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Body, Simon

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Body, Simon
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    Duration of Postoperative Atrial Fibrillation After Cardiac Surgery Is Associated With Worsened Long-Term Survival
    (Elsevier BV, 2016) Sigurdsson, Martin I.; Longford, Nicholas T.; Heydarpour, Mahyar; Saddic, Louis; Chang, Tzuu-Wang; Fox, Amanda A.; Collard, Charles D.; Aranki, Sary; Shekar, Prem; Shernan, Stanton; Muehlschlegel, Jochen; Body, Simon
    Background. Studies of the effects of postoperative atrial fibrillation (poAF) on long-term survival are con- flicting, likely because of comorbidities that occur with poAF and the patient populations studied. Furthermore, the effects of poAF duration on long-term survival are poorly understood. Methods. We utilized a prospectively collected data- base on outcomes of cardiac surgery at a large tertiary care institution between August 2001 and December 2010 with survival follow-up through June 2015 to analyze long-term survival of patients with poAF. In addition, we identified patient- and procedure-related variables asso- ciated with poAF, and estimated overall comorbidity burden using the Elixhauser comorbidity index. Survival was compared between patients with poAF (n [ 513) and a propensity score matched control cohort, both for all patients and separately for subgroups of patients with poAF lasting less than 2 days (n [ 218) and patients with prolonged poAF (n [ 265). Postoperative atrial fibrillation (poAF) is observed in 26% to 32% of patients after isolated coronary artery bypass graft (CABG) surgery, and 30% to 50% of patients after isolated valve or combined valve and CABG sur- gery [1]. Several clinical risk factors for poAF have been identified, including older age [2, 3], male sex [2], and obesity [4]. Comorbidities such as history of prior atrial fibrillation (AF) [5], hypertension [3], congestive heart failure [5], chronic obstructive lung disease [5], and chronic kidney disease [6] have also been associated with poAF. Furthermore, valve repair or replacement and an increased aortic cross-clamp time also contribute to an increased risk of poAF [2, 5]. More recently, several Accepted for publication May 2, 2016. Address correspondence to Dr Body, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115; email: scbody@partners.org. ! 2016 by The Society of Thoracic Surgeons Published by Elsevier Results. Patients with poAF were older and had a higher burden of comorbidities. Survival was signifi- cantly worse for patients with poAF than for the matched control group (hazard ratio 1.43, 95% confi- dence interval: 1.11 to 1.86). That was driven by decreased survival among patients with prolonged poAF (hazard ratio 1.97, 95% confidence interval: 1.37 to 2.80), whereas survival of patients with poAF for less than 2 days was not significantly different from that of matched controls (hazard ratio 0.91, 95% confidence interval: 0.60 to 1.39). Conclusions. After close matching based on comor- bidity burden, prolonged poAF is still associated with decreased survival. Therefore, vigilance is warranted in monitoring and treating patients with prolonged poAF after cardiac surgery.
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    Genetic and Clinical Risk Prediction Model for Postoperative Atrial Fibrillation
    (Ovid Technologies (Wolters Kluwer Health), 2015) Kolek, M. J.; Muehlschlegel, Jochen; Bush, W. S.; Parvez, B.; Murray, K. T.; Stein, C. M.; Shoemaker, M. B.; Blair, M. A.; Kor, K. C.; Roden, D. M.; Donahue, B. S.; Fox, A. A.; Shernan, S. K.; Collard, C. D.; Body, Simon; Darbar, D.
    Background—Postoperative atrial fibrillation (PoAF) is common after coronary artery bypass grafting. We previously showed that atrial fibrillation susceptibility single nucleotide polymorphisms (SNPs) at the chromosome 4q25 locus are associated with PoAF. Here, we tested the hypothesis that a combined clinical and genetic model incorporating atrial fibrillation risk SNPs would be superior to a clinical-only model. Methods and Results—We developed and externally validated clinical and clinical/genetic risk models for PoAF. The discovery and validation cohorts included 556 and 1164 patients, respectively. Clinical variables previously associated with PoAF and 13 SNPs at loci associated with atrial fibrillation in genome-wide association studies were considered. PoAF occurred in 30% and 29% of patients in the discovery and validation cohorts, respectively. In the discovery cohort, a logistic regression model with clinical factors had good discrimination, with an area under the receiver operator characteristic curve of 0.76. The addition of 10 SNPs to the clinical model did not improve discrimination (area under receiver operator characteristic curve, 0.78; P=0.14 for difference between the 2 models). In the validation cohort, the clinical model had good discrimination (area under the receiver operator characteristic curve, 0.69) and addition of genetic variables resulted in a marginal improvement in discrimination (area under receiver operator characteristic curve, 0.72; P<0.0001). Conclusions—We developed and validated a model for the prediction of PoAF containing common clinical variables. Addition of atrial fibrillation susceptibility SNPs did not improve model performance. Tools to accurately predict PoAF are needed to risk stratify patients undergoing coronary artery bypass grafting and identify candidates for prophylactic therapies.
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    Association between bicuspid aortic valve morphotype and regional dilatation of the aortic root and trunk
    (Springer Nature, 2016) Habchi, Karam M.; undefined, undefined; Ashikhmina, Elena; Vieira, Vanessa Montiero; Shahram, Jasmin T.; Isselbacher, Eric; Sundt, Thoralf; Shekar, Prem; Muehlschlegel, Jochen; Body, Simon
    Thoracic aortic disease, including thoracic aor- tic aneurysm (TAA), is frequently seen in patients with bicuspid aortic valve (BAV). We hypothesized that BAV morphotype would be associated with aortic aneurysm phe- notypes but that other patient variables would signiicantly modify this relationship. 829 patients between 18 and 90 years with BAV and available raw imaging of the aortic valve and the ascending aorta to its mid-portion prior to aortic valve and aortic surgery were examined. The sinuses of Valsalva and proximal ascending aorta were measured from 2-dimensional co-planar echocardiographic images. We observed strong associations between patient habitus and raw and normalized dimensions of the aortic root and ascending aorta. Patients with R–L morphotype presented at an older age with larger aortic root but similar ascend- ing aortic dimensions. After accounting for patient mor- phometric characteristics and severity of aortic valve dis- ease, patients with R–L valve morphotype were marginally more likely to have an aortic root aneurysm (86% vs. 78%; P=0.043), deined as aortic root dimension Z score ≥3 We observed only small diferences in aortic dimensions between BAV morphotypes, that are eclipsed by variation in patient habitus. We interpret these indings to mean that BAV patients will not likely beneit from therapies based on aortic valve morphotype. Rather, we propose that all BAV patients should undergo longitudinal follow-up, inde- pendent of valve morphotype. Guidelines for aortic surgery based upon dimensions alone may be improved by con- sidering patient characteristics such as age, body size and other characteristics.
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    Length Polymorphisms in Heme Oxygenase-1 and AKI after Cardiac Surgery
    (American Society of Nephrology (ASN), 2016) Leaf, David; Body, Simon; Muehlschlegel, Jochen; McMahon, Gearoid; Lichtner, P.; Collard, C. D.; Shernan, S. K.; Fox, A. A.; Waikar, Sushrut
    Heme oxygenase-1 (HO-1) catalyzes the degradation of heme, which may be involved in the pathogenesis of AKI. Length polymorphisms in the number of GT dinucleotide repeats in the HO-1 gene (HMOX1) promoter inversely associate with HMOX1 mRNA expression. We analyzed the association between allelic frequencies of GT repeats in the HMOX1 gene promoter and postoperative AKI in 2377 white patients who underwent cardiac surgery with cardiopulmonary bypass. We catego- rized patients as having the short allele (S; ,27 GT repeats) or long allele (L; $27 GT repeats), and defined AKI as an increase in serum creatinine $0.3 mg/dl within 48 hours or $50% within 5 days, or the need for RRT. Compared with patients with the SS genotype, patients with the LL genotype had 1.58-fold (95% confidence interval, 1.06 to 2.34; P=0.02) higher odds of AKI. After adjusting for baseline and operative characteristics, the odds ratio for AKI per L allele was 1.26 (95% confidence interval, 1.05 to 1.50; P=0.01). In conclusion, longer GT repeats in the HMOX1 gene pro- moter associate with increased risk of AKI after cardiac surgery, consistent with heme toxicity as a pathogenic feature of cardiac surgery-associated AKI, and with HO-1 as a potential therapeutic target.
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    Plasma Corin Decreases After Coronary Artery Bypass Graft Surgery and Is Associated With Postoperative Heart Failure: A Pilot Study
    (Elsevier BV, 2015) Barnet, Caryn S.; Liu, Xiaoxiao; Body, Simon; Collard, Charles D.; Shernan, Stanton; Muehlschlegel, Jochen; Jarolim, Petr; Fox, Amanda A.
    Objective: Corin is a natriuretic peptide-converting enzyme that cleaves precursor pro-B-type natriuretic peptide to active B-type natriuretic peptide (BNP) (diuretic, natriuretic, and vaso- dilatory properties). Increased plasma BNP is a known diag- nostic and prognostic heart failure (HF) biomarker in ambulatory and surgical patients. Recent studies indicate that plasma corin is decreased significantly in chronic HF patients, yet perioper- ative plasma corin concentrations have not been assessed in cardiac surgical patients. The objectives of this study were to determine the effect of coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass (CPB) on plasma corin concentrations and to assess the association between change in perioperative plasma corin concentration and long-term postoperative HF hospitalization or death. It was hypothesized that plasma corin concentrations decrease significantly from preoperative baseline during postoperative days 1 to 4 and that hospitalization or death from HF during the 5 years after surgery is associated with higher relative difference (preoperative base- line to postoperative nadir) in plasma corin concentrations. Design: Prospective observational pilot study. Setting: Two institutions: Brigham and Women’s Hospi- tal, Boston, Massachusetts and the Texas Heart Institute, St. Luke’s Hospital, Houston, Texas. Participants: 99 patients of European ancestry who under- went isolated primary CABG surgery with CPB. Interventions: Nonemergency isolated primary CABG sur- gery with CPB. Measurements and Main Results: Plasma corin concen- tration was assessed preoperatively and at 4 postoperative time points (postoperative days 1-4). HF hospitalization or HF death events during the 5 years after surgery were identified by review of hospital and death records. Post- operative plasma corin concentrations were significantly lower than preoperative baseline concentrations (p o 0.0001). Perioperative corin concentrations were sig- nificantly higher in males than in females (p o 0.0001). Fifteen patients experienced long-term postoperative HF events. Patients who experienced HF hospitalization or HF death during study follow-up had significantly higher rela- tive difference in plasma corin concentration (preoperative baseline to postoperative nadir) than patients who did not experience HF events during study follow-up (p 1⁄4 0.03). Conclusions: Plasma corin concentrations decrease signif- icantly from preoperative concentrations after CABG sur- gery. HF hospitalization or HF death during the 5 years after CABG surgery with CPB is associated with larger relative decrease in plasma corin concentration from preoperative baseline. Further investigation is warranted to determine the role of corin in postoperative HF biology.
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    Engineering a 3D-Bioprinted Model of Human Heart Valve Disease Using Nanoindentation-Based Biomechanics
    (MDPI, 2018) van der Valk, Dewy C.; van der Ven, Casper F. T.; Blaser, Mark; Grolman, Joshua; Wu, Pin-Jou; Fenton, Owen S.; Lee, Lang H.; Tibbitt, Mark W.; Andresen, Jason L.; Wen, Jennifer R.; Ha, Anna H.; Buffolo, Fabrizio; van Mil, Alain; Bouten, Carlijn V. C.; Body, Simon; Mooney, David; Sluijter, Joost P. G.; Aikawa, Masanori; Hjortnaes, Jesper; Langer, Robert; Aikawa, Elena
    In calcific aortic valve disease (CAVD), microcalcifications originating from nanoscale calcifying vesicles disrupt the aortic valve (AV) leaflets, which consist of three (biomechanically) distinct layers: the fibrosa, spongiosa, and ventricularis. CAVD has no pharmacotherapy and lacks in vitro models as a result of complex valvular biomechanical features surrounding resident mechanosensitive valvular interstitial cells (VICs). We measured layer-specific mechanical properties of the human AV and engineered a three-dimensional (3D)-bioprinted CAVD model that recapitulates leaflet layer biomechanics for the first time. Human AV leaflet layers were separated by microdissection, and nanoindentation determined layer-specific Young’s moduli. Methacrylated gelatin (GelMA)/methacrylated hyaluronic acid (HAMA) hydrogels were tuned to duplicate layer-specific mechanical characteristics, followed by 3D-printing with encapsulated human VICs. Hydrogels were exposed to osteogenic media (OM) to induce microcalcification, and VIC pathogenesis was assessed by near infrared or immunofluorescence microscopy. Median Young’s moduli of the AV layers were 37.1, 15.4, and 26.9 kPa (fibrosa/spongiosa/ventricularis, respectively). The fibrosa and spongiosa Young’s moduli matched the 3D 5% GelMa/1% HAMA UV-crosslinked hydrogels. OM stimulation of VIC-laden bioprinted hydrogels induced microcalcification without apoptosis. We report the first layer-specific measurements of human AV moduli and a novel 3D-bioprinted CAVD model that potentiates microcalcification by mimicking the native AV mechanical environment. This work sheds light on valvular mechanobiology and could facilitate high-throughput drug-screening in CAVD.
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    The Long Noncoding RNA Landscape of the Ischemic Human Left Ventricle
    (Ovid Technologies (Wolters Kluwer Health), 2017) Saddic, Louis A.; Sigurdsson, Martin I.; Chang, Tzuu-Wang; Mazaika, Erica; Heydarpour, Mahyar; Shernan, Stanton; Seidman, Christine; Seidman, Jonathan; Aranki, Sary; Body, Simon; Muehlschlegel, Jochen
    Background—The discovery of functional classes of long noncoding RNAs (lncRNAs) has expanded our understanding of the variety of RNA species that exist in cells. In the heart, lncRNAs have been implicated in the regulation of development, ischemic and dilated cardiomyopathy, and myocardial infarction. Nevertheless, there is a limited description of expression profiles for these transcripts in human subjects. Methods and Results—We obtained left ventricular tissue from human patients undergoing cardiac surgery and used RNA sequencing to describe a lncRNA profile. We then identified a list of lncRNAs that were differentially expressed between pairs of samples before and after the ischemic insult of cardiopulmonary bypass. The expression of some of these lncRNAs correlates with ischemic time. Coding genes in close proximity to differentially expressed lncRNAs as well as coding genes that have coordinated expression with these lncRNAs are enriched in functional categories related to myocardial infarction including: heart function, metabolism, the stress response, and the immune system. Conclusions—We describe a list of lncRNAs that are differentially expressed after ischemia in the human heart. These genes are predicted to function in pathways consistent with myocardial injury. As a result, lncRNAs may serve as novel diagnostic and therapeutic targets for ischemic heart disease.
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    Embryonic Development of the Bicuspid Aortic Valve
    (2016) Martin, Peter S.; Kloesel, Benjamin; Norris, Russell A.; Lindsay, Mark; Milan, David; Body, Simon
    Bicuspid aortic valve (BAV) is the most common congenital valvular heart defect with an overall frequency of 0.5%–1.2%. BAVs result from abnormal aortic cusp formation during valvulogenesis, whereby adjacent cusps fuse into a single large cusp resulting in two, instead of the normal three, aortic cusps. Individuals with BAV are at increased risk for ascending aortic disease, aortic stenosis and coarctation of the aorta. The frequent occurrence of BAV and its anatomically discrete but frequent co-existing diseases leads us to suspect a common cellular origin. Although autosomal-dominant transmission of BAV has been observed in a few pedigrees, notably involving the gene NOTCH1, no single-gene model clearly explains BAV inheritance, implying a complex genetic model involving interacting genes. Several sequencing studies in patients with BAV have identified rare and uncommon mutations in genes of cardiac embryogenesis. But the extensive cell-cell signaling and multiple cellular origins involved in cardiac embryogenesis preclude simplistic explanations of this disease. In this review, we examine the series of events from cellular and transcriptional embryogenesis of the heart, to development of the aortic valve.
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    Post-operative atrial fibrillation examined using whole-genome RNA sequencing in human left atrial tissue
    (BioMed Central, 2017) Sigurdsson, Martin I; Saddic, Louis; Heydarpour, Mahyar; Chang, Tzuu-Wang; Shekar, Prem; Aranki, Sary; Couper, Gregory S; Shernan, Stanton; Muehlschlegel, Jochen; Body, Simon
    Background: Both ambulatory atrial fibrillation (AF) and post-operative AF (poAF) are associated with substantial morbidity and mortality. Analyzing the tissue-specific gene expression in the left atrium (LA) can identify novel genes associated with AF and further the understanding of the mechanism by which previously identified genetic variants associated with AF mediate their effects. Methods: LA free wall samples were obtained intraoperatively immediately prior to mitral valve surgery in 62 Caucasian individuals. Gene expression was quantified on mRNA harvested from these samples using RNA sequencing. An expression quantitative trait loci (eQTL) analysis was performed, comparing gene expression between different genotypes of 1.0 million genetic markers, emphasizing genomic regions and genes associated with AF. Results: Comparison of whole-genome expression between patients who later developed poAF and those who did not identified 23 differentially expressed genes. These included genes associated with the resting membrane potential modified by potassium currents, as well as genes within Wnt signaling and cyclic GMP metabolism. The eQTL analysis identified 16,139 cis eQTL relationships in the LA, including several involving genes and single nucleotide polymorphisms (SNPs) linked to AF. A previous relationship between rs3744029 and MYOZ1 expression was confirmed, and a novel relationship between rs6795970 and the expression of the SCN10A gene was identified. Conclusions: The current study is the first analysis of the human LA expression landscape using high-throughput RNA sequencing. Several novel genes and variants likely involved in AF pathogenesis were identified, thus furthering the understanding of how variants associated with AF mediate their effects via altered gene expression. Trial registration ClinicalTrials.gov ID: NCT00833313, registered 5. January 2009 Electronic supplementary material The online version of this article (doi:10.1186/s12920-017-0270-5) contains supplementary material, which is available to authorized users.
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    Allele-specific expression in the human heart and its application to postoperative atrial fibrillation and myocardial ischemia
    (BioMed Central, 2016) Sigurdsson, Martin I.; Saddic, Louis; Heydarpour, Mahyar; Chang, Tzuu-Wang; Shekar, Prem; Aranki, Sary; Couper, Gregory S.; Shernan, Stanton; Seidman, Jon G.; Body, Simon; Muehlschlegel, Jochen
    Background: Allele-specific expression (ASE) is differential expression of each of the two chromosomal alleles of an autosomal gene. We assessed ASE patterns in the human left atrium (LA, n = 62) and paired samples from the left ventricle (LV, n = 76) before and after ischemia, and tested the utility of differential ASE to identify genes associated with postoperative atrial fibrillation (poAF) and myocardial ischemia. Methods: Following genotyping from whole blood and whole-genome sequencing of LA and LV samples, we called ASE using sequences overlapping heterozygous SNPs using rigorous quality control to minimize false ASE calling. ASE patterns were compared between cardiac chambers and with a validation cohort from cadaveric tissue. ASE patterns in the LA were compared between patients who had poAF and those who did not. Changes in ASE in the LV were compared between paired baseline and post-ischemia samples. Results: ASE was found for 3404 (5.1%) and 8642 (4.0%) of SNPs analyzed in the LA and LV, respectively. Out of 6157 SNPs with ASE analyzed in both chambers, 2078 had evidence of ASE in both LA and LV (p < 0.0001). The SNP with the greatest ASE difference in the LA of patients with and without postoperative atrial fibrillation was within the gelsolin (GSN) gene, previously associated with atrial fibrillation in mice. The genes with differential ASE in poAF were enriched for myocardial structure genes, indicating the importance of atrial remodeling in the pathophysiology of AF. The greatest change in ASE between paired post-ischemic and baseline samples of the LV was in the zinc finger and homeodomain protein 2 (ZHX2) gene, a modulator of plasma lipids. Genes with differential ASE in ischemia were enriched in the ubiquitin ligase complex pathway associated with the ischemia-reperfusion response. Conclusions: Our results establish a pattern of ASE in the human heart, with a high degree of shared ASE between cardiac chambers as well as chamber-specific ASE. Furthermore, ASE analysis can be used to identify novel genes associated with (poAF) and myocardial ischemia. Electronic supplementary material The online version of this article (doi:10.1186/s13073-016-0381-1) contains supplementary material, which is available to authorized users.