Conduit selection and early graft failure in coronary artery bypass surgery: A post hoc analysis of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) coronary artery bypass grafting study.

OBJECTIVES: Relative rates of early graft failure and conduit selection in coronary artery bypass grafting (CABG) surgery remain controversial. Therefore, we sought to determine the incidence and determinants of graft failure of the left internal mammary artery (LIMA), radial artery, saphenous vein, and right internal mammary artery (RIMA) 1 year after CABG surgery. METHODS: A post hoc analysis of the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) CABG study, involving patients from 83 centers in 22 countries. We completed an analysis of 3480 grafts from 1068 patients who underwent CABG surgery with complete computed tomography angiography data. The primary outcome was graft failure as diagnosed by computed tomography angiography 1 year after surgery. RESULTS: Graft failure occurred in 6.4% (68/1068) for LIMA, 9.9% (9/91) for radial artery, 10.4% (232/2239) for saphenous vein, and 26.8% (22/82) for RIMA grafts. The RIMA had a greater rate of graft failure (26.8%) than radial artery (9.9%) and veins (10.4%) (adjusted odds ratio, 2.69; 95% confidence interval, 1.30-5.57; P = .008 and adjusted odds ratio, 2.07; 95% confidence interval, 1.33-3.21; P = .001, respectively). CONCLUSIONS: In this international trial dataset, LIMA and radial artery performed as expected, whereas vein grafts performed better. However, high rates of RIMA failure are worrisome and highlight the need for a thorough evaluation of the patency and safety of the RIMA in CABG surgery.

High-Dose Thiamine Supplementation in Older Patients With Heart Failure: A Pilot Randomized Controlled Crossover Trial (THIAMINE-HF).

Background: Thiamine supplementation may improve cardiac function in older adults with heart failure (HF). Our objectives were to determine the following: (i) the feasibility of conducting a large trial of thiamine supplementation in HF; and (ii) the effects of thiamine on clinical outcomes. Methods: We conducted a double-blinded randomized placebo-controlled 2-period crossover feasibility study from June 2018 to April 2021. Adults aged ≥ 60 years with symptomatic HF and reduced ejection fraction (≤ 45%) were included. Participants were randomized to thiamine mononitrate 500 mg, or placebo, for 90 days and were switched to the opposite treatment for 90 days after a 6-week washout period. The primary feasibility outcome was recruitment of 24 participants in 11 months. Results: We screened 330 patients over 21 months to recruit 24 patients. Participants' mean age was 73.4 years. The targets for refusal rate, retention rate, and adherence rate were met. Nonsignificant improvements occurred in left ventricular ejection fraction and N-terminal pro-brain natriuretic peptide (NT-proBNP) level with thiamine. A total of 13 serious adverse events occurred in 7 patients; none were related to the study drug. Conclusions: Although we did not reach our recruitment target, we found high-dose thiamine supplementation to be well tolerated, with potential improvements in biomarker outcomes. A larger trial of thiamine supplementation is warranted.

Introduction: La supplémentation en thiamine peut améliorer la fonction cardiaque chez les personnes âgées atteintes d'insuffisance cardiaque (IC). Nos objectifs visaient à déterminer : (i) la faisabilité d'un essai de grande envergure sur la supplémentation en thiamine lors d'IC ; (ii) les effets de la thiamine sur les résultats cliniques. Méthodes: Nous avons réalisé une étude de faisabilité croisée à double insu et à répartition aléatoire contre placebo sur deux périodes de juin 2018 à avril 2021. Nous avons retenu les adultes de ≥ 60 ans qui avaient une IC symptomatique et une fraction d'éjection réduite (≤ 45 %). Nous avons réparti les participants de façon aléatoire pour recevoir 500 mg de mononitrate de thiamine ou le placebo durant 90 jours, et avons inversé le traitement durant 90 jours après une période de lavage de 6 semaines. Le principal critère de faisabilité était le recrutement de 24 participants en 11 mois. Résultats: Nous avons recruté 24 patients sur les 330 patients sélectionnés durant 21 mois. L'âge moyen des participants était de 73,4 ans. Les cibles des taux de refus, des taux de rétention et des taux d'adhésion ont été atteintes. Avec la thiamine, nous avons observé des améliorations non significatives de la fraction d'éjection ventriculaire gauche et de la concentration de propeptide natriurétique de type B N-terminal (NT-proBNP). Parmi les 13 événements indésirables sérieux qu'ont subis sept patients, aucun n'a été associé au médicament étudié. Conclusions: Bien que nous n'ayons pas atteint notre cible de recrutement, nous avons observé que la supplémentation en thiamine à dose élevée était bien tolérée et qu'il y avait des améliorations potentielles des résultats des biomarqueurs. Un essai de plus grande envergure sur la supplémentation en thiamine est justifié.

Analysis of serum tranexamic acid in patients undergoing open heart surgery.

BACKGROUND: Tranexamic acid is a drug used during open cardiac surgery to prevent blood loss. The blood levels of 10-100 µg/mL are reported to be in the therapeutic range and higher levels are linked to increased incidence of adverse effects. The aim of this study was to optimize and validate an LC-MS/MS method for serum tranexamic acid and measure its levels in patients from the DEPOSITION Pilot trial in order to prove the concept that topical administration will yield lower serum concentration. METHODS: The method development was carried out in several steps including sample preparation, and optimization of chromatography and tandem mass spectrometry parameters. Method validation including day-to-day precision with 4 QC levels, limit of detection, sample stability, carryover, and concentration-signal linearity was carried out. Ninety patient samples were analyzed using the validated method. RESULTS: Fast and efficient LC-MS/MS method for analysis of tranexamic acid in serum was developed. The run time was 7 min with the total time of one hour including the sample preparation. The method precision was acceptable (%CV = 10.5-12.6%) with no sample carryover observed. The matrix effect on the analytical sensitivity was negligible and the lower limit of detection was 0.5 µg/mL. The difference in the mean adjusted concentrations between topical (45 patients) and intravenous (45 patients) groups was statistically significant (0.1154 µg/mL/kg vs. 0.2542 µg/mL/kg, p < 0.0001) CONCLUSIONS: Rapid and simple LC-MS/MS method for analysis of tranexamic acid was optimized and validated. The laboratory has played a crucial role in proving the concept that topical administration yields significantly lower systemic levels of tranexamic acid, and thus decreases the risk of adverse outcomes in patients undergoing open cardiac surgery.

Feasibility of studying the association between intraoperative regional cerebral oxygen saturation and postoperative functional decline (ReFUNCTION): a pilot sub-study of NeuroVISION-Cardiac Surgery.

PURPOSE: Function describes an individual's ability to perform everyday activities. In the context of cardiac surgery, functional changes quantify the effect of surgery on one's day-to-day life. Decreases in regional cerebral oxygen saturation (rScO2) measured using near-infrared spectroscopy (NIRS) has been associated with postoperative cognitive decline but its relationship with function has not been studied. We sought to determine the feasibility of conducting a large observational study examining the relationship between decreases in rScO2 during cardiac surgery and postoperative functional decline. METHODS: We undertook a single-centre, pilot sub-study of the NeuroVISION-Cardiac Surgery pilot study, which included adults undergoing isolated coronary artery bypass grafting on cardiopulmonary bypass; all patients enrolled in NeuroVISION-Cardiac Surgery were included. Function was evaluated at baseline, 30 days, and three months using the Standardized Assessment of Global activities in the Elderly (SAGE) scale. Blinded NIRS monitors were affixed for the duration of surgery. Our feasibility outcomes were to recruit one patient per week, obtain complete NIRS data in ≥ 90%, obtain SAGE at all time-points in ≥ 90%, and determine the time required for NIRS data to be transcribed into case report forms. RESULTS: 49/50 patients enrolled in NeuroVISION-Cardiac Surgery were recruited over 48 weeks (1.02 patients/week). Of the 49 included patients, 49 (100%) had complete NIRS data and 44 (90%) had complete SAGE data. The time required for NIRS data collection was a mean (standard deviation) of 5.5 (1.8) min per patient. CONCLUSION: This pilot study shows the feasibility of conducting a large observational study examining the relationship between decreases in cerebral saturation during cardiac surgery and postoperative functional decline. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT04241289); registered 27 January 2020.

RéSUMé: OBJECTIF : La capacité fonctionnelle constitue la capacité d'une personne à accomplir des activités quotidiennes. Dans le contexte d'une chirurgie cardiaque, les changements fonctionnels permettent de quantifier l'effet de la chirurgie sur le quotidien des individus. Les baisses de la saturation en oxygène cérébral régional (rScO2) mesurées à l'aide de la spectroscopie proche infrarouge (NIRS) ont été associées à un déclin cognitif postopératoire, mais leur relation par rapport à la capacité fonctionnelle n'a pas été étudiée. Nous avons tenté de déterminer s'il était possible de réaliser une vaste étude observationnelle examinant la relation entre les baisses de rScO2 pendant une chirurgie cardiaque et le déclin fonctionnel postopératoire. MéTHODE : Nous avons entrepris une sous-étude pilote monocentrique de l'étude pilote NeuroVISION-Cardiac Surgery, qui incluait des adultes subissant une chirurgie de pontage aortocoronarien sous circulation extracorporelle; tous les patients recrutés dans l'étude NeuroVISION-Cardiac Surgery ont été inclus dans ce volet. La capacité fonctionnelle a été évaluée avant l'opération, puis à 30 jours et trois mois à l'aide de l'échelle SAGE (Standardized Assessment of Global activities in the Elderly, soit Évaluation standardisée de la fonction globale chez la personne âgée). Des moniteurs de NIRS étaient installés pour toute la durée de la chirurgie sans que les valeurs ne soient connues de l'équipe traitante. Nos critères de faisabilité consistaient à recruter un patient par semaine, obtenir des données de NIRS complètes pour ≥ 90 % des patients, obtenir des données de SAGE pour tous les points dans le temps pour ≥ 90 % des patients, et déterminer le temps nécessaire à retranscrire les données de NIRS dans les formulaires d'étude de cas. RéSULTATS : Au total, 49/50 patients recrutés dans l'étude NeuroVISION-Cardiac Surgery ont été recrutés sur une période de 48 semaines (1,02 patients/semaine). Parmi les 49 patients inclus, les données de NIRS ont été obtenues pour 49 (100 %) patients et les données de SAGE pour 44 (90 %) patients. Le temps nécessaire à la collecte de données de NIRS était en moyenne (écart type) de 5,5 (1,8) min par patient. CONCLUSION : L'étude pilote a démontré la faisabilité d'une vaste étude observationnelle examinant la relation entre les baisses de la saturation cérébrale pendant la chirurgie cardiaque et le déclin fonctionnel postopératoire. ENREGISTREMENT DE L'éTUDE : www.clinicaltrials.gov (NCT04241289); enregistrée le 27 janvier 2020.

Perioperative covert stroke in patients undergoing coronary artery bypass graft surgery.

Objectives: Covert stroke is a complication of coronary artery bypass graft surgery that is increasingly recognized as a serious problem. In noncardiac surgery settings, covert stroke is associated with the development of delirium, long-term cognitive decline, and future clinical stroke. Therefore, we sought to determine the feasibility of conducting a large, prospective cohort study of the influence of covert stroke on neurocognitive outcomes in patients undergoing coronary artery bypass graft surgery. Methods: NeuroVISION Cardiac pilot was a prospective cohort study enrolling patients aged ≥21 years undergoing isolated coronary artery bypass graft surgery to receive diffusion-weighted magnetic resonance imaging of the brain after surgery to identify patients with covert stroke. Patients were screened for postoperative delirium in-hospital and were administered questionnaires of cognitive and global function (once before and twice after surgery). Regional cerebral oxygen saturation was recorded during surgery using near-infrared spectroscopy. Results: Between March 27, 2017, and February 11, 2018, 50 of 66 patients enrolled (76%) completed the brain magnetic resonance imaging (1 patient per week). Among the 49 patients included in the analysis, 19 (39%; 95% confidence interval, 26%-53%) experienced perioperative covert stroke and 3 (6%) had a clinical stroke within 30 days of surgery. Postoperative delirium occurred in 5 (26%) patients with covert stroke and in 3 (10%) patients who did not experience covert stroke. Conclusions: The NeuroVISION Cardiac pilot study established the feasibility of conducting a large, prospective cohort study of the determinants and consequences of covert stroke in patients undergoing coronary artery bypass graft surgery.

Decreasing Postoperative Blood Loss by Topical vs. Intravenous Tranexamic Acid in Open Cardiac Surgery (DEPOSITION) study: Results of a pilot study.

BACKGROUND: Cardiac surgery patients are at high risk for postoperative bleeding. Intravenous (IV) tranexamic acid (TxA) is a commonly used antifibrinolytic drug, but is associated with postoperative seizures. We conducted this pilot randomized controlled trial (RCT) to determine the feasibility of a larger trial that will be designed to investigate the impact of TxA administration route, intrapericardial (IP) vs IV, on postoperative bleeding and seizures. METHODS: In this single-center, double-blinded, pilot RCT we enrolled adult patients undergoing nonemergent on-pump cardiac operations through a median sternotomy. Participants were randomized to IP or IV TxA groups. The primary outcomes were cumulative chest tube drainage, transfusion requirements, and incidence of postoperative seizures. RESULTS: A total of 97 participants were randomized to the intervention and control groups. Baseline characteristics were similar in both groups. Most participants underwent a CABG and/or aortic valve replacement. There was no statistical difference. The IP TxA group was found to have a tendency for less chest tube drainage in comparison to the IV TxA group, 500.5 (370.0-700.0) and 540.0 (420.0-700.0) mL, respectively, which was not statistically significant (P = 0.2854). Fewer participants in the IP TxA group with cardiac tamponade and/or required a reoperation for bleeding and fewer packed red blood cell transfusions. None of the IP TxA group developed seizure vs one from the IV TxA group. CONCLUSION: This is the first known pilot RCT to investigate the role of TxA route of administration in open cardiac surgery. Intrapericardial TxA shows promising results with decreased bleeding, transfusion requirements, reoperations, and postoperative seizures. A larger RCT is needed to confirm these results and lead to a change in practice.

Prenatal and postnatal findings in serpentine fibula polycystic kidney syndrome and a review of the NOTCH2 spectrum disorders.

Serpentine fibula polycystic kidney syndrome (SFPKS; OMIM600330) is a rare skeletal dysplasia with a characteristic phenotype that includes polycystic kidneys, S-shaped fibulas, and abnormal craniofacial features. SFPKS shares features with Alagille (AGS; OMIM) and Hajdu-Cheney (HCS; OMIM10250) syndromes. All three syndromes result from mutations in the gene that encodes NOTCH2, one of the receptors involved in Notch signaling. Notch signaling is a major developmental signaling pathway, as well as a key regulator of numerous cellular processes. In this report, we present the prenatal ultrasound and postnatal findings in a 23-week fetus with severe manifestations of SPKS and heterozygosity for a de novo mutation in exon 34 of NOTCH2. These findings expand the phenotypic spectrum of NOTCH2 mutations and demonstrate the findings in the prenatal period.

Whole exome sequencing in dominant cataract identifies a new causative factor, CRYBA2, and a variety of novel alleles in known genes.

Pediatric cataracts are observed in 1-15 per 10,000 births with 10-25 % of cases attributed to genetic causes; autosomal dominant inheritance is the most commonly observed pattern. Since the specific cataract phenotype is not sufficient to predict which gene is mutated, whole exome sequencing (WES) was utilized to concurrently screen all known cataract genes and to examine novel candidate factors for a disease-causing mutation in probands from 23 pedigrees affected with familial dominant cataract. Review of WES data for 36 known cataract genes identified causative mutations in nine pedigrees (39 %) in CRYAA, CRYBB1, CRYBB3, CRYGC (2), CRYGD, GJA8 (2), and MIP and an additional likely causative mutation in EYA1; the CRYBB3 mutation represents the first dominant allele in this gene and demonstrates incomplete penetrance. Examination of crystallin genes not yet linked to human disease identified a novel cataract gene, CRYBA2, a member of the ßγ-crystallin superfamily. The p.(Val50Met) mutation in CRYBA2 cosegregated with disease phenotype in a four-generation pedigree with autosomal dominant congenital cataracts with incomplete penetrance. Expression studies detected cryba2 transcripts during early lens development in zebrafish, supporting its role in congenital disease. Our data highlight the extreme genetic heterogeneity of dominant cataract as the eleven causative/likely causative mutations affected nine different genes, and the majority of mutant alleles were novel. Furthermore, these data suggest that less than half of dominant cataract can be explained by mutations in currently known genes.

ETV5 as a regulator of matrix metalloproteinase 2 in human chondrosarcoma.

Chondrosarcoma is a unique type of bone cancer in that it does not respond to chemotherapy or radiation therapy, and therefore many affected patients die from metastatic disease. Metastasis has been correlated with the upregulation of the matrix metalloproteinase (MMP) family of proteases, which can degrade extracellular components. ETV5 is a transcription factor which has shown to be overexpressed in various types of invasive tumors. We hypothesized that ETV5 regulates MMP2 in human chondrosarcoma with the protease acting as a downstream effector. Gene knock-down of ETV5 in human chondrosarcoma cells reduces MMP2 mRNA expression as well as decreased protein production and significantly decreased MMP2 activity. With plasmid transfected ETV5 upregulation, MMP2 expression is similarly upregulated at the gene expression and protein levels. Data from our bone resorption studies revealed that when a matrix metalloproteinase-2 inhibitor is added to the growth media of chondrosarcoma cells, collagen released from bone chips incubated with the cells decreased by 27%. This data suggests that ETV5 has a significant role in regulating MMP2 expression and therefore matrix resorption in human chondrosarcoma, and thus may be a targetable upstream effector of the metastatic cascade in this cancer.

Sub-telomeric core X and Y' elements in S. cerevisiae suppress extreme variations in gene silencing.

Telomere Position Effect (TPE) is governed by strong repression signals emitted by telomeres via the Sir2/3/4 Histone Deacetylase complex. These signals are then relayed by weak proto-silencers residing in the subtelomeric core X and Y' elements. Subtelomeres also contain Sub-Telomeric Anti-silencing Regions (STARs). In this study we have prepared telomeres built of different combinations of core X, Y' and STARs and have analyzed them in strains lacking Histone-Acetyltransferase genes as well as in cdc6-1 and Δrif1 strains. We show that core X and Y' dramatically reduce both positive and negative variations in TPE, that are caused by these mutations. We also show that the deletion of Histone-Acetyltransferase genes reduce the silencing activity of an ACS proto-silencer, but also reduce the anti-silencing activity of a STAR. We postulate that core X and Y' act as epigenetic "cushioning" cis-elements.

Gene transfection in primary stem-like cells of giant cell tumor of bone.

The neoplastic stem-like stromal cell of giant cell tumor of bone (GCT) survives for multiple passages in primary culture with a stable phenotype, and exhibits multipotent characteristics. The pathophysiology of this tumor has been studied through the primary culture of these cells. However, successful gene transfer of these cells has not been reported to date. In this short report, we describe the development of the first reported technique that results in efficient gene transfection in primary stem-like cells of GCT.

Steroid sulfatase deficiency and contiguous gene deletion syndrome amongst pregnant patients with low serum unconjugated estriols.

OBJECTIVE: To ascertain all prenatally diagnosed cases of Steroid Sulfatase (STS) deficiency in British Columbia between August 2002 and July 2007 to determine the incidence of this condition, the clinical and laboratory findings, and the risk of a contiguous gene deletion syndrome. METHODS: We reviewed the medical records of these patients to obtain detailed information about the maternal serum screening results, family history, investigations performed, and outcome of the pregnancy. RESULTS: Thirty pregnant patients were found to have a male fetus/infant with STS deficiency, giving a minimal estimated incidence of this condition of approximately 1 in 1513 males. In twenty nine cases, this condition was isolated. One patient was found to have a contiguous gene deletion syndrome. In cases of sporadic STS deficiency diagnosed prenatally, the frequency of contiguous gene deletion syndrome in this study was 1 out of 12 (8.3%). CONCLUSION: The clinical, cytogenetic and molecular data on this series of prenatally diagnosed cases of STS deficiency indicates that this is a common condition and in cases with no family history, the risk of contiguous gene deletion syndrome is significant, and warrants additional molecular genetic investigations of the mother and/or fetus.

Aortic root dilatation is a rare complication of Noonan syndrome.

Molecular analysis of the gene encoding the protein tyrosine phospatase, nonreceptor type 11 (PTPN11), identified a single base change at nucleotide 228 in an individual manifesting Noonan syndrome with aortic root widening and dysplastic aortic and mitral valves. This missense mutation changes glutamate to aspartate at position 76 of the protein (E76D or Glu76Asp), which likely disrupts intramolecular hydrogen bonding of this protein. There are few reports of aortic root dilatation in Noonan syndrome, and to our knowledge this is the first case with a confirmed PTPN11 mutation.

Genotype-phenotype correlation in congenital heart disease.

PURPOSE OF REVIEW: The understanding of the etiology of congenital cardiac lesions is rapidly progressing from the recognition of embryologic origins to insight into the genetic basis for these disorders. Concurrently, in this era, great effort is being expended to gather data that will generate clinically useful genotype-phenotype correlation. This rapidly evolving area of inquiry, in which the clinical implications of mutation status are fully explored, makes available information applicable to those involved in all aspects of congenital cardiac disease. RECENT FINDINGS: Three syndromes with cardiovascular phenotypes were selected for review. Each has received a great deal of attention in the recent past based on improved understanding of the range of mutations expressed and the relation of these mutations to clinical findings. These three syndromes--Noonan, Marfan, and long QT syndrome--span the range of congenital heart disease and provide examples of genotype-phenotype correlation. SUMMARY: Better understanding of the clinical implications of specific mutations should allow not only for more sensitive and specific diagnoses to be made but also for improvements in therapeutic options and efficacy.