporting on new or worsened MR after SAVR. Data collected included number of patients studied; patient characteristics; incidences of new or worsened MR; timing of diagnosis; and treatment.

Results: Thirty-six full-text citations were included in this review. The prevalence of new or worsened MR after SAVR was 8.4%. Sixteen percent of new MR occurrences were from an organic etiology, and 83% of new MR occurrences were that of a functional etiology. Most diagnoses were made in the late or unspecified postoperative period using echocardiography (range: 0 minutes to 18 years postoperatively). While no patients died from this complication, 7.7% of patients (16 out of 207) required emergent procedural re-intervention.

Conclusions: This systematic review underscores the importance of identifying new or worsened MR following SAVR and accurate scoring of MR severity to guide treatment. It also outlines the associated clinical measures commonly documented following this complication, and the usefulness of transesophageal echocardiography for the detection of significant MR. These results reflect the current, limited state of the literature on this topic and warrant further investigation into MR detection and management strategies in SAVR patients.
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http://dx.doi.org/10.1177/1089253220982202DOI Listing
September 2021

Effectiveness of short vs long-course perioperative antibiotics in lung transplant recipients with donor positive respiratory cultures.

Transpl Infect Dis 2021 Jun 6;23(3):e13518. Epub 2020 Dec 6.

Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, OH, USA.

Lung transplant recipients are at increased risk for infection in the early postoperative phase, thus perioperative antibiotics are employed. This retrospective study evaluated the efficacy of short- vs long-course perioperative antibiotics in lung transplant patients. Lung transplant patients with donor positive cultures between August 2013 and September 2019 were evaluated, excluding those with cystic fibrosis, death within 14 days and re-transplants. The primary outcome was 30-day freedom from donor-derived respiratory infection. A total of 147 patients were included (57 short vs 90 long-course). Median perioperative antibiotic duration was 6 days in the short-course vs 14 days in the long-course group (P < .0001). Thirty-day freedom from donor-derived respiratory infection was present in 56 (98%) patients in the short-course vs 85 (94%) patients in the long-course group (P = .41). There was no difference in development of Clostridioides difficile infections (P = .41), while cumulative ventilator time and time to post-op extubation were longer in the long-course group (P = .001 and .004, respectively). Among lung transplant recipients with positive donor respiratory cultures, short-course perioperative antibiotics were as effective as long-course antibiotics in preventing donor-derived bacterial respiratory infections.
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http://dx.doi.org/10.1111/tid.13518DOI Listing
June 2021

Remodeling of the mA landscape in the heart reveals few conserved post-transcriptional events underlying cardiomyocyte hypertrophy.

J Mol Cell Cardiol 2021 02 12;151:46-55. Epub 2020 Nov 12.

Department of Physiology & Cell Biology, Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Wexner Medical Center, Columbus, OH, USA. Electronic address:

Regulation of gene expression plays a fundamental role in cardiac stress-responses. Modification of coding transcripts by adenosine methylation (mA) has recently emerged as a critical post-transcriptional mechanism underlying heart disease. Thousands of mammalian mRNAs are known to be mA-modified, suggesting that remodeling of the mA landscape may play an important role in cardiac pathophysiology. Here we found an increase in mA content in human heart failure samples. We then adopted genome-wide analysis to define all mA-regulated sites in human failing compared to non-failing hearts and identified targeted transcripts involved in histone modification as enriched in heart failure. Further, we compared all mA sites regulated in human hearts with the ones occurring in isolated rat hypertrophic cardiomyocytes to define cardiomyocyte-specific mA events conserved across species. Our results identified 38 shared transcripts targeted by mA during stress conditions, and 11 events that are unique to unstressed cardiomyocytes. Of these, further evaluation of select mRNA and protein abundances demonstrates the potential impact of mA on post-transcriptional regulation of gene expression in the heart.
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http://dx.doi.org/10.1016/j.yjmcc.2020.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880874PMC
February 2021

Commentary: Low cardiac output syndrome: A definition or a diagnosis code?

Authors:
Bryan A Whitson

J Thorac Cardiovasc Surg 2020 Sep 14. Epub 2020 Sep 14.

Division of Cardiac Surgery, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2020.09.040DOI Listing
September 2020

Unmasking Arrhythmogenic Hubs of Reentry Driving Persistent Atrial Fibrillation for Patient-Specific Treatment.

J Am Heart Assoc 2020 10 2;9(19):e017789. Epub 2020 Oct 2.

Department of Physiology & Cell Biology and Frick Center for Heart Failure and Arrhythmia The Ohio State University Wexner Medical Center Columbus OH.

Background Atrial fibrillation (AF) driver mechanisms are obscured to clinical multielectrode mapping approaches that provide partial, surface-only visualization of unstable 3-dimensional atrial conduction. We hypothesized that transient modulation of refractoriness by pharmacologic challenge during multielectrode mapping improves visualization of hidden paths of reentrant AF drivers for targeted ablation. Methods and Results Pharmacologic challenge with adenosine was tested in ex vivo human hearts with a history of AF and cardiac diseases by multielectrode and high-resolution subsurface near-infrared optical mapping, integrated with 3-dimensional structural imaging and heart-specific computational simulations. Adenosine challenge was also studied on acutely terminated AF drivers in 10 patients with persistent AF. Ex vivo, adenosine stabilized reentrant driver paths within arrhythmogenic fibrotic hubs and improved visualization of reentrant paths, previously seen as focal or unstable breakthrough activation pattern, for targeted AF ablation. Computational simulations suggested that shortening of atrial refractoriness by adenosine may (1) improve driver stability by annihilating spatially unstable functional blocks and tightening reentrant circuits around fibrotic substrates, thus unmasking the common reentrant path; and (2) destabilize already stable reentrant drivers along fibrotic substrates by accelerating competing fibrillatory wavelets or secondary drivers. In patients with persistent AF, adenosine challenge unmasked hidden common reentry paths (9/15 AF drivers, 41±26% to 68±25% visualization), but worsened visualization of previously visible reentry paths (6/15, 74±14% to 34±12%). AF driver ablation led to acute termination of AF. Conclusions Our ex vivo to in vivo human translational study suggests that transiently altering atrial refractoriness can stabilize reentrant paths and unmask arrhythmogenic hubs to guide targeted AF driver ablation treatment.
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http://dx.doi.org/10.1161/JAHA.120.017789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792422PMC
October 2020

Optical Mapping-Validated Machine Learning Improves Atrial Fibrillation Driver Detection by Multi-Electrode Mapping.

Circ Arrhythm Electrophysiol 2020 10 13;13(10):e008249. Epub 2020 Sep 13.

Department of Physiology and Cell Biology and Bob and Corrine Frick Center for Heart Failure and Arrhythmia (A.M.Z., B.J.H., K.M.H., N.L., P.M.L.J., P.J.M., V.V.F.), The Ohio State University Wexner Medical Center, Columbus, OH.

Background: Atrial fibrillation (AF) can be maintained by localized intramural reentrant drivers. However, AF driver detection by clinical surface-only multielectrode mapping (MEM) has relied on subjective interpretation of activation maps. We hypothesized that application of machine learning to electrogram frequency spectra may accurately automate driver detection by MEM and add some objectivity to the interpretation of MEM findings.

Methods: Temporally and spatially stable single AF drivers were mapped simultaneously in explanted human atria (n=11) by subsurface near-infrared optical mapping (NIOM; 0.3 mm resolution) and 64-electrode MEM (higher density or lower density with 3 and 9 mm resolution, respectively). Unipolar MEM and NIOM recordings were processed by Fourier transform analysis into 28 407 total Fourier spectra. Thirty-five features for machine learning were extracted from each Fourier spectrum.

Results: Targeted driver ablation and NIOM activation maps efficiently defined the center and periphery of AF driver preferential tracks and provided validated annotations for driver versus nondriver electrodes in MEM arrays. Compared with analysis of single electrogram frequency features, averaging the features from each of the 8 neighboring electrodes, significantly improved classification of AF driver electrograms. The classification metrics increased when less strict annotation, including driver periphery electrodes, were added to driver center annotation. Notably, f1-score for the binary classification of higher-density catheter data set was significantly higher than that of lower-density catheter (0.81±0.02 versus 0.66±0.04, <0.05). The trained algorithm correctly highlighted 86% of driver regions with higher density but only 80% with lower-density MEM arrays (81% for lower-density+higher-density arrays together).

Conclusions: The machine learning model pretrained on Fourier spectrum features allows efficient classification of electrograms recordings as AF driver or nondriver compared with the NIOM gold-standard. Future application of NIOM-validated machine learning approach may improve the accuracy of AF driver detection for targeted ablation treatment in patients.
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http://dx.doi.org/10.1161/CIRCEP.119.008249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577986PMC
October 2020

Extracorporeal Cardiopulmonary Resuscitation (ECPR) for Out-of-Hospital Cardiac Arrest due to Pulseless Ventricular Tachycardia/Fibrillation.

J Interv Cardiol 2020 17;2020:6939315. Epub 2020 Jul 17.

Division of Cardiovascular Medicine, The Ohio State University, Columbus, Ohio, USA.

Background: Survival rates for out-of-hospital cardiac arrest are very low and neurologic recovery is poor. Innovative strategies have been developed to improve outcomes. A collaborative extracorporeal cardiopulmonary resuscitation (ECPR) program for out-of-hospital refractory pulseless ventricular tachycardia (VT) and/or ventricular fibrillation (VF) has been developed between The Ohio State University Wexner Medical Center and Columbus Division of Fire.

Methods: From August 15, 2017, to June 1, 2019, there were 86 patients that were evaluated in the field for cardiac arrest in which 42 (49%) had refractory pulseless VT and/or VF resulting from different underlying pathologies and were placed on an automated cardiopulmonary resuscitation device; from these 42 patients, 16 (38%) met final inclusion criteria for ECPR and were placed on extracorporeal membrane oxygenation (ECMO) in the cardiac catheterization laboratory (CCL).

Results: From the 16 patients who underwent ECPR, 4 (25%) survived to hospital discharge with cerebral perfusion category 1 or 2. Survivors tended to be younger (48.0 ± 16.7 vs. 59.3 ± 12.7 years); however, this difference was not statistically significant (=0.28) likely due to a small number of patients. Overall, 38% of patients underwent percutaneous coronary intervention (PCI). No significant difference was found between survivors and nonsurvivors in emergency medical services dispatch to CCL arrival time, lactate in CCL, coronary artery disease severity, undergoing PCI, and pre-ECMO PaO, pH, and hemoglobin. Recovery was seen in different underlying pathologies.

Conclusion: ECPR for out-of-hospital refractory VT/VF cardiac arrest demonstrated encouraging outcomes. Younger patients may have a greater chance of survival, perhaps the need to be more aggressive in this subgroup of patients.
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http://dx.doi.org/10.1155/2020/6939315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382749PMC
November 2020

Pegylated-Catalase Is Protective in Lung Ischemic Injury and Oxidative Stress.

Ann Thorac Surg 2021 03 22;111(3):1019-1027. Epub 2020 Jul 22.

COPPER Laboratory, Ohio State University Wexner Medical Center, Columbus, Ohio; Department of Surgery, Ohio State University Wexner Medical Center, Columbus, Ohio; Comprehensive Transplant Center, Ohio State University Wexner Medical Center, Columbus, Ohio. Electronic address:

Background: Lung transplant ischemia-reperfusion injury is typified by toxic metabolites and oxygen free radicals leading to worse graft function. Catalase is an enzyme involved in oxidative-stress detoxification. We hypothesize that direct delivery of highly concentrated polyethylene glycol-catalase (PEG-CAT) during normothermic ex vivo lung perfusion (EVLP) significantly reduces ischemia-reperfusion injury.

Methods: To demonstrate protection, primary culture porcine endothelial cells were treated with PEG-CAT (0 to 1250 U/mL) in a model of oxidative stress (400 μM Ho). In vivo, rat lungs were subjected to 0 hours or 1 hour of warm ischemic injury and 2 hours of EVLP with or without PEG-CAT. Perfusate was collected throughout the perfusion duration and tissue was collected at the end. Tissue and perfusate underwent analysis for markers of apoptosis and a biometric signature of lung health.

Results: Uptake of PEG-CAT into primary endothelial cells was demonstrated with Alexa Fluor 488-labeled PEG-CAT. Oxidatively stressed cells pretreated with PEG-CAT had significantly decreased cytotoxicity and caspase 3/7 activity and increased cell viability and cell membrane integrity. In a rat model of warm ischemia with EVLP, PEG-CAT improved allograft viability as measured by indications of cell membrane integrity (lactate dehydrogenase and hyaluronic acid), presence of vasoconstrictive peptides (endothelin-1 and big endothelin-1) released from endothelial cells, and reduced apoptosis (terminal deoxynucleotidyl transferase dUTP nick-end labeling).

Conclusions: In vitro and ex vivo, PEG-CAT protects against oxidative stress-induced cytotoxicity, maintains cellular metabolism, and mitigates lung ischemia-reperfusion in an experimental model. Together, these data suggest that PEG-CAT is a potential therapeutic target for donor organs at risk for ischemia-reperfusion injury.
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http://dx.doi.org/10.1016/j.athoracsur.2020.05.131DOI Listing
March 2021

Silencing miR-370-3p rescues funny current and sinus node function in heart failure.

Sci Rep 2020 07 9;10(1):11279. Epub 2020 Jul 9.

Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 2200N, Copenhagen, Denmark.

Bradyarrhythmias are an important cause of mortality in heart failure and previous studies indicate a mechanistic role for electrical remodelling of the key pacemaking ion channel HCN4 in this process. Here we show that, in a mouse model of heart failure in which there is sinus bradycardia, there is upregulation of a microRNA (miR-370-3p), downregulation of the pacemaker ion channel, HCN4, and downregulation of the corresponding ionic current, I, in the sinus node. In vitro, exogenous miR-370-3p inhibits HCN4 mRNA and causes downregulation of HCN4 protein, downregulation of I, and bradycardia in the isolated sinus node. In vivo, intraperitoneal injection of an antimiR to miR-370-3p into heart failure mice silences miR-370-3p and restores HCN4 mRNA and protein and I in the sinus node and blunts the sinus bradycardia. In addition, it partially restores ventricular function and reduces mortality. This represents a novel approach to heart failure treatment.
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http://dx.doi.org/10.1038/s41598-020-67790-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347645PMC
July 2020

Commentary: Stop the leak before it floods.

Authors:
Bryan A Whitson

J Thorac Cardiovasc Surg 2020 12 4;160(6):1502-1503. Epub 2020 May 4.

Division of Cardiac Surgery, Department of Surgery, The Ohio State University Medical Center, Columbus, Ohio. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2020.04.071DOI Listing
December 2020

Continuous-Flow Left Ventricular Assist Devices and the Aortic Valve: Interactions, Issues, and Surgical Therapy.

Curr Heart Fail Rep 2020 08;17(4):97-105

Division of Cardiac Surgery, Department of Surgery, Wexner Medical Center Ohio State University, Columbus, OH, USA.

Purpose Of Review: Concomitant valve disease is common in patients undergoing continuous-flow left ventricular assist device (CF-LVAD) implantation. In this review, we characterize the epidemiology and management of aortic valve disease following CF-LVAD.

Recent Findings: Studies suggest that 20-40% of patients have mild or greater aortic insufficiency (AI) at baseline and that AI progresses following CF-LVAD implantation. AI, either pre-existing or de novo, can have deleterious effects on LVAD efficacy and clinical outcomes. Surgical methods to correct AI in patients supported with CF-LVAD include central oversewing of the aortic valve, complete closure of the aortic valve, patch closure of the ventriculo-aortic junction, or aortic valve replacement with a bioprosthesis. Transcatheter options have recently emerged as feasible modalities to address AI. CF-LVADs contribute to the progression of aortic insufficiency (AI) and its development de novo. Prompt recognition, assessment, and treatment are important. Aortic valve repairs and replacements, now including TAVR, are the primary surgical methods to correct AI.
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http://dx.doi.org/10.1007/s11897-020-00464-0DOI Listing
August 2020
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