Publications by authors named "Paul W M Fedak"

173 Publications

Dye-Mediated Photo-Oxidation Biomaterial Fixation: Analysis of Bioinductivity and Mechanical Properties of Bovine Pericardium for Use in Cardiac Surgery.

Int J Mol Sci 2021 Oct 5;22(19). Epub 2021 Oct 5.

Department of Cardiac Sciences, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada.

Extracellular matrix bioscaffolds can influence the cardiac microenvironment and modulate endogenous cellular mechanisms. These materials can optimize cardiac surgery for repair and reconstruction. We investigated the biocompatibility and bioinductivity of bovine pericardium fixed via dye-mediated photo-oxidation on human cardiac fibroblast activity. We compared a dye-mediated photo-oxidation fixed bioscaffold to glutaraldehyde-fixed and non-fixed bioscaffolds reported in contemporary literature in cardiac surgery. Human cardiac fibroblasts from consenting patients were seeded on to bioscaffold materials to assess the biocompatibility and bioinductivity. Human cardiac fibroblast gene expression, secretome, morphology and viability were studied. Dye-mediated photo-oxidation fixed acellular bovine pericardium preserves human cardiac fibroblast phenotype and viability; and potentiates a pro-vasculogenic paracrine response. Material tensile properties were compared with biomechanical testing. Dye-mediated photo-oxidation fixed acellular bovine pericardium had higher compliance compared to glutaraldehyde-fixed bioscaffold in response to tensile force. The biocompatibility, bioinductivity, and biomechanical properties of dye-mediated photo-oxidation fixed bovine pericardium demonstrate its feasibility as a bioscaffold for use in cardiac surgery. As a fixed yet bioinductive solution, this bioscaffold demonstrates enhanced compliance and retains bioinductive properties that may leverage endogenous reparative pathways. Dye-mediated photo-oxidation fixed bioscaffold warrants further investigation as a viable tool for cardiac repair and reconstruction.
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http://dx.doi.org/10.3390/ijms221910768DOI Listing
October 2021

Commentary: Cell therapy goes subcellular.

J Thorac Cardiovasc Surg 2021 Sep 9. Epub 2021 Sep 9.

Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada; Section of Cardiac Surgery, Department of Cardiac Sciences, Cumming School of Medicine, Calgary, Alberta, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2021.09.004DOI Listing
September 2021

An Intact Pericardium Ischemic Rodent Model.

J Vis Exp 2021 09 2(175). Epub 2021 Sep 2.

Section of Cardiac Surgery, Department of Cardiac Sciences, Libin Cardiovascular Institute, Cumming School of Medicine; Department of Pharmacology and Physiology, University of Calgary;

This protocol has shown that the pericardium and its contents play an essential anti-fibrotic role in the ischemic rodent model (coronary ligation to induce myocardial injury). The majority of pre-clinical myocardial infarction models require the disruption of pericardial integrity with loss of the homeostatic cellular milieu. However, recently a methodology has been developed by us to induce myocardial infarction, which minimizes pericardial damage and retains the heart's resident immune cell population. An improved cardiac functional recovery in mice with an intact pericardial space following coronary ligation has been observed. This method provides an opportunity to study inflammatory responses in the pericardial space following myocardial infarction. Further development of the labeling techniques can be combined with this model to understand the fate and function of pericardial immune cells in regulating the inflammatory mechanisms that drive remodeling in the heart, including fibrosis.
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http://dx.doi.org/10.3791/62720DOI Listing
September 2021

International Consensus Statement on Nomenclature and Classification of the Congenital Bicuspid Aortic Valve and Its Aortopathy, for Clinical, Surgical, Interventional and Research Purposes.

Radiol Cardiothorac Imaging 2021 Aug 22;3(4):e200496. Epub 2021 Jul 22.

St Paul's Hospital, University of British Columbia, Vancouver, Canada.

This International Consensus Classification and Nomenclature for the congenital bicuspid aortic valve condition recognizes 3 types of bicuspid valves: 1. The fused type (right-left cusp fusion, right-non-coronary cusp fusion and left-non-coronary cusp fusion phenotypes); 2. The 2-sinus type (latero-lateral and antero-posterior phenotypes); and 3. The partial-fusion (forme fruste) type. The presence of raphe and the symmetry of the fused type phenotypes are critical aspects to describe. The International Consensus also recognizes 3 types of bicuspid valve-associated aortopathy: 1. The ascending phenotype; 2. The root phenotype; and 3. Extended phenotypes. ©  2021 Jointly between the RSNA, the European Association for Cardio-Thoracic Surgery, The Society of Thoracic Surgeons, and the American Association for Thoracic Surgery. The articles are identical except for minor stylistic and spelling differences in keeping with each journal's style. All rights reserved. Bicuspid Aortic Valve, Aortopathy, Nomenclature, Classification.
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http://dx.doi.org/10.1148/ryct.2021200496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424700PMC
August 2021

Potential role of epicardial adipose tissue in coronary artery endothelial cell dysfunction in type 2 diabetes.

FASEB J 2021 10;35(10):e21878

Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Cardiovascular disease is the most prevalent cause of morbidity and mortality in diabetes. Epicardial adipose tissue (EAT) lies in direct contact with the myocardium and coronary arteries and can influence cardiac (patho) physiology through paracrine signaling pathways. This study hypothesized that the proteins released from EAT represent a critical molecular link between the diabetic state and coronary artery endothelial cell dysfunction. To simulate type 2 diabetes-associated metabolic and inflammatory status in an ex vivo tissue culture model, human EAT samples were treated with a cocktail composed of high glucose, high palmitate, and lipopolysaccharide (gplEAT) and were compared with control EAT (conEAT). Compared to conEAT, gplEAT showed a markedly increased gene expression profile of proinflammatory cytokines, corroborating EAT inflammation, a hallmark feature observed in patients with type 2 diabetes. Luminex assay of EAT-secretome identified increased release of various proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), interferon-alpha 2 (IFNA2), interleukin 1 beta (IL1B), interleukin 5 (IL5), interleukin 13 (IL13), and CCL5, among others, in response to high glucose, high palmitate, and lipopolysaccharide. Conditioned culture media was used to collect the concentrated proteins (CPs). In response to gplEAT-CPs, human coronary artery endothelial cells (HCAECs) exhibited an inflammatory endothelial cell phenotype, featuring a significantly increased gene expression of proinflammatory cytokines and cell surface expression of VCAM-1. Moreover, gplEAT-CPs severely decreased Akt-eNOS signaling, nitric oxide production, and angiogenic potential of HCAECs, when compared with conEAT-CPs. These findings indicate that EAT inflammation may play a key role in coronary artery endothelial cell dysfunction in type 2 diabetes.
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http://dx.doi.org/10.1096/fj.202100684RRDOI Listing
October 2021

Post-Operative Adhesions: A Comprehensive Review of Mechanisms.

Biomedicines 2021 Jul 22;9(8). Epub 2021 Jul 22.

Section of Cardiac Surgery, Department of Cardiac Sciences, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 2N9, Canada.

Post-surgical adhesions are common in almost all surgical areas and are associated with significant rates of morbidity, mortality, and increased healthcare costs, especially when a patient requires repeat operative interventions. Many groups have studied the mechanisms driving post-surgical adhesion formation. Despite continued advancements, we are yet to identify a prevailing mechanism. It is highly likely that post-operative adhesions have a multifactorial etiology. This complex pathophysiology, coupled with our incomplete understanding of the underlying pathways, has resulted in therapeutic options that have failed to demonstrate safety and efficacy on a consistent basis. The translation of findings from basic and preclinical research into robust clinical trials has also remained elusive. Herein, we present and contextualize the latest findings surrounding mechanisms that have been implicated in post-surgical adhesion formation.
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http://dx.doi.org/10.3390/biomedicines9080867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8389678PMC
July 2021

Association of Regional Wall Shear Stress and Progressive Ascending Aorta Dilation in Bicuspid Aortic Valve.

JACC Cardiovasc Imaging 2021 Aug 11. Epub 2021 Aug 11.

Department of Radiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA; Department of Biomedical Engineering, McCormick School of Engineering, Northwestern University, Evanston, Illinois, USA. Electronic address:

Objectives: The aim of this study was to evaluate the role of wall shear stress (WSS) as a predictor of ascending aorta (AAo) growth at 5 years or greater follow-up.

Background: Aortic 4-dimensional flow cardiac magnetic resonance (CMR) can quantify regions exposed to high WSS, a known stimulus for arterial wall dysfunction. However, its association with longitudinal changes in aortic dilation in patients with bicuspid aortic valve (BAV) is unknown.

Methods: This retrospective study identified 72 patients with BAV (45 ± 12 years) who underwent CMR for surveillance of aortic dilation at baseline and ≥5 years of follow-up. Four-dimensional flow CMR analysis included the calculation of WSS heat maps to compare regional WSS in individual patients with population averages of healthy age- and sex-matched subjects (database of 136 controls). The relative areas of the AAo and aorta (in %) exposed to elevated WSS (outside the 95% CI of healthy population averages) were quantified.

Results: At a median follow-up duration of 6.0 years, the mean AAo growth rate was 0.24 ± 0.20 mm/y. The fraction of the AAo exposed to elevated WSS at baseline was increased for patients with higher growth rates (>0.24 mm/y, n = 32) compared with those with growth rates <0.24 mm/y (19.9% [interquartile range (IQR): 10.2-25.5] vs 5.7% [IQR: 1.5-21.3]; P = 0.008). Larger areas of elevated WSS in the AAo and entire aorta were associated with higher rates of AAo dilation >0.24 mm/y (odds ratio: 1.51; 95% CI: 1.05-2.17; P = 0.026 and odds ratio: 1.70; 95% CI: 1.01-3.15; P = 0.046, respectively).

Conclusions: The area of elevated AAo WSS as assessed by 4-dimensional flow CMR identified BAV patients with higher rates of aortic dilation and thus might determine which patients require closer follow-up.
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http://dx.doi.org/10.1016/j.jcmg.2021.06.020DOI Listing
August 2021

Prevention of Post-Operative Adhesions: A Comprehensive Review of Present and Emerging Strategies.

Biomolecules 2021 07 14;11(7). Epub 2021 Jul 14.

Section of Cardiac Surgery, Department of Cardiac Sciences, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 2N9, Canada.

Post-operative adhesions affect patients undergoing all types of surgeries. They are associated with serious complications, including higher risk of morbidity and mortality. Given increased hospitalization, longer operative times, and longer length of hospital stay, post-surgical adhesions also pose a great financial burden. Although our knowledge of some of the underlying mechanisms driving adhesion formation has significantly improved over the past two decades, literature has yet to fully explain the pathogenesis and etiology of post-surgical adhesions. As a result, finding an ideal preventative strategy and leveraging appropriate tissue engineering strategies has proven to be difficult. Different products have been developed and enjoyed various levels of success along the translational tissue engineering research spectrum, but their clinical translation has been limited. Herein, we comprehensively review the agents and products that have been developed to mitigate post-operative adhesion formation. We also assess emerging strategies that aid in facilitating precision and personalized medicine to improve outcomes for patients and our healthcare system.
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http://dx.doi.org/10.3390/biom11071027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301806PMC
July 2021

Aorta-specific DNA methylation patterns in cell-free DNA from patients with bicuspid aortic valve-associated aortopathy.

Clin Epigenetics 2021 Jul 28;13(1):147. Epub 2021 Jul 28.

Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

Background: The dilation of the aorta that occurs as a consequence of a congenitally bicuspid aortic valve (BAV) is associated with a risk of dissection, aneurysm or rupture. With progressive aortopathy, surgery is often recommended, but current patient selection strategies have limitations. A blood-based assay to identify those who would most benefit from prophylactic surgery would be an important medical advance. In a proof-of-concept study, we sought to identify aorta-specific differentially methylated regions (DMRs) detectable in plasma cell-free DNA (cfDNA) obtained from patients undergoing surgery for BAV-associated aortopathy.

Methods: We used bioinformatics and publicly available human methylomes to identify aorta-specific DMRs. We used data from 4D-flow cardiac magnetic resonance imaging to identify regions of elevated aortic wall shear stress (WSS) in patients with BAV-associated aortopathy undergoing surgery and correlated WSS regions with aortic tissue cell death assessed using TUNEL staining. Cell-free DNA was isolated from patient plasma, and levels of candidate DMRs were correlated with aortic diameter and aortic wall cell death.

Results: Aortic wall cell death was not associated with maximal aortic diameter but was significantly associated with elevated WSS. We identified 24 candidate aorta-specific DMRs and selected 4 for further study. A DMR on chromosome 11 was specific for the aorta and correlated significantly with aortic wall cell death. Plasma levels of total and aorta-specific cfDNA did not correlate with aortic diameter.

Conclusions: In a cohort of patients undergoing surgery for BAV-associated aortopathy, elevated WSS created by abnormal flow hemodynamics was associated with increased aortic wall cell death which supports the use of aorta-specific cfDNA as a potential tool to identify aortopathy and stratify patient risk.
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http://dx.doi.org/10.1186/s13148-021-01137-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320174PMC
July 2021

Consumption of a high-fat-high-sucrose diet partly diminishes mechanical and structural adaptations of cardiac muscle following resistance training.

Phys Act Nutr 2021 Jun 30;25(2):8-14. Epub 2021 Jun 30.

Human Performance Laboratory, University of Calgary, Calgary, Canada.

Purpose: The purpose of this study was to investigate the effects of a high-fat high-sucrose (HFHS) diet on previously reported adaptations of cardiac morphological and contractile properties to resistance training.

Methods: Twelve-week-old rats participated in 12-weeks of resistance exercise training and consumed an HFHS diet. Echocardiography and skinned cardiac muscle fiber bundle testing were performed to determine the structural and mechanical adaptations.

Results: Compared to chow-fed sedentary animals, both HFHS- and chow-fed resistance-trained animals had thicker left ventricular walls. Isolated trabecular fiber bundles from chow-fed resistance-trained animals had greater force output, shortening velocities, and calcium sensitivities than those of chow-fed sedentary controls. However, trabeculae from the HFHS resistance-trained animals had greater force output but no change in unloaded shortening velocity or calcium sensitivity than those of the chow-fed sedentary group animals.

Conclusion: Resistance exercise training led to positive structural and mechanical adaptations of the heart, which were partly offset by the HFHS diet.
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http://dx.doi.org/10.20463/pan.2021.0009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8342188PMC
June 2021

International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes.

J Thorac Cardiovasc Surg 2021 Sep 22;162(3):e383-e414. Epub 2021 Jul 22.

St Paul's Hospital, University of British Columbia, Vancouver, Canada.

This International Consensus Classification and Nomenclature for the congenital bicuspid aortic valve condition recognizes 3 types of bicuspid valves: 1. The fused type (right-left cusp fusion, right-non-coronary cusp fusion and left-non-coronary cusp fusion phenotypes); 2. The 2-sinus type (latero-lateral and antero-posterior phenotypes); and 3. The partial-fusion (forme fruste) type. The presence of raphe and the symmetry of the fused type phenotypes are critical aspects to describe. The International Consensus also recognizes 3 types of bicuspid valve-associated aortopathy: 1. The ascending phenotype; 2. The root phenotype; and 3. Extended phenotypes.
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http://dx.doi.org/10.1016/j.jtcvs.2021.06.019DOI Listing
September 2021

Summary: International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional, and research purposes.

J Thorac Cardiovasc Surg 2021 09 22;162(3):781-797. Epub 2021 Jul 22.

St Paul's Hospital, University of British Columbia, Vancouver, Canada; aeCedars Sinai Heart Institute, Los Angeles, Calif; afDivision of Cardiology, Columbia University Irving Medical Center/NY Presbyterian Hospital, New York, NY.

This International evidence-based nomenclature and classification consensus on the congenital bicuspid aortic valve and its aortopathy recognizes 3 types of bicuspid aortic valve: 1. Fused type, with 3 phenotypes: right-left cusp fusion, right-non cusp fusion and left-non cusp fusion; 2. 2-sinus type with 2 phenotypes: Latero-lateral and antero-posterior; and 3. Partial-fusion or forme fruste. This consensus recognizes 3 bicuspid-aortopathy types: 1. Ascending phenotype; root phenotype; and 3. extended phenotypes.
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http://dx.doi.org/10.1016/j.jtcvs.2021.05.008DOI Listing
September 2021

Summary: International Consensus Statement on Nomenclature and Classification of the Congenital Bicuspid Aortic Valve and Its Aortopathy, for Clinical, Surgical, Interventional and Research Purposes.

Ann Thorac Surg 2021 09 22;112(3):1005-1022. Epub 2021 Jul 22.

St Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.

This International evidence-based nomenclature and classification consensus on the congenital bicuspid aortic valve and its aortopathy recognizes 3 types of bicuspid aortic valve: 1. Fused type, with 3 phenotypes: right-left cusp fusion, right-non cusp fusion and left-non cusp fusion; 2. 2-sinus type with 2 phenotypes: Latero-lateral and antero-posterior; and 3. Partial-fusion or forme fruste. This consensus recognizes 3 bicuspid-aortopathy types: 1. Ascending phenotype; root phenotype; and 3. extended phenotypes.
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http://dx.doi.org/10.1016/j.athoracsur.2021.05.001DOI Listing
September 2021

International Consensus Statement on Nomenclature and Classification of the Congenital Bicuspid Aortic Valve and Its Aortopathy, for Clinical, Surgical, Interventional and Research Purposes.

Ann Thorac Surg 2021 09 22;112(3):e203-e235. Epub 2021 Jul 22.

St Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.

This International Consensus Classification and Nomenclature for the congenital bicuspid aortic valve condition recognizes 3 types of bicuspid valves: 1. The fused type (right-left cusp fusion, right-non-coronary cusp fusion and left-non-coronary cusp fusion phenotypes); 2. The 2-sinus type (latero-lateral and antero-posterior phenotypes); and 3. The partial-fusion (forme fruste) type. The presence of raphe and the symmetry of the fused type phenotypes are critical aspects to describe. The International Consensus also recognizes 3 types of bicuspid valve-associated aortopathy: 1. The ascending phenotype; 2. The root phenotype; and 3. Extended phenotypes.
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http://dx.doi.org/10.1016/j.athoracsur.2020.08.119DOI Listing
September 2021

International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes.

Eur J Cardiothorac Surg 2021 09;60(3):448-476

St Paul's Hospital, University of British Columbia, Vancouver, Canada.

This International Consensus Classification and Nomenclature for the congenital bicuspid aortic valve condition recognizes 3 types of bicuspid valves: 1. The fused type (right-left cusp fusion, right-non-coronary cusp fusion and left-non-coronary cusp fusion phenotypes); 2. The 2-sinus type (latero-lateral and antero-posterior phenotypes); and 3. The partial-fusion (forme fruste) type. The presence of raphe and the symmetry of the fused type phenotypes are critical aspects to describe. The International Consensus also recognizes 3 types of bicuspid valve-associated aortopathy: 1. The ascending phenotype; 2. The root phenotype; and 3. Extended phenotypes.
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http://dx.doi.org/10.1093/ejcts/ezab038DOI Listing
September 2021

Summary: international consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes.

Eur J Cardiothorac Surg 2021 09;60(3):481-496

St Paul's Hospital, University of British Columbia, Vancouver, Canada.

This International evidence-based nomenclature and classification consensus on the congenital bicuspid aortic valve and its aortopathy recognizes 3 types of bicuspid aortic valve: 1. Fused type, with 3 phenotypes: right-left cusp fusion, right-non cusp fusion and left-non cusp fusion; 2. 2-sinus type with 2 phenotypes: Latero-lateral and antero-posterior; and 3. Partial-fusion or forme fruste. This consensus recognizes 3 bicuspid-aortopathy types: 1. Ascending phenotype; root phenotype; and 3. extended phenotypes.
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http://dx.doi.org/10.1093/ejcts/ezab039DOI Listing
September 2021

Commentary: The 4AT score-Reducing confusion about delirium diagnosis after cardiac surgery.

J Thorac Cardiovasc Surg 2021 Jun 18. Epub 2021 Jun 18.

Section of Cardiac Surgery, Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2021.06.023DOI Listing
June 2021

Bicuspid aortic valve disease is associated with abnormal wall shear stress, viscous energy loss, and pressure drop within the ascending thoracic aorta: A cross-sectional study.

Medicine (Baltimore) 2021 Jul;100(26):e26518

Department of Cardiac Sciences.

Abstract: Bicuspid aortic valve (BAV) disease has significant gaps in its clinical management practices. To highlight the potential utility of advanced hemodynamic biomarkers in strengthening BAV assessment, we used 4-dimentional flow magnetic resonance imaging to investigate altered hemodynamics in the ascending aorta (AAo).A total of 32 healthy controls and 53 age-matched BAV patients underwent cardiac magnetic resonance imaging at 3T, with cine imaging and 4D-flow. Analysis planes were placed along 3D-segmented aortas at the left ventricular outflow tract (LVOT), sinuses of Valsalva, mid-ascending aorta (MAA), and proximal to the first aortic branch. Locations were analyzed for aortic diameter (normalized to body surface area), pressure drop (PD), viscous energy loss (EL), and wall shear stress (WSS) sub-vectors (axial wall shear stress, circumferential wall shear stress [WSSC], magnitude wall shear stress). Student's t tests, or non-parametric equivalents, compared parameters between cohorts. Univariable and multivariable analyses explored the associations of AAo diameter with hemodynamics within the BAV cohort.Compared to control cohort, BAV patients showed significantly greater PD (MAA: 9.5 ± 8.0 vs 2.8 ± 2.4 mm Hg; P < .01), EL (from LVOT-AA1: 7.39 ± 4.57 mW vs 2.90 ± 1.07 mW; P < .01), and WSSC (MAA: 0.3 ± 0.1 vs 0.2 ± 0.06 Pa; P ≤ .01) throughout the AAo. Correlational analyses revealed an inverse association between AAo diameter and both magnitude wall shear stress and axial wall shear stress.BAV patients exhibited increased PD, EL, and WSSC in the AAo, and an inverse association between AAo diameter and WSS sub-vectors. This demonstrated the impact of PD, EL, and WSS in BAV disease and the importance of altered hemodynamics in aortic remodelling.
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http://dx.doi.org/10.1097/MD.0000000000026518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257908PMC
July 2021

Commentary: How to save and improve the lives of families with heritable aortic diseases.

J Thorac Cardiovasc Surg 2021 Mar 2. Epub 2021 Mar 2.

Department of Cardiac Sciences, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2021.02.088DOI Listing
March 2021

Mechanical and Structural Remodeling of Cardiac Muscle after Aerobic and Resistance Exercise Training in Rats.

Med Sci Sports Exerc 2021 08;53(8):1583-1594

Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Libin Cardiovascular Institute, Calgary, Alberta, CANADA.

Introduction: Aerobic and resistance exercise training results in distinct structural changes of the heart. The mechanics of how cardiac cells adapt to resistance training and the benefits to cells when combining aerobic and resistance exercise remains largely unknown. The purpose of this study was to compare mechanical adaptations of skinned cardiac fiber bundles after chronic resistance, aerobic and combined exercise training in rats. We hypothesized that differences in mechanical function on the fiber bundle level coincide with differences previously reported in the structure of the heart.

Method: Twelve-week-old rats were assigned to (i) an aerobic running group (n = 6), (ii) a ladder climbing resistance group (n = 6), (iii) a combination group subjected to aerobic and resistance training (n = 6), or (iv) a sedentary (control) group (n = 5). Echocardiography was used to measure cardiac structural remodeling. Skinned cardiac fiber bundles were used to determine active and passive force properties, maximal shortening velocity, and calcium sensitivity.

Results: Aerobically trained animals had 43%-49% greater ventricular volume and myocardial thickness, and a 4%-17% greater shortening velocity and calcium sensitivity compared with control group rats. Resistance-trained rats had 37%-71% thicker ventricular walls, a 56% greater isometric force production, a 9% greater shortening velocity, and a 4% greater calcium sensitivity compared with control group rats. The combination exercise-trained rats had 25%-43% greater ventricular volume and myocardial wall thickness, a 55% greater active force production, a 7% greater shortening velocity, and a 60% greater cross-bridge cooperativity compared with control group rats.

Conclusions: The heart adapts differently to each exercise modality, and a combination of aerobic and resistance training may have the greatest benefit for cardiac health and performance.
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http://dx.doi.org/10.1249/MSS.0000000000002625DOI Listing
August 2021

Commentary: Past is Prologue - Leveraging Big Data to Optimize Future Operative Risk Prediction.

Semin Thorac Cardiovasc Surg 2021 Mar 1. Epub 2021 Mar 1.

Department of Cardiac Sciences, Section of Cardiac Surgery, Cumming School of Medicine, University of Calgary, Libin Cardiovascular Institute, Calgary, Alberta, Canada. Electronic address:

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http://dx.doi.org/10.1053/j.semtcvs.2021.02.020DOI Listing
March 2021

Commentary: A picture is worth a thousand words: Improving surgical approaches using advanced multimodal cardiac imaging.

J Thorac Cardiovasc Surg 2021 Feb 4. Epub 2021 Feb 4.

Section of Cardiac Surgery, Department of Cardiac Sciences, Libin Cardiovascular Institute, Cumming School of Medicine, Calgary, Alberta, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2021.01.125DOI Listing
February 2021

Commentary: Fluoroquinolone antibiotics are antiaortic.

J Thorac Cardiovasc Surg 2020 Nov 20. Epub 2020 Nov 20.

Section of Cardiac Surgery, Department of Cardiac Sciences, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2020.11.036DOI Listing
November 2020

KCa channel activation normalizes endothelial function in Type 2 Diabetic resistance arteries by improving intracellular Ca mobilization.

Metabolism 2021 01 8;114:154390. Epub 2020 Oct 8.

Dept. of Physiology and Pharmacology, Libin Cardiovascular Institute of Alberta, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 4N1, Canada. Electronic address:

Background: Endothelial dysfunction is an early pathogenic event in the progression of cardiovascular disease in patients with Type 2 Diabetes (T2D). Endothelial KCa2.3 and KCa3.1 K channels are important regulators of arterial diameter, and we thus hypothesized that SKA-31, a small molecule activator of KCa2.3 and KCa3.1, would positively influence agonist-evoked dilation in myogenically active resistance arteries in T2D.

Methodology: Arterial pressure myography was utilized to investigate endothelium-dependent vasodilation in isolated cremaster skeletal muscle resistance arteries from 22 to 24 week old T2D Goto-Kakizaki rats, age-matched Wistar controls, and small human intra-thoracic resistance arteries from T2D subjects. Agonist stimulated changes in cytosolic free Ca in acutely isolated, single endothelial cells from Wistar and T2D Goto-Kakizaki cremaster and cerebral arteries were examined using Fura-2 fluorescence imaging.

Main Findings: Endothelium-dependent vasodilation in response to acetylcholine (ACh) or bradykinin (BK) was significantly impaired in isolated cremaster arteries from T2D Goto-Kakizaki rats compared with Wistar controls, and similar results were observed in human intra-thoracic arteries. In contrast, inhibition of myogenic tone by sodium nitroprusside, a direct smooth muscle relaxant, was unaltered in both rat and human T2D arteries. Treatment with a threshold concentration of SKA-31 (0.3 μM) significantly enhanced vasodilatory responses to ACh and BK in arteries from T2D Goto-Kakizaki rats and human subjects, whereas only modest effects were observed in non-diabetic arteries of both species. Mechanistically, SKA-31 enhancement of evoked dilation was independent of vascular NO synthase and COX activities. Remarkably, SKA-31 treatment improved agonist-stimulated Ca elevation in acutely isolated endothelial cells from T2D Goto-Kakizaki cremaster and cerebral arteries, but not from Wistar control vessels. In contrast, SKA-31 treatment did not affect intracellular Ca release by the sarco/endoplasmic reticulum Ca-ATPase (SERCA) inhibitor cyclopiazonic acid.

Conclusions: Collectively, our data demonstrate that KCa channel modulation can acutely restore endothelium-dependent vasodilatory responses in T2D resistance arteries from rats and humans, which appears to involve improved endothelial Ca mobilization.
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http://dx.doi.org/10.1016/j.metabol.2020.154390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736096PMC
January 2021

Commentary: Transplanting the powerhouse of the cell to enhance cardiopulmonary repair.

J Thorac Cardiovasc Surg 2020 Sep 5. Epub 2020 Sep 5.

Section of Cardiac Surgery, Department of Cardiac Sciences, Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2020.09.007DOI Listing
September 2020

Commentary: The mutation matters: Improving precision for surgical management of hereditary aortic syndromes.

J Thorac Cardiovasc Surg 2020 Aug 28. Epub 2020 Aug 28.

Section of Cardiac Surgery, Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Libin Cardiovascular Institute, Calgary, Alberta, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2020.08.077DOI Listing
August 2020

Commentary: The return on investment for cardiothoracic surgeon-scientists.

Authors:
Paul W M Fedak

J Thorac Cardiovasc Surg 2020 Jul 24. Epub 2020 Jul 24.

Section of Cardiac Surgery, Department of Cardiac Sciences, Cumming School of Medicine, University of Calgary, Libin Cardiovascular Institute, Calgary, Alberta, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2020.07.064DOI Listing
July 2020

Surgical management of the aorta in BAV patients.

Prog Cardiovasc Dis 2020 Jul - Aug;63(4):475-481. Epub 2020 Jul 5.

University Clinic of Cardiac Surgery, Leipzig Heart Center, Leipzig, Germany. Electronic address:

Patients with a bicuspid aortic valve (BAV) frequently develop aneurysms of the aortic root and tubular ascending aorta. Aneurysms of the aortic arch, in the absence of concomitant aortopathies, are much less common. According to the 2018 American Association of Thoracic Surgery consensus guidelines on BAV-related aortopathy, prophylactic surgical aortic repair / replacement is recommended starting at a maximum aortic diameter of 50 mm in patients with risk factors. Concomitant aortic surgery is also recommended at an aortic diameter of 45 mm in those patients with other indications for cardiac surgery (most commonly aortic valve procedures). The ultimate goal of prophylactic aortic surgery is the prevention of aortic catastrophes, e.g. aortic rupture or acute aortic dissection, which are associated with high morbidity and mortality. The surgical technique used - in elective and emergency cases - depends on the involvement and nature of the aortic valve disease, as well as the extent of aortic aneurysm formation. The current review focusses on the surgical management of the aortic root, tubular ascending aorta, and proximal aortic arch in BAV patients. Despite the abovementioned recommendations, many BAV patients develop acute aortic syndromes below the recommended aortic diameter thresholds. Further research is therefore required in order to identify high-risk BAV subgroups that would benefit from earlier surgical repair.
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http://dx.doi.org/10.1016/j.pcad.2020.06.013DOI Listing
October 2020

The science of BAV aortopathy.

Prog Cardiovasc Dis 2020 Jul - Aug;63(4):465-474. Epub 2020 Jun 26.

Department of Translational Medical Sciences, University of Campania "L. Vanvitelli", Naples, Italy. Electronic address:

The aortopathy associated with bicuspid aortic valve (BAV) is an epidemiologically relevant source of chronic and acute aortic disease (aneurysm and dissection). However, its pathogenesis is still the object of scientific uncertainties and debates. Indeed, the mechanisms determining the diseases of the ascending aorta in BAV patients are most likely complex and multifactorial, i.e. resulting from variable modes of interplay between genetic and hemodynamic factors. Although few scientific studies have so far taken into adequate account this complexity, leaving the precise sequence of pathogenetic events still undiscovered, the accumulated evidence from previous research approaches have at least brought about important insights. While genetic studies have so far identified variants relevant to either valve malformation or aortic complications (including those in the genes NOTCH1, TGFBR2, ACTA2, GATA5, NKX2.5, SMAD6, ROBO4), however each explaining not more than 5% of the study population, other investigations have thoroughly described both the flow features, with consequent forces acting on the arterial wall (including skewed flow jet direction, rotational flow, wall shear stress), and the main changes in the molecular and cellular wall structure (including extracellular matrix degradation, smooth muscle cell changes, oxidative stress, unbalance of TGF-β signaling, aberrant endothelial-to-mesenchymal transition). All of this evidence, together with the recognition of the diverse phenotypes that the aortopathy can assume in BAV patients, holding possible prognostic significance, is reviewed in this chapter. The complex and multifaceted body of knowledge resulting from clinical and basic science studies on BAV aortopathy has the potential to importantly influence modes of clinical management of this disease in the near future.
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http://dx.doi.org/10.1016/j.pcad.2020.06.009DOI Listing
October 2020

Acellular bioscaffolds redirect cardiac fibroblasts and promote functional tissue repair in rodents and humans with myocardial injury.

Sci Rep 2020 06 11;10(1):9459. Epub 2020 Jun 11.

Section of Cardiac Surgery, Department of Cardiac Sciences, Cumming School of Medicine, Libin Cardiovascular Institute, University of Calgary, Calgary, Alberta, Canada.

Coronary heart disease is a leading cause of death. Tissue remodeling and fibrosis results in cardiac pump dysfunction and ischemic heart failure. Cardiac fibroblasts may rebuild damaged tissues when prompted by suitable environmental cues. Here, we use acellular biologic extracellular matrix scaffolds (bioscaffolds) to stimulate pathways of muscle repair and restore tissue function. We show that acellular bioscaffolds with bioinductive properties can redirect cardiac fibroblasts to rebuild microvascular networks and avoid tissue fibrosis. Specifically, when human cardiac fibroblasts are combined with bioactive scaffolds, gene expression is upregulated and paracrine mediators are released that promote vasculogenesis and prevent scarring. We assess these properties in rodents with myocardial infarction and observe bioscaffolds to redirect fibroblasts, reduce tissue fibrosis and prevent maladaptive structural remodeling. Our preclinical data confirms that acellular bioscaffold therapy provides an appropriate microenvironment to stimulate pathways of functional repair. We translate our observations to patients with coronary heart disease by conducting a first-in-human observational cohort study. We show that bioscaffold therapy is associated with improved perfusion of infarcted myocardium, reduced myocardial scar burden, and reverse structural remodeling. We establish that clinical use of acellular bioscaffolds is feasible and offers a new frontier to enhance surgical revascularization of ischemic heart muscle.
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http://dx.doi.org/10.1038/s41598-020-66327-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289874PMC
June 2020
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