Plasma metabolomic and lipidomic profiles accurately classify mothers of children with congenital heart disease: an observational study.

INTRODUCTION: Congenital heart disease (CHD) is the most common congenital anomaly, representing a significant global disease burden. Limitations exist in our understanding of aetiology, diagnostic methodology and screening, with metabolomics offering promise in addressing these. OBJECTIVE: To evaluate maternal metabolomics and lipidomics in prediction and risk factor identification for childhood CHD. METHODS: We performed an observational study in mothers of children with CHD following pregnancy, using untargeted plasma metabolomics and lipidomics by ultrahigh performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). 190 cases (157 mothers of children with structural CHD (sCHD); 33 mothers of children with genetic CHD (gCHD)) from the children OMACp cohort and 162 controls from the ALSPAC cohort were analysed. CHD diagnoses were stratified by severity and clinical classifications. Univariate, exploratory and supervised chemometric methods were used to identify metabolites and lipids distinguishing cases and controls, alongside predictive modelling. RESULTS: 499 metabolites and lipids were annotated and used to build PLS-DA and SO-CovSel-LDA predictive models to accurately distinguish sCHD and control groups. The best performing model had an sCHD test set mean accuracy of 94.74% (sCHD test group sensitivity 93.33%; specificity 96.00%) utilising only 11 analytes. Similar test performances were seen for gCHD. Across best performing models, 37 analytes contributed to performance including amino acids, lipids, and nucleotides. CONCLUSIONS: Here, maternal metabolomic and lipidomic analysis has facilitated the development of sensitive risk prediction models classifying mothers of children with CHD. Metabolites and lipids identified offer promise for maternal risk factor profiling, and understanding of CHD pathogenesis in the future.

Immunotherapy in the Context of Aortic Valve Diseases.

PURPOSE: Aortic valve disease (AVD) affects millions of people around the world, with no pharmacological intervention available. Widely considered a multi-faceted disease comprising both regurgitative pathogenesis, in which retrograde blood flows back through to the left ventricle, and aortic valve stenosis, which is characterized by the thickening, fibrosis, and subsequent mineralization of the aortic valve leaflets, limiting the anterograde flow through the valve, surgical intervention is still the main treatment, which incurs considerable risk to the patient. RESULTS: Though originally thought of as a passive degeneration of the valve or a congenital malformation that has occurred before birth, the paradigm of AVD is shifting, and research into the inflammatory drivers of valve disease as a potential mechanism to modulate the pathobiology of this life-limiting pathology is taking center stage. Following limited success in mainstay therapeutics such as statins and mineralisation inhibitors, immunomodulatory strategies are being developed. Immune cell therapy has begun to be adopted in the cancer field, in which T cells (chimeric antigen receptor (CAR) T cells) are isolated from the patient, programmed to attack the cancer, and then re-administered to the patient. Within cardiac research, a novel T cell-based therapeutic approach has been developed to target lipid nanoparticles responsible for increasing cardiac fibrosis in a failing heart. With clonally expanded T-cell populations recently identified within the diseased valve, their unique epitope presentation may serve to identify novel targets for the treatment of valve disease. CONCLUSION: Taken together, targeted T-cell therapy may hold promise as a therapeutic platform to target a multitude of diseases with an autoimmune aspect, and this review aims to frame this in the context of cardiovascular disease, delineating what is currently known in the field, both clinically and translationally.

Medium-Term Outcomes of Stent Therapy for Aortic Coarctation in Children Under 30 kg with New Generation Low-Profile Stents: A Follow-Up Study of a Single Centre Experience.

We previously reported short-term outcomes for stenting of aortic coarctation (CoA) (native or re-coarctation) with newer generation low-profile stents (Valeo, Formula, and Begraft stents) in children under 30 kg. We present here the medium-term outcomes of this procedure. Retrospective review of patients weighing under 30 kg who had percutaneous stent treatments for coarctation between 2012 and 2021 was performed. Clinical and procedural data were collected; 19 patients were included. The median age at the time of procedure was 5.1 [4.1-6.4] years and median weight 21.0 [17.3-22.3] kg. One patient had a history of re-coarctation. Thirteen (68%) patients were on anti-hypertensives pre-procedure. Different types of stents were used (14 Valeo™, 4 Formula® 535, 1 BeGraft), which can all be dilated to 18 mm or larger. One patient required a 9 F sheath, all others required a 7 F sheath. The narrowest diameter in the aorta increased from a median of 3.5 [3.0-4.5] to 9.4 [8.9-9.8] mm, p < 0.001; there was a reduction in the median pressure gradient across the coarctation from 35.0 [30.0-43.0] to 5.0 [0-10.0] mmHg, p < 0.001. There were no intra-procedural complications. Follow-up was for a median of 56.0 [13.0-65.0] months. Five (26%) of patients underwent re-intervention after a median time frame of 40.0 [39.5-52.0] months; four had balloon dilation, one had repeat stent implantation. Five (26%) patients were on anti-hypertensive agent(s) post-intervention. Our single centre experience demonstrates that percutaneous stenting for coarctation of aorta in children under 30 kg, with low-profile stents, had no significant complications during the median follow-up time of 56 months. This study demonstrated that the procedure is safe and effective for short and medium-term therapy in this group of patients with a 26% re-intervention rate. A quarter of patients remained on anti-hypertensive medication post stenting, emphasizing the importance of long-term follow-up.

Influence of improved antenatal detection on the outcomes of complete atrioventricular block diagnosed in fetal-neonatal life and childhood periods - a single-centre experience in South Wales for 55 years.

OBJECTIVE: This study aimed to analyse the influence of improved antenatal detection on the course, contemporary outcomes, and mortality risk factors of the complete atrioventricular block during fetal-neonatal and childhood periods in South Wales. METHODS: The clinical characteristics and outcomes of complete atrioventricular block in patients without structural heart disease at the University Hospital of Wales from January 1966 to April 2021 were studied. Patients were divided into two groups according to their age at diagnosis: I-fetal-neonatal and II-childhood. Contemporary outcomes during the post-2001 era were compared with historical data preceding fetal service development and hence earlier detection. RESULTS: There were 64 patients: 26 were identified in the fetal-neonatal period and the remaining 38 in the childhood period. Maternal antibodies/systemic lupus erythematosus disease (anti-Ro/Sjögren's-syndrome-related Antigen A and/or anti-La/Sjögren's-syndrome-related Antigen B) were present in 15 (57.7%) of the fetal-neonatal. Fetal/neonatal and early diagnosis increased after 2001 with an incidence of 1:25000 pregnancies. Pacemaker implantation was required in 34 patients, of whom 13 were diagnosed in the fetal-neonatal group. Survival rates in cases identified before 2001 were at 96.3% (26/27), whereas it was 83.8% (31/37) in patients diagnosed after 2001 (P > 0.05). Other mortality risk factors comprised a lower gestational week at birth, maternal antibodies, and an average ventricular heart rate of < 55 bpm. CONCLUSIONS: Fetal diagnosis of complete atrioventricular block is still portends high fetal and neonatal mortality and morbidity despite significantly improved antenatal detection after 2001. Pacemaker intervention is needed earlier in the fetal-neonatal group. Whether routine antenatal medical treatment might alter this outcome calls for further prospective multicentre studies.

Altered Inflammatory State and Mitochondrial Function Identified by Transcriptomics in Paediatric Congenital Heart Patients Prior to Surgical Repair.

Congenital heart disease (CHD) remains the most common birth defect, with surgical intervention required in complex cases. Right ventricle (RV) function is known to be a major predictor of sustained cardiac health in these patients; thus, by elucidating the divergent profiles between CHD and the control through tissue analysis, this study aims to identify new avenues of investigation into the mechanisms surrounding reduced RV function. Transcriptomic profiling, in-silico deconvolution and functional network analysis were conducted on RV biopsies, identifying an increase in the mitochondrial dysfunction genes RPPH1 and RMPR (padj = 4.67 × 10-132, 2.23 × 10-107), the cytotoxic T-cell markers CD8a, LAGE3 and CD49a (p = 0.0006, p < 0.0001, and p = 0.0118) and proinflammatory caspase-1 (p = 0.0055) in CHD. Gene-set enrichment identified mitochondrial dysfunctional pathways, predominately changes within oxidative phosphorylation processes. The negative regulation of mitochondrial functions and metabolism was identified in the network analysis, with dysregulation of the mitochondrial complex formation. A histological analysis confirmed an increase in cellular bodies in the CHD RV tissue and positive staining for both CD45 and CD8, which was absent in the control. The deconvolution of bulk RNAseq data suggests a reduction in CD4+ T cells (p = 0.0067) and an increase in CD8+ T cells (p = 0.0223). The network analysis identified positive regulation of the immune system and cytokine signalling clusters in the inflammation functional network, as there were lymphocyte activation and leukocyte differentiation. Utilising RV tissue from paediatric patients undergoing CHD cardiac surgery, this study identifies dysfunctional mitochondrial pathways and an increase in inflammatory T-cell presence prior to reparative surgery.

The effect of maternal BMI, smoking and alcohol on congenital heart diseases: a Mendelian randomisation study.

BACKGROUND: Congenital heart diseases (CHDs) remain a significant cause of infant morbidity and mortality. Epidemiological studies have explored maternal risk factors for offspring CHDs, but few have used genetic epidemiology methods to improve causal inference. METHODS: Three birth cohorts, including 65,510 mother/offspring pairs (N = 562 CHD cases) were included. We used Mendelian randomisation (MR) analyses to explore the effects of genetically predicted maternal body mass index (BMI), smoking and alcohol on offspring CHDs. We generated genetic risk scores (GRS) using summary data from large-scale genome-wide association studies (GWAS) and validated the strength and relevance of the genetic instrument for exposure levels during pregnancy. Logistic regression was used to estimate the odds ratio (OR) of CHD per 1 standard deviation (SD) higher GRS. Results for the three cohorts were combined using random-effects meta-analyses. We performed several sensitivity analyses including multivariable MR to check the robustness of our findings. RESULTS: The GRSs associated with the exposures during pregnancy in all three cohorts. The associations of the GRS for maternal BMI with offspring CHD (pooled OR (95% confidence interval) per 1SD higher GRS: 0.95 (0.88, 1.03)), lifetime smoking (pooled OR: 1.01 (0.93, 1.09)) and alcoholic drinks per week (pooled OR: 1.06 (0.98, 1.15)) were close to the null. Sensitivity analyses yielded similar results. CONCLUSIONS: Our results do not provide robust evidence of an effect of maternal BMI, smoking or alcohol on offspring CHDs. However, results were imprecise. Our findings need to be replicated, and highlight the need for more and larger studies with maternal and offspring genotype and offspring CHD data.

Zebrafish as a model for cardiac disease; Cryo-EM structure of native cardiac thin filaments from Danio Rerio.

Actin, tropomyosin and troponin, the proteins that comprise the contractile apparatus of the cardiac thin filament, are highly conserved across species. We have used cryo-EM to study the three-dimensional structure of the zebrafish cardiac thin and actin filaments. With 70% of human genes having an obvious zebrafish orthologue, and conservation of 85% of disease-causing genes, zebrafish are a good animal model for the study of human disease. Our structure of the zebrafish thin filament reveals the molecular interactions between the constituent proteins, showing that the fundamental organisation of the complex is the same as that reported in the human reconstituted thin filament. A reconstruction of zebrafish cardiac F-actin demonstrates no deviations from human cardiac actin over an extended length of 14 actin subunits. Modelling zebrafish homology models into our maps enabled us to compare, in detail, the similarity with human models. The structural similarities of troponin-T in particular, a region known to contain a hypertrophic cardiomyopathy 'hotspot', confirm the suitability of zebrafish to study these disease-causing mutations.

Maternal metabolomic profiling and congenital heart disease risk in offspring: A systematic review of observational studies.

Aetiological understanding and screening methods for congenital heart disease (CHD) are limited. Maternal metabolomic assessment offers the potential to identify risk factors and biomarkers. We performed a systematic review (PROSPERO CRD42022308452) investigating the association between fetal/childhood CHD and endogenous maternal metabolites. Ovid-MEDLINE, Ovid-EMBASE and Cochrane Library were searched between inception and 06/09/2022. Case control studies included analysing maternal blood or urine metabolites in pregnancy or postpartum where there was foetal/childhood CHD. Risk of bias assessment utilised the Scottish Intercollegiate Guidelines Network methodology checklist and narrative synthesis was performed. A total of 134 records were screened with eight eligible studies (n = 3242 pregnancies, n = 842 CHD-affected offspring). Five studies performed metabolomic analysis in pregnancy. Metabolites distinguishing case and control groups spanned lipid, glucose and amino-acid pathways, with the development of sensitive risk prediction models. No single metabolite consistently distinguished cases and controls across studies. Three studies performed targeted analysis postnatally with altered lipid and amino acid metabolites and raised homocysteine and markers of oxidative stress identified in cases. Included studies reported small sample sizes, analysing different biosamples at variable time points using differing techniques. At present, there is not enough evidence to confidently associate maternal metabolomic profiles with offspring CHD risk. However, several identified pathways warrant further investigation.

A review and meta-analysis of conventional sternotomy versus minimally invasive mitral valve surgery for degenerative mitral valve disease focused on the last decade of evidence.

OBJECTIVES: Early meta-analyses comparing minimally invasive mitral valve surgery (MIMVS) with conventional sternotomy (CS) have determined the safety of MIMVS. We performed this review and meta-analysis based on studies from 2014 onwards to examine the differences in outcomes between MIMVS and CS. Specifically, some outcomes of interest included renal failure, new onset atrial fibrillation, mortality, stroke, reoperation for bleeding, blood transfusion and pulmonary infection. METHODS: A systematic search was performed in six databases for studies comparing MIMVS with CS. Although the initial search identified 821 papers in total, nine studies were suitable for the final analysis. All studies included compared CS with MIMVS. The Mantel - Haenszel statistical method was chosen due the use of inverse variance and random effects. A meta-analysis was performed on the data. RESULTS: MIMVS had significantly lower odds of renal failure (OR: 0.52; 95% CI 0.37 to 0.73, p < 0.001), new onset atrial fibrillation (OR: 0.78; 95% CI 0.67 to 0.90, p < 0.001), reduced prolonged intubation (OR: 0.50; 95% CI 0.29 to 0.87, p = 0.01) and reduced mortality (OR: 0.58; 95% CI 0.38 to 0.87, p < 0.01). MIMVS had shorter ICU stay (WMD: -0.42; 95% CI -0.59 to -0.24, p < 0.001) and shorter time to discharge (WMD: -2.79; 95% CI -3.86 to -1.71, p < 0.001). CONCLUSION: In the modern era, MIMVS for degenerative disease is associated with improved short-term outcomes when compared to the CS.

Propensity matched analysis of minimally invasive versus conventional isolated aortic valve replacement.

OBJECTIVE: To analyse the early and mid-term outcome of patients undergoing conventional aortic valve replacement (AVR) versus minimally invasive via hemi-sternotomy aortic valve replacement (MIAVR). METHODS: A single centre retrospective study involving 653 patients who underwent isolated aortic valve replacement (AVR) either via conventional AVR (n = 516) or MIAVR (n = 137) between August 2015 and March 2020. Using pre-operative characteristics, patients were propensity matched (PM) to produce 114 matched pairs. Assessment of peri-operative outcomes, early and mid-term survival and echocardiographic parameters was performed. RESULTS: The mean age of the PM conventional AVR group was 71.5 (±8.9) years and the number of male (n = 57) and female (n = 57) patients were equal. PM MIAVR group mean age was 71.1 (±9.5) years, and 47% of patients were female (n = 54) and 53% male (n = 60). Median follow-up for PM conventional AVR and MIAVR patients was 3.4 years (minimum 0, maximum 4.8 years) and 3.4 years (minimum 0, maximum 4.8 years), respectively. Larger sized aortic valve prostheses were inserted in the MIAVR group (median 23, IQR = 4) versus conventional AVR group (median 21, IQR = 2; p = 0.02, SMD = 0.34). Cardiopulmonary bypass (CPB) time was longer with MIAVR (94.4 ± 19.5 minutes) compared to conventional AVR (83.1 ± 33.3; p = 0.0001, SMD = 0.41). Aortic cross-clamp (AoX) time was also longer in MIAVR (71.6 ± 16.5 minutes) compared to conventional AVR (65.0 ± 52.8; p = 0.0001, SMD = 0.17). There were no differences in the early post-operative complications and mortality between the two groups. Follow-up echocardiographic data showed significant difference in mean aortic valve gradients between conventional AVR and MIAVR groups (17.3 ± 8.2 mmHg vs 13.0 ± 5.1 mmHg, respectively; p = 0.01, SMD = -0.65). There was no significant difference between conventional AVR and MIAVR in mid-term survival at 3 years (88.6% vs 92.1%; log-rank test p = 0.31). CONCLUSION: Despite the longer CPB and AoX times in the MIAVR group, there was no significant difference in early complications, mortality and mid-term survival between MIAVR and conventional AVR.

Network meta-analysis comparing blood cardioplegia, Del Nido cardioplegia and custodiol cardioplegia in minimally invasive cardiac surgery.

INTRODUCTION: Minimally invasive cardiac surgery has been evolving, with the intention of reducing surgical trauma, improve cosmesis and patient satisfaction. Single dose, crystalloid cardioplegia such as Del Nido cardioplegia and Custoidol solution have been increasingly used to reduce the interruption from repeating cardioplegia dosing to minimise the cardiopulmonary bypass and cross clamp time. However, the best cardioplegia for myocardial protection in adult minimally invasive cardiac surgery remains controversial. We aimed to conduct a meta-analysis to analyse the current evidence in the literature. METHOD: A systematic review and meta-analysis was performed following the updated 2020 PRISMA guideline. Articles published in the five major electronic databases up 1st of April 2021 were identified and reviewed. The primary outcome was in-hospital or 30-day mortality. Traditional pairwise and Bayesian network meta-analyses were conducted. RESULTS: Nine articles were included in this study. The use of Del Nido cardioplegia was associated with a lower volume of cardioplegia used (Del Nido vs Blood, 1105.62 mL+/-123.47 vs 2569.46 mL+/-1515.52, p<0.001), cardiopulmonary bypass (Del Nido vs Custoidol vs Blood: 91.67+/-14.78 vs 138.05 +/- 21.30 vs 119.38+/-26.91 minutes, p<0.001) and cross-clamp time (Del Nido vs Custoidol vs Blood: 74.99+/-18.55 vs 82.01 +/- 17.28 vs 93.66+/-8.88 minutes, p < 0.001). No differences were observed in the incidence of in-hospital/30-day mortality rate, new onset of atrial fibrillation and stroke. Ranking analysis showed the Custoidol solution has the highest probability to be the first ranked cardioplegia. CONCLUSION: No differences were found between blood and crystalloid cardioplegia in adult minimally invasive cardiac surgery in several clinical outcomes. The cardioplegia of choice in minimally invasive cardiac surgery remains the surgeons' decision and preference.

Interdisciplinarity and Patient Engagement: New Representations of Cardiovascular Anatomy.

Background: This article presents and discusses the genesis, making and public presentation of two artworks by British artist Sofie Layton, namely Blueprints and The Bud, which explore the anatomy of the heart infusing it with experiential and narrative elements. Methods: Artist-led workshops with a range of audiences (cardiac patients, medical staff, medical students, creative professionals, and patient relatives) led to explore narratives and imagery that, in turn, was re-presented in artworks exploring the complexity of the cardiovascular system. Results: While positioning themselves in a long tradition of artistic representations of the heart, often purely anatomical or autobiographical, these artworks stem from a process of patient involvement and participation. Integral to the pieces is an interdisciplinary approach, which is central to arts-and-health collaborations. Conclusions: At a time in which the role of the arts in improving health and wellbeing is increasingly recognised and supported by evidence, these artworks offer an opportunity to reflect not only on ways of representing cardiovascular anatomy, but also on its experiential value and on the important of patient engagement and involvement.

Early mortality and neurologic outcomes following mitral valve surgery in the very elderly.

OBJECTIVES: Valve repair is the gold standard for treatment of degenerative mitral valve disease. As the population ages, patients undergoing valve degeneration and therefore considered for mitral valve surgery will naturally be getting older. We sought to evaluate whether mitral repair retained a survival advantage over replacement in patients ≥80 years old. METHODS: A retrospective cohort study was performed using data acquired from the United Kingdom National Adult Cardiac Surgery Audit for the outcomes of in-hospital mortality and postoperative cerebrovascular event (CVA). Individual multivariable logistic regression models were created to investigate adjusted associations between these outcomes and type of mitral valve operation, repair or replacement. Additionally, associations between the individual model parameters and in-hospital mortality and CVA were investigated. RESULTS: A total of 1140 patients underwent mitral repair (66.4%, median age 82.3), and 577 patients underwent mitral replacement (33.6%, median age 82.1). The overall age range was 80-92. The incidence of in-hospital mortality favored the repair group (4.4% vs. 8.3%, p = .001). Multivariable logistic regression modeling demonstrated an increased adjusted odds of in-hospital mortality for mitral valve replacement (MVR) (odd ratio [OR]: 2.01, 1.15-3.50, p = .01). The only other parameter associated with an increased adjusted odds of in-hospital mortality was postoperative dialysis (OR: 14.2, 7.67-26.5, p < .001). There was not a demonstrated association between MVR and perioperative CVA (OR: 1.11, 0.49-2.4, p = .8). CONCLUSIONS: In patients ≥80 years old, mitral valve repair (MVr) was shown to be associated with a decreased adjusted odds of mortality, with a null association with CVA. These results suggest that, if feasible, MVr should remain the preferred management strategy, even in the very elderly.

Surgical outcomes and optimal approach to treatment of aortic valve endocarditis with aortic root abscess.

OBJECTIVES: To evaluate the impact of aortic root abscess (ARA) on the postoperative outcomes of surgically managed infective endocarditis (IE) and to inform optimal surgical approach. METHODS: Between 2009 and 2020, 143 consecutive patients who underwent surgical management for aortic-valve IE were included in a retrospective cohort study. Multivariable and propensity-weighted analyses were used to adjust for demographic imbalances between those without (n = 93; NARA) and with an ARA (n = 50). Additionally, empirical subgroup analysis appraised the two most used surgical techniques; patch reconstruction (PR) and aortic root replacement (ARR). RESULTS: Demographic characteristics were similar between ARA and NARA except for logistic EuroSCORE, previous valve surgery, and multivalvular infection. In-hospital mortality was 8% and 12% in NARA and ARA, respectively (p = .38), with mortality rates consistently nonsignificantly higher in ARA across all time periods. The overall reoperation rate was also higher in ARA (27% vs. 14%; p = .09) and ARA was shown to be associated with late reoperation (odds ratio [OR] = 2.74; 95% confidence interval [CI] = 1.18-6.36). Patients treated with an ARR showed a 16% increase in late mortality when compared with PR (40% vs. 24%; p = .27) and a 17% lower reoperation rate (14% vs. 31%; p = .24). Propensity-weighted analysis identified ARR as a significant protective factor for reoperation (hazard ratio = 0.05; 95% CI = 0.01-0.34). CONCLUSIONS: The presence of an ARA in aortic valve endocarditis was not associated with significantly higher early and late mortality but is linked with a higher reoperation rate at our institution. ARR in ARA is protective from reoperation so should be considered best practice in this setting.

The ongoing impact of COVID-19 on adult cardiac surgery and suggestions for safe continuation throughout the pandemic: a review of expert opinions.

OBJECTIVES: To establish the impact of the COVID-19 pandemic on adult cardiac surgery by reviewing current data and use this to establish methods for safely continuing to carry out surgery. METHODS: Conduction of a literature search via PubMed using the search terms: '(adult cardiac OR cardiothoracic OR surgery OR minimally invasive OR sternotomy OR hemi-sternotomy OR aortic valve OR mitral valve OR elective OR emergency) AND (COVID-19 or coronavirus OR SARS-CoV-2 OR 2019-nCoV OR 2019 novel coronavirus OR pandemic)'. Thirty-two articles were selected. RESULTS: Cardiac surgery patients have an increased risk of complications from COVID-19 and require vital finite resources such as intensive care beds, also required by COVID-19 patients. Thus reducing their admission and potential hospital-acquired infection with COVID-19 is paramount. During the peak, only emergencies such as acute aortic dissections were treated, triaging patients according to surgical priority and cancelling all elective procedures. Screening and 2-week quarantine prior to admission were essential changes, alongside additional levels of PPE. Focus was on reducing length of stay and switching to day-cases to reduce post-operative transmission risk, whilst several hospitals adopted 'hot' and 'cold' operating theatres for covid-confirmed and covid-negative patients. CONCLUSIONS: This paper suggests a 'CARDIO' approach for reintroducing elective procedures: 'Care, Assess, Re-Evaluate, Develop, Implement, Overcome'; prioritising the mental and physical health of the workforce, learning from and sharing experiences and objectively prioritising patients to improve case load.

Surgical outcomes and optimal approach to treatment of aortic valve endocarditis with aortic root abscess - systematic review and meta-analysis.

BACKGROUND: Data on the postoperative outcomes for patients with infective endocarditis complicated by an aortic root abscess is sparse due to the condition's low incidence and high mortality rates. This systematic review and meta-analysis aims to evaluate existing data on the impact of aortic root abscesses on the postoperative outcomes and to inform optimal surgical approach. METHODS: The online databases MEDLINE, EMBASE and Cochrane library were searched from 1990 to 2022 for studies comparing cohorts of surgically managed infective endocarditis patients with and without an aortic root abscess. Data was extracted by two independent investigators and aggregated in a random-effects model. Risk of bias was assessed using an adapted version of the Newcastle-Ottawa scale. RESULTS: Six clinical studies were included in the meta-analysis (n 1982). The abscess group was associated with increased in-hospital mortality (OR 1.74 95%: CI 1.18-2.56) and late mortality (HR 1.27 95% CI:1.03-1.58). The reoperation meta-analysis was complicated by high rates of heterogeneity (I2 = 59%) and found no significant differences in reoperation between abscess and no abscess groups (HR=1.48: 95% CI:0.92-2.40). Post-hoc scatter graph showed a strong linear relationship (r 0.998), suggesting hospitals with higher rates of aortic root replacement achieve lower rates of reoperation for aortic root abscess patients compared with patch reconstruction. CONCLUSIONS: The presence of an aortic root abscess in aortic valve endocarditis is associated with elevated early and late mortality despite modern standards of care. Additionally, aortic root replacement should be considered to have a favourable postoperative profile for use in this context.

A survey of minimally invasive cardiac surgery during the COVID-19 pandemic.

BACKGROUND: Lack of scientific data on the feasibility and safety of minimally invasive cardiac surgery (MICS) during the COVID-19 pandemic has made clinical decision making challenging. This survey aimed to appraise MICS activity in UK cardiac units and establish a consensus amongst front-line MICS surgeons regarding standard best MICS practise during the pandemic. METHODS: An online questionnaire was designed through the 'googleforms' platform. Responses were received from 24 out of 28 surgeons approached (85.7%), across 17 cardiac units. RESULTS: There was a strong consensus against a higher risk of conversion from minimally invasive to full sternotomy (92%; n = 22) nor there is increased infection (79%; n = 19) or bleeding (96%; n = 23) with MICS compared to full sternotomy during the pandemic. The majority of respondents (67%; n = 16) felt that it was safe to perform MICS during COVID-19, and that it should not be halted (71%; n = 17). London cardiac units experienced a decrease in MICS (60%; n = 6), whereas non-London units saw no reduction. All London MICS surgeons wore an FP3 mask compared to 62% (n = 8) of non-London MICS surgeons, 23% (n = 3) of which only wore a surgical mask. London MICS surgeons felt that routine double gloving should be done (60%; n = 6) whereas non-London MICS surgeons held a strong consensus that it should not (92%; n = 12). CONCLUSION: Whilst more robust evidence on the effect of COVID-19 on MICS is awaited, this survey provides interesting insights for clinical decision-making regarding MICS and aids to facilitate the development of standardised MICS guidelines for an effective response during future pandemics.

Minimally invasive versus transcatheter closure of secundum atrial septal defects: a systematic review and meta-analysis.

BACKGROUND: Limited data exists demonstrating the efficacy of minimally invasive surgery (MIS) compared to transcatheter (TC) closure of atrial septal defects (ASD). This systematic review and meta-analysis aims to compare post-operative outcomes of MIS versus TC repair in ASD closure. METHODS: PubMed, Medline and EMBASE were searched from inception until June 2018 for randomised and observational studies comparing post-operative outcomes for MIS and TC repair. The studies were reviewed for bias using the ROBINS-I Score and pooled in a meta-analysis using STATA (version 15). RESULTS: Six observational studies, involving 1524 patients assessing three primary and five secondary outcomes were included. Evidence suggests TC repair yielded shorter hospital stay (MD = 3.32, 95% CI 1.04-5.60) and lower rates of transient atrial fibrillation (AF) (RR = 0.48, 95% CI 0.20-1.15). TC repair patients also had fewer pericardial effusions (RR = 0.27, 95% CI 0.05-1.54, I2 = 0.0%) and pneumothoraxes (RR = 0.18, 95% CI 0.04-0.80, I2 = 0.0%). However, TC repair results in more minor residual shunts (RR = 6.04, 95% CI 1.69-21.63 in favour of MIS, I2 = 39.0%). No differences were found for incidences of strokes (RR = 1.58, 95% CI 0.23-10.91, I2 = 19.3%), unexpected bleeding (RR = 0.44, 95% CI 0.19-1.04, I2 = 0.0%) and blood transfusion (RR = 0.39, 95% CI 0.09-1.59, I2 = 0.0%). CONCLUSIONS: MIS closure for ASD has similar outcomes compared to TC repair. However, the lack of randomised literature related to MIS versus TC repair for ASD closure warrants further evidence in the form of RCTs to further support these findings.

Nrf2-Keap-1 imbalance under acute shear stress induces inflammatory response in venous endothelial cells.

Vascular endothelial cell stimulation is associated with the activation of different signalling pathways and transcription factors. Acute shear stress is known to induce different pro-inflammatory mediators such as IL-8. Nrf2 is activated by prolonged high shear stress promoting an antiinflammatory and athero-protective environment. However, little is known about the impact of acute shear stress on Nrf2 and Keap1 function and its role in IL-8 regulation. We aimed to examine Nrf2-Keap1 complex activation in-vitro and its role in regulating IL-8 transcripts under acute arterial shear stress (12 dyn/cm2) in venous endothelial cells (ECs). We note that acute high shear stress caused a significant upregulation of Nrf2 target genes, HO-1 and GCLM and an increased IL-8 upregulation at 90 and 120 minutes. Mechanistically, acute high shear did not affect Nrf2 nuclear translocation but resulted in reduced nuclear Keap1, suggesting that the reduction in nuclear Keap1 may result in increased free nuclear nrf2 to induce transcription. Consistently, the suppression of Keap1 using shRNA (shKeap1) resulted in significant upregulation of IL-8 transcripts in response to acute shear stress. Interestingly; the over expression of Nrf2 using Nrf2-Ad-WT or Sulforaphane was also associated with significant upregulation of IL-8 compared to controls. This study highlights the role of Keap1 in Nrf2 activation under shear stress and indicates that activation of Nrf2 may be deleterious in ECs in the context of acute haemodynamic injury.

The SARS-CoV-2 Spike protein disrupts human cardiac pericytes function through CD147 receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a broad range of clinical responses including prominent microvascular damage. The capacity of SARS-CoV-2 to infect vascular cells is still debated. Additionally, the SARS-CoV-2 Spike (S) protein may act as a ligand to induce non-infective cellular stress. We tested this hypothesis in pericytes (PCs), which are reportedly reduced in the heart of patients with severe coronavirus disease-2019 (COVID-19). Here we newly show that the in vitro exposure of primary human cardiac PCs to the SARS-CoV-2 wildtype strain or the α and δ variants caused rare infection events. Exposure to the recombinant S protein alone elicited signalling and functional alterations, including: (1) increased migration, (2) reduced ability to support endothelial cell (EC) network formation on Matrigel, (3) secretion of pro-inflammatory molecules typically involved in the cytokine storm, and (4) production of pro-apoptotic factors causing EC death. Next, adopting a blocking strategy against the S protein receptors angiotensin-converting enzyme 2 (ACE2) and CD147, we discovered that the S protein stimulates the phosphorylation/activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) through the CD147 receptor, but not ACE2, in PCs. The neutralisation of CD147, either using a blocking antibody or mRNA silencing, reduced ERK1/2 activation, and rescued PC function in the presence of the S protein. Immunoreactive S protein was detected in the peripheral blood of infected patients. In conclusion, our findings suggest that the S protein may prompt PC dysfunction, potentially contributing to microvascular injury. This mechanism may have clinical and therapeutic implications.