A rare case report of tissue infection caused by Pantoea piersonii (basionym Kalamiella piersonii).

In 2019, Pantoea piersonii was initially isolated from the interior surfaces of the International Space Station. This microorganism is a species within the genus Pantoea in the family Erwiniaceae, belonging to the order Enterobacterales. Recent literature has documented four cases of its isolation. Despite initial predictions suggesting the non-pathogenicity of P. piersonii strains, evidence from observed cases indicates potential pathogenicity. According to documented evidence in the literature, this microorganism is capable of causing severe and life-threatening conditions, including sepsis. Traditional tests, as well as automated systems, may fail to provide complete differentiation due to these similarities. While MALDI-TOF MS is a valuable tool for identification in clinical diagnostic microbiology, sequencing may be necessary for precise identification. To determine the antibiotic susceptibility profile, various methods can be utilized, including minimum inhibitory concentration determination, disk diffusion testing (Kirby-Bauer test), genotypic resistance assays (PCR and sequencing), and automated systems. The literature reports a limited number of cases associating P. piersonii with human infection. This study contributes to this body of knowledge by reporting a novel case in which P. piersonii was isolated from a tissue sample for the first time. In this case report, the patient achieved recovery following the administration of appropriate antibiotic treatment based on the diagnosis. It underscores the need for precise identification and understanding of its pathogenicity.

Physiological Insights From Asymptomatic Severe Valvular Disease in a Highly Trained Athlete.

Parameters relied on as tools for prognostication in valvular disease can be confounded by athletic physiological remodeling. This case describes how cardiopulmonary exercise testing and multimodality imaging may be helpful in assessment of a 46-year-old female athlete with bicuspid aortic valve and subaortic membrane with associated asymptomatic severe mixed aortic valve disease.

Comparative study of quality of life after aortic valve replacement through partial upper ministernotomy versus full median sternotomy.

BACKGROUND: Upper ministernotomy for sutureless aortic prosthesis implantation provides an attractive opportunity compared to conventional access. Although in the last decade, the former has gained popularity, data comparing quality of life (QoL) following these procedures are scarce. OBJECTIVES: The purpose of this study was to assess the patient's QoL after aortic valve replacement (AVR) using a ministernotomy approach compared to a full sternotomy. MATERIAL AND METHODS: One hundred fifteen AVR patients were operated on using either minimally invasive access with sutureless valve implantation through an upper median ministernotomy (group I; n = 58) or through a full sternotomy (group II; n = 57) with either biological Edwards Perimount Magna™ (Edwards Lifescience, Irvine, USA) (n = 30) or mechanical On-X™ (Carbomedics, Austin, USA) (n = 27) aortic valve prostheses implantation by 1 experienced surgeon. At the end of the follow-up period, QoL was assessed using the EQ-5D-5L scale telephone survey. RESULTS: In group I, there were significantly fewer problems with mobility, pain and usual activities than in group II (p < 0.05). Moreover, the visual analogue scale (VAS) and Health Index (HI) scores were more favorable for patients treated with ministernotomy. Additionally, group II participants provided comments beyond the survey questions, such as tiredness, dyspnea or pain. These kinds of remarks were not reported in group I. Ultimately, the EQ-5D-5L Index Score (IS) was consistent with the variables and more beneficial for group I subjects. Each group was compatible with the benefits for patients in group I. CONCLUSIONS: Cardiac surgical procedures for severe aortic stenosis through minimally invasive access are associated with improved QoL parameters.

VCAM-1 targeted nanocarriers of shRNA-Smad3 mitigate endothelial-to-mesenchymal transition triggered by high glucose concentrations and osteogenic factors in valvular endothelial cells.

Endothelial to mesenchymal transition (EndMT) of valvular endothelial cells (VEC) is a key process in the development and progression of calcific aortic valve disease (CAVD). High expression of the Smad3 transcription factor is crucial in the transition process. We hypothesize that silencing Smad3 could hinder EndMT and provide a novel treatment for CAVD. We aimed at developing nanoparticles encapsulating short-hairpin (sh)RNA sequences specific for Smad3 targeted to the aortic valve. We synthesized VCAM-1-targeted lipopolyplexes encapsulating shRNA-Smad3 plasmid (V-LPP/shSmad3) and investigated their potential to reduce the EndMT of human VEC. VEC incubation in a medium containing high glucose concentrations and osteogenic factors (HGOM) triggers EndMT and increased expression of Smad3. Exposed to lipopolyplexes, VEC took up efficiently the V-LPP/shSmad3. The latter reduced the EndMT process in VEC exposed to HGOM by downregulating the expression of αSMA and S100A4 mesenchymal markers and increasing the expression of the CD31 endothelial marker. In vivo, V-LPP/shSmad3 accumulated in the aortic root and aorta of a murine model of atherosclerosis complicated with diabetes, without affecting the liver and kidney function. The results suggest that targeting activated VEC with lipopolyplexes to silence Smad3 could be an effective, novel treatment for CAVD mediated by the EndMT process.

Higher serum phosphate within the normal range is associated with the development of calcified aortic valve disease.

Background: Despite the essential role of ectopic osteogenic calcium-phosphate metabolism in the development of calcific aortic valve disease (CAVD), the implications of high serum phosphate levels in CAVD development are not fully understood. Methods: Asymptomatic individuals who underwent health screening using serial cardiac computed tomography (CT) and echocardiography were selected from a multicenter registry. CAVD was identified and quantified on CT images using the aortic valve calcification (AVC) score. The associations between initial serum phosphate levels and the presence of baseline CAVD, development of new CAVD, and the AVC score progression rate were investigated using multivariable regression models. Results: A total of 736 individuals were selected for analysis, and the median interscan duration was 36.4 months. On initial CT, 83 (13.7%) participants had baseline CAVD, while 52 (7.0%) individuals developed new CAVD during follow-up. Serum phosphate levels were not associated with a higher probability of baseline CAVD but were predictive of newly developed CAVD (odds ratio per 1 mg/dl, 1.05; 95% confidence interval, 1.01-1.10; p = 0.02). Higher phosphate levels were also associated with a faster AVC score progression in those with baseline CAVD (regression coefficient per 1 mg/dl, 15.55 Agatston units/year; 95% confidence interval, 6.02-25.07; p < 0.01), an association which remained significant when the analysis was extended to include newly developed CAVD. Conclusion: Even slight elevations in serum phosphate are associated with accelerated CAVD progression from an early stage. Further studies are needed to investigate whether the regulation of phosphate metabolism can slow the progression of CAVD to aortic stenosis.

Impact of a New Preoperative Stratification Based on Cardiac Structural Compromise in Patients with Severe Aortic Stenosis Undergoing Valve Replacement Surgery.

Introduction and objectives: Aortic valve replacement surgery (SAVR) remains a recommended indication, though its pre-surgical stratification is an ongoing challenge. Despite the widespread use of scores like the STS and EuroSCORE II, they have a number of limitations, while often neglecting structural parameters like left ventricular hypertrophy or left atrium volume. This study aimed to evaluate whether a new adaptation of the Généreux classification in the preoperative risk stratification of severe aortic stenosis (AS) is associated with the primary outcome, and to compare it with the original classification versus the traditional scores in short- and long-term follow-up. Methods: We conducted a retrospective, single-center study involving patients with confirmed severe AS who underwent SAVR. The new stratification categorized patients into three stages. Cox regression analyses were conducted to identify factors associated with mortality, with survival analysis performed using Kaplan-Meier curves. A p-value < 0.05 was considered statistically significant. Results: A total of 508 patients were included. Stage 3 patients had a lower median age (67 years). The median EuroSCORE II and STS scores were 2.75 and 2.62%, respectively (p ≤ 0.001). Over a median follow-up of 81 months, 56 deaths occurred (11%). Kaplan-Meier curve analysis revealed significant differences in all-cause mortality among the three groups (HR 4.073, log-rank p ≤ 0.001). Multivariable analysis identified the three preoperative stages (HR 3.22, [95% CI 1.44-7.20], p = 0.004) and mean transaortic gradient (HR 0.96, [95% CI 0.92-0.99], p = 0.021) as independent variables of mortality. The original Généreux scale AUC was higher (AUC: 0.760, 95% CI: 0.692-0.829) compared to the modified Généreux scale (AUC: 0.758, 95% CI: 0.687-0.829). However, no statistical differences were found between the different scales. Conclusions: Preoperative three-stage classification and low transaortic gradient are factors associated with increased all-cause mortality in patients undergoing SAVR. The proposed staging system performed better in the mortality analysis than EuroSCORE II and STS and was similar to the original classification.

Successful Balloon Valvuloplasty in a Case of Neonatal Aortic Critical Stenosis With Bicuspid Aortic Valve (BAV): A Case Report.

A bicuspid aortic valve (BAV) refers to a condition in which the valve has two cusps rather than three. Usually ignored, this manifests itself later in life. This bicuspid valve may manifest earlier in children with significant aortic stenosis because they have a severe left ventricular outflow tract restriction that worsens over time. This syndrome commonly results in congestive heart failure in newborns and early neonatal life. There can be a small amount of significant risk in pediatric patients having this BAV causing stenosis and being one of the reasons for sudden, unexpected death. Morphological differences result from a congenital cardiac abnormality called BAV. This paper emphasizes the importance of a multidisciplinary team in managing BAV and critical aortic stenosis and provides evaluation and treatment guidelines for both conditions. Transcatheter or surgical intervention is used for symptomatic individuals or those with a moderate to severe obstruction of the left ventricular outflow tract.

The Role of Adiponectin and Leptin in Fibro-Calcific Aortic Valve Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Fibro-calcific aortic valve disease (FCAVD) is a progressive disorder characterized by the thickening and calcification of the aortic valve, eventually leading to aortic stenosis. Adiponectin and leptin, known for their anti-inflammatory and proinflammatory properties, respectively, have been implicated in cardiovascular diseases, but their associations with FCAVD are controversial. This meta-analysis aims to evaluate the relationships between adiponectin and leptin levels and FCAVD, particularly in patients with severe aortic stenosis (AS). METHODS: A systematic search was conducted across the PubMed, Scopus, and Web of Science databases to identify studies on adiponectin and leptin levels in FCAVD. The methodological quality of each study was assessed using the Newcastle-Ottawa Scale. Standardized mean differences (SMDs) and 95% confidence intervals (CIs) were calculated, and publication bias was evaluated using Egger's test and funnel plots. RESULTS: Out of 191 articles identified, 10 studies involving 2360 patients (989 with FCAVD and 1371 controls) were included. The analysis suggested trends in the associations of lower adiponectin levels (SMD = -0.143, 95% CI: -0.344, 0.057, p = 0.161) and higher leptin levels (SMD = 0.175, 95% CI: -0.045, 0.395, p = 0.119) with FCAVD. The association remained a trend for low adiponectin but showed a significant correlation with high leptin in severe AS patients (SMD = 0.29, 95% CI: 0.036, 0.543, p = 0.025). CONCLUSION: This meta-analysis indicates a potential association between elevated leptin levels and severe aortic stenosis, while the relationship with adiponectin levels remains inconclusive. These findings highlight the need for further and dedicated research to clarify the roles of these adipokines in the pathogenesis of FCAVD and their potential roles as biomarkers for disease progression.

Bicuspid Aortic Valve Disease: From Pathophysiology to Treatment.

The Bicuspid Aortic Valve (BAV) is the most common congenital anomaly in adults, with a global incidence of 1.3%. Despite being well documented, BAV presents significant clinical challenges due to its phenotypic heterogeneity, diverse clinical manifestations, and variable outcomes. Pathophysiologically, BAV differs from tricuspid valves in calcification patterns and hemodynamic effects, leading to increased shear stress and aortic root dilatation, while it is influenced by genetic and hemodynamic factors. This is why therapeutically, BAV presents challenges for both surgical and transcatheter interventions, with surgical approaches being traditionally preferred, especially when aortopathy is present. However, transcatheter aortic valve implantation (TAVI) has emerged as a viable option, with studies showing comparable outcomes to surgery in selected patients, while advancements in TAVI and a better understanding of BAV's genetic and pathophysiological nuances are expanding treatment options. The choice between mechanical and bioprosthetic valves also presents considerations, particularly regarding long-term durability and the need for anticoagulation. Future research should focus on long-term registries and genetic studies to refine therapeutic strategies and improve patient outcomes. This review aims to evaluate current approaches in the surgical and interventional management of BAV, focusing on its anatomy, pathogenesis, pathophysiology, and therapeutic strategies.

Unprecedented nor-seco-diterpene lactones inhibited osteogenic differentiation of valve interstitial cells.

The first examples of ent-atisane and ent-isopimarane diterpene lactones with an unusual 2,3-seco-2-nor-tetrahydro-2H-pyran-2-one nucleus, eufislactones A (1) and B (2), were isolated from the roots of Euphorbia fischeriana, together with a new (3) and fifteen known biosynthetic congeners (4-18). Their structures incorporating absolute configurations were elucidated via the comprehensive spectroscopic analyses, electronic circular dichroism (ECD) calculation, and single-crystal X-ray diffraction analyses. Biogenetically, compounds 1 and 2 were constructed by the plausible monomeric precursors, ent-atis-16-ene-3,14-dione (6) and ent-isopimara-8(14),15-dien-3-one (17), respectively, via key Baeyer-Villiger oxidation, decarboxylation, and semi-acetalization reactions to create a unique 2,3-seco-2-nor-tetrahydro-2H-pyran-2-one core. Our bioassays have revealed that eufislactone A (EFA, 1) displayed significant inhibitory effect on the osteogenic differentiation of human valvular interstitial cells (VICs), highlighting its potential as a preventive agent against the progression of human calcific aortic valve disease (CAVD).

Lipoprotein(a) and cardiovascular disease.

Elevated plasma levels of lipoprotein(a) (Lp(a)) are a prevalent, independent, and causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve disease. Lp(a) consists of a lipoprotein particle resembling low density lipoprotein and the covalently-attached glycoprotein apolipoprotein(a) (apo(a)). Novel therapeutics that specifically and potently lower Lp(a) levels are currently in advanced stages of clinical development, including in large, phase 3 cardiovascular outcomes trials. However, fundamental unanswered questions remain concerning some key aspects of Lp(a) biosynthesis and catabolism as well as the true pathogenic mechanisms of the particle. In this review, we describe the salient biochemical features of Lp(a) and apo(a) and how they underlie the disease-causing potential of Lp(a), the factors that determine plasma Lp(a) concentrations, and the mechanism of action of Lp(a)-lowering drugs.

Flow quantification within the aortic ejection tract using 4D flow cardiac MRI in patients with bicuspid aortic valve: Implications for the assessment of aortic regurgitation.

PURPOSE: The purpose of this study was to evaluate the performance of four-dimensional (4D) flow cardiac MRI in quantifying aortic flow in patients with bicuspid aortic valve (BAV). MATERIALS AND METHODS: Patients with BAV who underwent transthoracic echocardiography (TTE) and 4D flow cardiac MRI were prospectively included. Aortic flow was quantified using two-dimensional phase contrast velocimetry at the sinotubular junction and in the ascending aorta and using 4D flow in the regurgitant jet, in the left ventricular outflow tract, at the aortic annulus, the sinotubular junction, and the ascending aorta, with or without anatomical tracking. Flow quantification was compared with ventricular volumes, pulmonary flow using Pearson correlation test, bias and limits of agreement (LOA) using Bland Altman method, and with multiparametric transthoracic echocardiography quantification using weighted kappa test. RESULTS: Eighty-eight patients (63 men, 25 women) with a mean age of 50.5 ± 14.8 (standard deviation) years (age range: 20.8-78.3) were included. Changes in flow with or without tracking were modest (< 5 mL). The best correlation was obtained at the aortic annulus for forward volume (r = 0.84; LOA [-28.4; 25.3] mL) and at the regurgitant jet and sinotubular junction for regurgitant volume (r = 0.68; LOA [-27.8; 33.8] and r = 0.69; LOA [-28.6; 24.2] mL). A combined approach for regurgitant fraction and net volume calculations using forward volume measured at ANN and regurgitant volume at sinotubular junction performed better than each level taken separately (r = 0.90; LOA [-20.7; 10.0] mL and r = 0.48, LOA [-33.8; 33.4] %). The agreement between transthoracic echocardiography and 4D flow cardiac MRI for aortic regurgitation grading was poor (kappa, 0.13 to 0.42). CONCLUSION: In patients with BAV, aortic flow quantification by 4D flow cardiac MRI is the most accurate at the annulus for the forward volume, and at the sinotubular junction or directly in the jet for the regurgitant volume.

Cardiovascular Management of Aortopathy in Children: A Scientific Statement From the American Heart Association.

Aortopathy encompasses a spectrum of conditions predisposing to dilation, aneurysm, dissection, or rupture of the aorta and other blood vessels. Aortopathy is diagnosed commonly in children, from infancy through adolescence, primarily affecting the thoracic aorta, with variable involvement of the peripheral vasculature. Pathogeneses include connective tissue disorders, smooth muscle contraction disorders, and congenital heart disease, including bicuspid aortic valve, among others. The American Heart Association has published guidelines for diagnosis and management of thoracic aortic disease. However, these guidelines are predominantly focused on adults and cannot be applied adeptly to growing children with emerging features, growth and developmental changes, including puberty, and different risk profiles compared with adults. Management to reduce risk of progressive aortic dilation and dissection or rupture in children is complex and involves genetic testing, cardiovascular imaging, medical therapy, lifestyle modifications, and surgical guidance that differ in many ways from adult management. Pediatric practice varies widely, likely because aortopathy is pathogenically heterogeneous, including genetic and nongenetic conditions, and there is limited published evidence to guide care in children. To optimize care and reduce variation in management, experts in pediatric aortopathy convened to generate this scientific statement regarding the cardiovascular care of children with aortopathy. Available evidence and expert consensus were combined to create this scientific statement. The most common causes of pediatric aortopathy are reviewed. This document provides a general framework for cardiovascular management of aortopathy in children, while allowing for modification based on the personal and familial characteristics of each child and family.

Oxygenator assisted dynamic microphysiological culture elucidates the impact of hypoxia on valvular interstitial cell calcification.

INTRODUCTION: Microphysiological systems (MPS) offer simulation of (patho)physiological parameters. Investigation includes items which lead to fibrosis and calcification in development and progress of calcific aortic valve disease, based e.g. on culturing of isolated valvular interstitial cells (VICs). Hypoxia regulated by hypoxia inducible factors impacts pathological differentiation in aortic valve (AV) disease. This is mimicked via an MPS implemented oxygenator in combination with calcification inducing medium supplementation. METHODS: Human valvular interstitial cells were isolated and dynamically cultured in MPS at hypoxic, normoxic, arterial blood oxygen concentration and cell incubator condition. Expression profile of fibrosis and calcification markers was monitored and calcification was quantified in induction and control media with and without hypoxia and in comparison to statically cultured counterparts. RESULTS: Hypoxic 24-hour culture of human VICs leads to HIF1α nuclear localization and induction of EGLN1, EGLN3 and LDHA mRNA expression but does not directly impact expression of fibrosis and calcification markers. Dependent on medium formulation, induction medium induces monolayer calcification and elevates RUNX2, ACTA2 and FN1 but reduces SOX9 mRNA expression in dynamic and static MPS culture. But combining hypoxic oxygen concentration leads to higher calcification potential of human VICs in calcification and standard medium formulation dynamically cultured for 96 h. CONCLUSION: In hypoxic oxygen concentration an increased human VIC calcification in 2D VIC culture in an oxygenator assisted MPS was detected. Oxygen regulation therefore can be combined with calcification induction media to monitor additional effects of pathological marker expression. Validation of oxygenator dependent VIC behavior envisions future advancement and transfer to long term aortic valve tissue culture MPS.

Alterations in Left Atrial and Ventricular Coupling in Mixed Aortic Valve Disease.

AIMS: To characterize left atrial (LA) and left ventricular (LV) function and atrioventricular (AV) coupling in patients with moderate mixed aortic valve disease (MMAVD) against those with isolated moderate or severe aortic valve disease and controls. METHODS & RESULTS: Retrospective LA and LV peak longitudinal strain (LS) analysis were performed on 260 patients (46 MMAVD, 81 moderate aortic stenosis (AS), 50 severe AS, 48 moderate aortic regurgitation (AR), and 35 severe AR) and 66 controls. Peak LV and LA LS and AV coupling, assessed by combined peak LA and LV strain, was compared between the groups. ANOVA and 2-sided t-tests were used and a p-value of <0.01 was considered significant.LV strain was significantly lower in those with MMAVD compared to controls and those with moderate or severe isolated AR but comparable to those with moderate or severe AS (-17.1±1.1% MMAVD vs. -17.7±1.5% moderate AS p=0.02; vs. -17.0%±1.5% severe AS, p=0.74). AV coupling was significantly lower in those with MMAVD compared to controls and those with moderate AS or AR but comparable to those with severe AS or AR (47.1±6.8% MMAVD vs. 45.1±5.6% severe AS, p=0.13; vs. 50.4±9% severe AR, p=0.07). CONCLUSIONS: Impairments in AV coupling are comparable for patients with MMAVD and those with severe isolated AS or AR. Impairments in LV GLS in MMAVD mirror those found in severe AS. These findings suggest that haemodynamic consequences and adverse remodelling are similar for patients with MMAVD and isolated severe disease.

Demographics and outcomes of patients younger than 75 years undergoing aortic valve interventions in Rotterdam.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is considered a safe and effective alternative to surgical aortic valve replacement (SAVR) for elderly patients across the operative risk spectrum. In the Netherlands, TAVI is reimbursed only for patients with a high operative risk. Despite this, one fifth of TAVI patients are < 75 years of age. We aim to compare patient characteristics and outcomes of TAVI and SAVR patients < 75 years. METHODS: This study included all patients < 75 years without active endocarditis undergoing TAVI or SAVR for severe aortic stenosis, mixed aortic valve disease or degenerated aortic bioprosthesis between 2015 and 2020 at the Erasmus University Medical Centre. Dutch authority guidelines were used to classify operative risk. RESULTS: TAVI was performed in 292 patients, SAVR in 386 patients. Based on the Dutch risk algorithm, 59.6% of TAVI patients and 19.4% of SAVR patients were at high operative risk. There was no difference in 30-day all-cause mortality between TAVI and SAVR (2.4% vs 0.8%, p = 0.083). One-year and 5­year mortality was higher after TAVI than after SAVR (1-year: 12.5% vs 4.3%, p < 0.001; 5­year: 36.8% vs 12.0%, p < 0.001). Within risk categories we found no difference between treatment strategies. Independent predictors of mortality were cardiovascular comorbidities (left ventricular ejection fraction < 30%, atrial fibrillation, pulmonary hypertension) and the presence of malignancies, liver cirrhosis or immunomodulatory drug use. CONCLUSION: At the Erasmus University Medical Centre, in patients < 75 years, TAVI is selected for higher-risk phenotypes and overall has higher long-term mortality than SAVR. We found no evidence for worse outcome within risk categories.