Adverse events during reoperative cardiac surgery: Frequency, characterization, and rescue

ObjectivesTo (1) determine frequency of occurrence and risk factors for intraoperative adverse events (IAE) during reoperative cardiac surgery, (2) characterize them with respect to structure injured, timing, and use of preventive strategies, and (3) identify the impact on outcome in terms of successful and unsuccessful rescue and cost.MethodsOperative notes of 1847 patients undergoing reoperative cardiac surgery were reviewed to identify and characterize documented intraoperative adverse events. Logistic regression modeling was used to identify risk factors for intraoperative adverse events and outcomes. Expected versus observed poor outcomes (stroke, myocardial infarction, death) was used to measure rescue.ResultsAmong 127 patients, 145 (7%) intraoperative adverse events occurred. These included injuries to bypass grafts (n = 47), heart (n = 38), and great vessels (n = 28) and ischemia without graft injury (n = 22). Most occurred on opening (n = 34, 23%) and during prebypass dissection (n = 57, 39%). Risk incremented as reoperations increased. Seventy-seven patients experienced 1 or more lapses in preventive strategies. Patients with intraoperative adverse events had a greater number of poor outcomes (n = 24 [19%] vs n = 107 [6.2%]; P < .0001) and incurred higher direct technical intraoperative and postoperative costs (ratio 1.3). Twelve patients with intraoperative adverse events were predicted to have poor outcomes versus 24 who did (P < .0001), indicating 12 “failures to rescue.”ConclusionsAdverse events still occur regularly during cardiac reoperation, are related to complexity of the procedure, and occur particularly during dissection and often when preventive strategies have not been used. Compensatory rescue measures are not always successful. Adverse events lead to poor patient outcome and higher cost

A comprehensive review of the PARTNER trial

ObjectivePercutaneous transcatheter aortic valve replacement was introduced in 2002, but its effectiveness remained to be assessed.MethodsA prospective, randomized trial (the Placement of Aortic Transcatheter Valves, or PARTNER) was designed with 2 arms: PARTNER A (n = 699) for high-risk surgical patients (Society of Thoracic Surgeons score >10%, surgeon assessed risk of mortality >15%) and PARTNER B (n = 358, patients inoperable by assessment of 2 surgeons). PARTNER A patients were divided into femoral artery access transcatheter aortic valve replacement or none (n = 207), and then randomized to open aortic valve replacement (n = 351) or device (n = 348). Inclusion criteria included valve area <0.8 cm2, gradient >40 mm Hg or peak >64 mm Hg, and survival >1 year. The end point of the study was 1-year mortality.ResultsThirty-day mortality for PARTNER A was 3.4% for transcatheter aortic valve replacement and 6.5% for aortic valve replacement; 1-year mortality was 24.2% and 26.8%, respectively (P = .001 for noninferiority). The respective prevalence of stroke was 3.8% and 2.1% (P = .2), although for all neurologic events, the difference between transcatheter aortic valve replacement and aortic valve replacement was significant (P = .04), including 4.6% for femoral artery access transcatheter aortic valve replacement versus 1.4% for open aortic valve replacement (P = .05). For PARTNER B—transcatheter aortic valve replacement versus medical treatment—30-day mortality was 5.0% versus 2.8% (P = .41), and at 1 year, mortality was 30.7% versus 50.7% (P < .001), respectively. Hospitalization cost of transcatheter aortic valve replacement for PARTNER B was $78,542, or$50,200 per year of life gained. Analysis of PARTNER A strokes showed that hazard with transcatheter aortic valve replacement peaked early, but thereafter remained constant in relation to aortic valve replacement. Two-year PARTNER A data showed paravalvular regurgitation was associated with increased mortality, even when mild (P < .001). Continued access to transapical transcatheter aortic valve replacement (n = 853) showed a mortality of 8.2% and decline in strokes to 2.0%. Of the 1801 Cleveland Clinic patients reviewed to December 2010, 214 (12%) underwent transcatheter aortic valve replacement with a mortality of 1%; in 2011, 105 underwent transcatheter aortic valve replacement: 34 transapical aortic valve replacement, with no deaths, and 71 femoral artery access aortic valve replacement with 1 death.ConclusionsThe PARTNER A and B trials showed that survival has been remarkably good, but stroke and perivalvular leakage require further device development

Trisomy 21 dysregulates T cell lineages toward an autoimmunity-prone state associated with interferon hyperactivity

Trisomy 21 (T21) causes Down syndrome (DS), a condition characterized by high prevalence of autoimmune disorders. However, the molecular and cellular mechanisms driving this phenotype remain unclear. Building upon our previous finding that T cells from people with DS show increased expression of interferon (IFN)stimulated genes, we have completed a comprehensive characterization of the peripheral T cell compartment in adults with DS with and without autoimmune conditions. CD8+ T cells from adults with DS are depleted of naïve subsets and enriched for differentiated subsets, express higher levels of markers of activation and senescence (e.g., IFN-γ, Granzyme B, PD-1, KLRG1), and overproduce cytokines tied to autoimmunity (e.g., TNF-α). Conventional CD4+ T cells display increased differentiation, polarization toward the Th1 and Th1/17 states, and overproduction of the autoimmunity-related cytokines IL-17A and IL-22. Plasma cytokine analysis confirms elevation of multiple autoimmunity-related cytokines (e.g., TNF-α, IL17A–D, IL-22) in people with DS, independent of diagnosis of autoimmunity. Although Tregs are more abundant in DS, functional assays show that CD8+ and CD4+ effector T cells with T21 are resistant to Treg-mediated suppression, regardless of Treg karyotype. Transcriptome analysis of white blood cells and T cells reveals strong signatures of T cell differentiation and activation that correlate positively with IFN hyperactivity. Finally, mass cytometry analysis of 8 IFN-inducible phosphoepitopes demonstrates that T cell subsets with T21 show elevated levels of basal IFN signaling and hypersensitivity to IFN-α stimulation. Therefore, these results point to T cell dysregulation associated with IFN hyperactivity as a contributor to autoimmunity in DS.Fil: Araya, Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Waugh, Katherine A.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Sullivan, Kelly D.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Núñez, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Roselli, Emiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Smith, Keith P.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Granrath, Ross E.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Rachubinski, Angela L.. University of Colorado; Estados UnidosFil: Enriquez Estrada, Belinda. University Of Colorado. School Of Medicine.; Estados UnidosFil: Butcher, Eric T.. University of Colorado; Estados UnidosFil: Minter, Ross. University of Colorado; Estados UnidosFil: Tuttle, Kathryn D.. University of Colorado; Estados UnidosFil: Bruno, Tullia C.. University Of Colorado. School Of Medicine.; Estados UnidosFil: Maccioni, Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Espinosa, Joaquín M.. University Of Colorado. School Of Medicine.; Estados Unido

The Earliest Evidence of Holometabolan Insect Pupation in Conifer Wood

Background: The pre-Jurassic record of terrestrial wood borings is poorly resolved, despite body fossil evidence of insect diversification among xylophilic clades starting in the late Paleozoic. Detailed analysis of borings in petrified wood provides direct evidence of wood utilization by invertebrate animals, which typically comprises feeding behaviors.\ud \ud Methodology/Principal Findings: We describe a U-shaped boring in petrified wood from the Late Triassic Chinle Formation of southern Utah that demonstrates a strong linkage between insect ontogeny and conifer wood resources. Xylokrypta durossi new ichnogenus and ichnospecies is a large excavation in wood that is backfilled with partially digested xylem, creating a secluded chamber. The tracemaker exited the chamber by way of a small vertical shaft. This sequence of behaviors is most consistent with the entrance of a larva followed by pupal quiescence and adult emergence — hallmarks of holometabolous insect ontogeny. Among the known body fossil record of Triassic insects, cupedid beetles (Coleoptera: Archostemata) are deemed the most plausible tracemakers of Xylokrypta, based on their body size and modern xylobiotic lifestyle.\ud \ud Conclusions/Significance: This oldest record of pupation in fossil wood provides an alternative interpretation to borings once regarded as evidence for Triassic bees. Instead Xylokrypta suggests that early archostematan beetles were leaders in exploiting wood substrates well before modern clades of xylophages arose in the late Mesozoic

Microbiomes of Inflammatory Thoracic Aortic Aneurysms Due to Giant Cell Arteritis and Clinically Isolated Aortitis Differ From Those of Non-Inflammatory Aneurysms

Objective: We sought to characterize microbiomes of thoracic aortas from patients with non-infectious aortitis due to giant cell arteritis (GCA) and clinically isolated aortitis (CIA) and to compare them to non-inflammatory aorta aneurysm controls. We also compared microbiomes from concurrently processed and separately reported temporal arteries (TA) and aortas. Methods: From 220 prospectively enrolled patients undergoing surgery for thoracic aorta aneurysm, 49 were selected. Inflammatory and non-inflammatory cases were selected based on ability to match for age (+/-10 years), gender, and race. Biopsies were collected under aseptic conditions and snap-frozen. Taxonomic classification of bacterial sequences was performed to the genus level and relative abundances were calculated. Microbiome differential abundances were analyzed by principal coordinates analysis. Results : Forty-nine patients with thoracic aortic aneurysms (12 CIA, 14 GCA, 23 non-inflammatory aneurysms) were enrolled. Alpha (P = 0.018) and beta (P = 0.024) diversity differed between specimens from aortitis cases and controls. There were no significant differences between CIA and GCA (P > 0.7). The largest differential abundances between non-infectious aortitis and non-inflammatory control samples includedEnterobacteriaceae, Phascolarctobacterium, Acinetobactor, Klebsiella, and Prevotella. Functional metagenomic predictions with PICRUSt revealed enrichment of oxidative phosphorylation and porphyrin metabolism pathways and downregulation of transcription factor pathways in aortitis compared to controls. Microbiomes of aortic samples differed significantly from temporal artery samples from a companion study, in both control and GCA groups (P = 0.0002). Conclusion: Thoracic aorta aneurysms, far from being sterile, contain unique microbiomes that differ from those found in temporal arteries. The aorta microbiomes are most similar between aneurysms that were associated with inflammation, GCA, and CIA, but differed from those associated with non-inflammatory etiologies. These findings are promising in that they indicate that microbes may play a role in the pathogenesis of aortitis-associated aneurysms or non-inflammatory aneurysms by promoting or protecting against inflammation. However, we cannot rule out that these changes are related to alterations in tissue substrate that favor secondary changes in microbial communities

The ARCH Projects: design and rationale (IAASSG 001)

OBJECTIVE A number of factors limit the effectiveness of current aortic arch studies in assessing optimal neuroprotection strategies, including insufficient patient numbers, heterogenous definitions of clinical variables, multiple technical strategies, inadequate reporting of surgical outcomes and a lack of collaborative effort. We have formed an international coalition of centres to provide more robust investigations into this topic. METHODS High-volume aortic arch centres were identified from the literature and contacted for recruitment. A Research Steering Committee of expert arch surgeons was convened to oversee the direction of the research. RESULTS The International Aortic Arch Surgery Study Group has been formed by 41 arch surgeons from 10 countries to better evaluate patient outcomes after aortic arch surgery. Several projects, including the establishment of a multi-institutional retrospective database, randomized controlled trials and a prospectively collected database, are currently underway. CONCLUSIONS Such a collaborative effort will herald a turning point in the surgical management of aortic arch pathologies and will provide better powered analyses to assess the impact of varying surgical techniques on mortality and morbidity, identify predictors for neurological and operative risk, formulate and validate risk predictor models and review long-term survival outcomes and quality-of-life after arch surger

Genome-wide association study reveals novel genetic loci:a new polygenic risk score for mitral valve prolapse

AIMS: Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of >2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder. METHODS AND RESULTS: We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors. CONCLUSION: We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-beta signalling molecules and spectrin beta. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention. KEY QUESTION: Expand our understanding of the genetic basis for mitral valve prolapse (MVP). Uncover relevant pathways and target genes for MVP pathophysiology. Leverage genetic data for MVP risk prediction. KEY FINDING: Sixteen genetic loci were significantly associated with MVP, including 13 novel loci. Interesting target genes at these loci included LTBP2, TGFB2, ALKP3, BAG3, RBM20, and SPTBN1. A risk score including clinical factors and a polygenic risk score, performed best at predicting MVP, with an area under the receiver operating characteristics curve of 0.677. TAKE-HOME MESSAGE: Mitral valve prolapse has a polygenic basis: many genetic variants cumulatively influence pre-disposition for disease. Disease risk may be modulated via changes to transforming growth factor-beta signalling, the cytoskeleton, as well as cardiomyopathy pathways. Polygenic risk scores could enhance the MVP risk prediction

Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery

Genetic analyses of the electrocardiographic QT interval and its components identify additional loci and pathways

The QT interval is an electrocardiographic measure representing the sum of ventricular depolarization and repolarization, estimated by QRS duration and JT interval, respectively. QT interval abnormalities are associated with potentially fatal ventricular arrhythmia. Using genome-wide multi-ancestry analyses (&gt;250,000 individuals) we identify 177, 156 and 121 independent loci for QT, JT and QRS, respectively, including a male-specific X-chromosome locus. Using gene-based rare-variant methods, we identify associations with Mendelian disease genes. Enrichments are observed in established pathways for QT and JT, and previously unreported genes indicated in insulin-receptor signalling and cardiac energy metabolism. In contrast for QRS, connective tissue components and processes for cell growth and extracellular matrix interactions are significantly enriched. We demonstrate polygenic risk score associations with atrial fibrillation, conduction disease and sudden cardiac death. Prioritization of druggable genes highlight potential therapeutic targets for arrhythmia. Together, these results substantially advance our understanding of the genetic architecture of ventricular depolarization and repolarization