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The editorial in the Journal of Clinical Medicine discusses the latest advances and prospects in transcatheter aortic valve replacement (TAVR) for patients with aortic stenosis. It highlights the importance of addressing complications such as new-onset conduction disturbances and optimizing post-procedural antithrombotic therapy. The document also emphasizes the need for ongoing research to improve clinical outcomes, particularly in younger, low-risk patients, and provides insights into the lifetime management of aortic stenosis, including considerations for patients with bicuspid aortic valve and the durability of transcatheter heart valves. [Extracted from the article]

Calcified areas in aortic valves often co-localize with amyloid fibrils that can promote calcification. Patient-derived amyloid fibrils contain arrays of acidic residues that can bind calcium and organize calcium phosphate nucleation clusters, while collagen fibrils guide crystal growth. This process is akin to functional biomineralization guided by Ca entrapment by acidic arrays in proteins, including amyloids. High shear stress and turbulent blood flow across the aortic valve, which are exacerbated in calcific aortic valve disease (CAVD), augment amyloid formation by plasma proteins. The main amyloid protein is probably apolipoprotein A-I (apoA-I), yet other proteins can also be involved. Lipoprotein(a) [Lp(a)], a genetic risk factor for CAVD, contributes to calcification. Enzymatic hydrolysis of oxidized phospholipids in Lp(a) helps generate orthophosphate, whereas apo(a) blocks collagen and amyloid fibril degradation by plasmin. Calcific aortic valve disease (CAVD) is a widely prevalent heart disorder in need of pharmacological interventions. Calcified areas in aortic valves often contain amyloid fibrils that promote calcification in vitro. This opinion paper suggests that amyloid contributes to CAVD development; amyloid-assisted nucleation can accelerate hydroxyapatite deposition onto collagen matrix. Notably, acidic arrays in amyloid match calcium–calcium spacing in the amorphous hydroxyapatite precursor, while oscillating hemodynamic perturbations promote amyloid deposition in the valve. Lipoprotein(a), a genetic risk factor for CAVD, augments calcification via several mechanisms, wherein hydrolysis of oxidized phospholipids (oxPLs) by Lp(a)-associated enzymes helps generate orthophosphate, and apolipoprotein(a) blocks plasmin-induced fibril degradation. Current studies of amyloid–calcium–collagen interactions in solution and in fibrillar complexes allow deeper insight into the role of amyloid in calcification. [ABSTRACT FROM AUTHOR]

Background: Infective endocarditis (IE) is a severe, life-threatening, and relatively common complication after valve replacement operations, with incidence rates varying between 1.8% and 5.8%, with an in-hospital mortality rate of up to 20%. Common microorganisms are (listed by decreasing incidence) Streptococci, Staphylococcus aureus, Enterococci, bacteria of the HACEK group, and fungi. Treatment of IE is complex, typically involving prolonged courses of antibiotics. However, in cases of aortic prosthetic valve endocarditis, root abscess formation with involvement of the aorto-mitral skeleton is not uncommon and complex surgical intervention is required. One of the notable advancements in surgical management is the use of homografts for aortic root endocarditis. Case Reports: We report the first case series of 8 patients successfully operated on for prosthetic valve endocarditis with extensive aortic root abscess formation in Greece at Onassis Cardiac Surgery Center with the use of aortic homograft. All cases were redo surgeries and had good outcomes. Interestingly, one of the cases had extensive aortic root involvement with abscess formation extending to the aorto-mitral fibrous skeleton, requiring aortic root replacement with homograft, aorto-mitral skeleton reconstruction with bovine pericardium and mitral valve replacement with a mechanical prosthesis. Two other patients required concomitant coronary bypass grafting of the right coronary artery with reversed saphenous vein grafts. Conclusions: Aortic root replacement with aortic homograft is the preferred choice for prosthetic valve endocarditis with aortic root abscess formation. Despite the technical complexity needed for implantation, this option offers a second chance for survival in patients with this challenging condition. [ABSTRACT FROM AUTHOR]

Coronary artery calcification (CAC) is an early marker for atherosclerosis and is mainly induced by the osteoblast-like phenotype conversion of vascular smooth muscle cells (VSMCs). Recent reports indicate that NOD-like receptor protein 3 (NLRP3)-mediated pyroptosis plays a significant role in the calcification of vascular smooth muscle cells (VSMCs), making it a promising target for treating calcific aortic valve disease (CAC). Ligustrazine, or tetramethylpyrazine (TMP), has been found effective in various cardiovascular and cerebrovascular diseases and is suggested to inhibit NLRP3-mediated pyroptosis. However, the function of TMP in CAC is unknown. Herein, influences of TMP on ß-glycerophosphate (ß-GP)-stimulated VSMCs and OPG-/-mice were explored. Mouse Aortic Vascular Smooth Muscle (MOVAS-1) cells were stimulated by ß-GP with si- caspase-3, si- Gasdermin E (GSDME) or TMP. Increased calcification, reactive oxygen species (ROS) level, Interleukin-1beta (IL-1ß) and Interleukin-18 (IL-18) levels, lactate dehydrogenase (LDH) release, enhanced apoptosis, and activated cysteine-aspartic acid protease-3 (caspase-3)/GSDME signaling were observed in ß-GP-stimulated MOVAS-1 cells, which was sharply alleviated by si-caspase-3, si-GSDME or TMP. Furthermore, the impact of TMP on the ß-GP-induced calcification and injury in MOVAS-1 cells was abolished by raptinal, an activator of caspase-3. Subsequently, OPG-/- mice were dosed with TMP or TMP combined with raptinal. Calcium deposition, increased nodules, elevated IL-1ß and IL- 18 levels, upregulated CASP3 and actin alpha 2, smooth muscle (ACTA2), and activated caspase-3/GSDME signaling in OPG-/- mice were markedly alleviated by TMP, which were notably reversed by the co-administration of raptinal. Collectively, TMP mitigated CAC by inhibiting caspase-3/GSDME mediated pyroptosis. [ABSTRACT FROM AUTHOR]

Heart disease is a leading cause of mortality, with calcific aortic valve disease (CAVD) being the most prevalent subset. Being able to predict this disease in its early stages is important for monitoring patients before they need aortic valve replacement surgery. Thus, this study explored hydrodynamic, mechanical, and hemodynamic differences in healthy and very mildly calcified porcine small intestinal submucosa (PSIS) bioscaffold valves to determine any notable parameters between groups that could, possibly, be used for disease tracking purposes. Three valve groups were tested: raw PSIS as a control and two calcified groups that were seeded with human valvular interstitial and endothelial cells (VICs/VECs) and cultivated in calcifying media. These two calcified groups were cultured in either static or bioreactor-induced oscillatory flow conditions. Hydrodynamic assessments showed metrics were below thresholds associated for even mild calcification. Young's modulus, however, was significantly higher in calcified valves when compared to raw PSIS, indicating the morphological changes to the tissue structure. Fluid–structure interaction (FSI) simulations agreed well with hydrodynamic results and, most notably, showed a significant increase in time-averaged wall shear stress (TAWSS) between raw and calcified groups. We conclude that tracking hemodynamics may be a viable biomarker for early-stage CAVD tracking. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Aneurysms of the internal iliac artery in infective endocarditis are extremely rare, with few cases reported in the literature, and Rothia dentocariosa infective endocarditis are rare. Analysis: We describe the case of a previously healthy 62-year-old male who presented a Rothia dentocariosa infective endocarditis. Results: Multi-modality imaging revealed an aneurysm of the left internal iliac artery, which was clinically silent. The patient was treated with antibiotics and semi-emergent bioprosthesis aortic valve replacement. Follow-up multi-modality imaging showed the regression of the aneurysm. Conclusion: This case shows that an aneurysm of the internal iliac artery in infective endocarditis can regress under antibiotherapy alone. This case also highlights the ability of PET/CT to identify and follow such an aneurysm. [ABSTRACT FROM AUTHOR]

Individuals with bicuspid aortic valve (BAV) have historically been advised to avoid contact sports and isometric exercise for risk of increasing aortic dilation and valve disease. There is mounting evidence that current sports participation guidelines qualify children for a high rate of sports exclusion, and that this population is at increased risk of obesity. The primary aim of this study was to evaluate relationship between sports participation and aortic dilation in children with bicuspid aortic valve and secondarily the relationship between competitive sports participation and obesity. We performed a review of children between the ages of 8 and 17 years with isolated BAV followed at Oregon Health & Science University. We excluded those with other congenital heart diseases, genetic conditions, prior cardiac intervention, and inability to ambulate independently. Parents completed a phone survey detailing their child's level of daily activity and participation in competitive sports. Demographic information and most recent echo findings were collected from the electronic medical record. We found no difference between the aortic diameters of athletes vs non-athletes. We also found that sports participation and daily activity were both associated with a decreased likelihood of obesity (OR 0.24, 95% CI 0.078–0.73 and OR 0.24, 95% CI 0.081–0.71 respectively). In summary, in our sample population, competitive sports participation was associated with a decreased risk of obesity. Competitive sports participation does not appear to be associated with an increased risk of aortic dilation in our population. [ABSTRACT FROM AUTHOR]

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 5‑year mortality was higher after TAVI than after SAVR (1-year: 12.5% vs 4.3%, p < 0.001; 5‑year: 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. [ABSTRACT FROM AUTHOR]

This article discusses three different studies related to heart failure and valvular heart disease. The first study examines the use of intravenous ferric carboxymaltose (FCM) in patients with heart failure with preserved ejection fraction (HFpEF) and iron deficiency. The study found that FCM improved exercise capacity and had fewer serious adverse events compared to a placebo. However, the study was small and did not assess other symptoms or quality of life. The second study compares transcatheter aortic valve implantation (TAVI) with surgery in low-risk patients with aortic stenosis. The study found that the rate of death, stroke, or rehospitalization at one year was similar between the two treatments. However, TAVI had different risks and outcomes for patients with bicuspid aortic stenosis. The third study explores sex differences in severe native valvular heart disease. It found that women were older, more symptomatic, and had poorer concordance with recommended treatment compared to men. However, survival at six months was similar between men and women. Overall, these studies provide valuable insights into the treatment and management of heart failure and valvular heart disease, but further research is needed to fully understand their impact. [Extracted from the article]

Background and Aims Valve interstitial cells (VICs) undergo a transition to intermediate state cells before ultimately transforming into the osteogenic cell population, which is a pivotal cellular process in calcific aortic valve disease (CAVD). Herein, this study successfully delineated the stages of VIC osteogenic transformation and elucidated a novel key regulatory role of lumican (LUM) in this process. Methods Single-cell RNA-sequencing (scRNA-seq) from nine human aortic valves was used to characterize the pathological switch process and identify key regulatory factors. The in vitro , ex vivo , in vivo , and double knockout mice were constructed to further unravel the calcification-promoting effect of LUM. Moreover, the multi-omic approaches were employed to analyse the molecular mechanism of LUM in CAVD. Results ScRNA-seq successfully delineated the process of VIC pathological transformation and highlighted the significance of LUM as a novel molecule in this process. The pro-calcification role of LUM is confirmed on the in vitro , ex vivo , in vivo level, and ApoE−/−//LUM−/− double knockout mice. The LUM induces osteogenesis in VICs via activation of inflammatory pathways and augmentation of cellular glycolysis, resulting in the accumulation of lactate. Subsequent investigation has unveiled a novel LUM driving histone modification, lactylation, which plays a role in facilitating valve calcification. More importantly, this study has identified two specific sites of histone lactylation, namely, H3K14la and H3K9la, which have been found to facilitate the process of calcification. The confirmation of these modification sites' association with the expression of calcific genes Runx2 and BMP2 has been achieved through ChIP-PCR analysis. Conclusions The study presents novel findings, being the first to establish the involvement of lumican in mediating H3 histone lactylation, thus facilitating the development of aortic valve calcification. Consequently, lumican would be a promising therapeutic target for intervention in the treatment of CAVD. [ABSTRACT FROM AUTHOR]

Introduction: Patients with severe aortic stenosis referred for transcatheter aortic valve implantation (TAVI) often present with concomitant coronary artery disease (CAD). The management of CAD in these patients remains a topic of debate, encompassing the evaluation and timing of percutaneous coronary intervention (PCI). Areas Covered: This review article aims to offer an overview of the role of coronary revascularization in TAVI patients, highlighting the advantages and disadvantages of different strategies: PCI before, concomitant with, and after TAVI. Considering that TAVI indications are expanding and patients with low surgical risk are now being referred for TAVI, the rate of PCI among patients undergoing TAVI is expected to increase. Historically, PCI was performed before TAVI. However, there is now a growing trend to defer PCI until after TAVI. Expert opinion: It is plausible that in the future, there will be an increase in PCI after TAVI due to several factors: first, multiple studies have shown the safety of TAVI even in patients with severe untreated CAD; second, improvements in TAVI device implantation techniques, such as commissural alignment and patient-specific device selection, have improved access to the coronary arteries post-TAVI. [ABSTRACT FROM AUTHOR]

One in five people are at high risk for atherosclerotic cardiovascular disease and aortic valve stenosis due to high lipoprotein(a). Lipoprotein(a) concentrations are lowest in people from east Asia, Europe, and southeast Asia, intermediate in people from south Asia, the Middle East, and Latin America, and highest in people from Africa. Concentrations are more than 90% genetically determined and 17% higher in post-menopausal women than in men. Individuals at a higher cardiovascular risk should have lipoprotein(a) concentrations measured once in their lifetime to inform those with high concentrations to adhere to a healthy lifestyle and receive medication to lower other cardiovascular risk factors. With no approved drugs to lower lipoprotein(a) concentrations, it is promising that at least five drugs in development lower concentrations by 65–98%, with three currently being tested in large cardiovascular endpoint trials. This Review covers historical perspectives, physiology and pathophysiology, genetic evidence of causality, epidemiology, role in familial hypercholesterolaemia and diabetes, management, screening, diagnosis, measurement, prevention, and future lipoprotein(a)-lowering drugs. [ABSTRACT FROM AUTHOR]

Medical therapy for aortic stenosis (AS) remains an elusive goal. This study sought to establish whether evogliptin, a dipeptidyl peptidase-4 inhibitor, could reduce AS progression. A total of 228 patients (age 67 ± 11 years; 33% women) with AS were randomly assigned to receive placebo (n = 75), evogliptin 5 mg (n = 77), or evogliptin 10 mg (n = 76). The primary endpoint was the 96-week change in aortic valve calcium volume (AVCV) on computed tomography. Secondary endpoints included the 48-week change in active calcification volume measured using 18F-sodium fluoride positron emission tomography (18F-NaF PET). There were no significant differences in the 96-week changes in AVCV between evogliptin 5 mg and placebo (−5.27; 95% CI: −55.36 to 44.82; P = 0.84) or evogliptin 10 mg and placebo (−18.83; 95% CI: −32.43 to 70.10; P = 0.47). In the placebo group, the increase in AVCV between 48 weeks and 96 weeks was higher than that between baseline and 48 weeks (136 mm3; 95% CI: 108–163 vs 102 mm3; 95% CI: 75–129; P = 0.0485). This increasing trend in the second half of the study was suppressed in both evogliptin groups. The 48-week change in active calcification volume on 18F-NaF PET was significantly lower in both the evogliptin 5 mg (−1,325.6; 95% CI: −2,285.9 to −365.4; P = 0.008) and 10-mg groups (−1,582.2; 95% CI: −2,610.8 to −553.5; P = 0.0038) compared with the placebo group. This exploratory study did not demonstrate the protective effect of evogliptin on AV calcification. Favorable 18F-NaF PET results and possible suppression of aortic valve calcification with longer medication use in the evogliptin groups suggest the need for larger confirmatory trials. (A Multicenter, Double-blind, Placebo-controlled, Stratified-randomized, Parallel, Therapeutic Exploratory Clinical Study to Evaluate the Efficacy and Safety of DA-1229 in Patients With Calcific Aortic Valve Disease; NCT04055883) [ABSTRACT FROM AUTHOR]

Calcific aortic valve disease (CAVD) is one of the most common forms of valvulopathy, with a 50 % elevated risk of a fatal cardiovascular event, and greater than 15,000 annual deaths in North America alone. The treatment standard is valve replacement as early diagnostic, mitigation, and drug strategies remain underdeveloped. The development of early diagnostic and therapeutic strategies requires the fabrication of effective in vitro valve mimetic models to elucidate early CAVD mechanisms. In this study, we developed a multilayered physiologically relevant 3D valve-on-chip (VOC) system that incorporated aortic valve mimetic extracellular matrix (ECM), porcine aortic valve interstitial cell (VIC) and endothelial cell (VEC) co-culture and dynamic mechanical stimuli. Collagen and glycosaminoglycan (GAG) based hydrogels were assembled in a bilayer to mimic healthy or diseased compositions of the native fibrosa and spongiosa. Multiphoton imaging and proteomic analysis of healthy and diseased VOCs were performed. Collagen-based bilayered hydrogel maintained the phenotype of the VICs. Proteins related to cellular processes like cell cycle progression, cholesterol biosynthesis, and protein homeostasis were found to be significantly altered and correlated with changes in cell metabolism in diseased VOCs. This study suggested that diseased VOCs may represent an early, adaptive disease initiation stage, which was corroborated by human aortic valve proteomic assessment. In this study, we developed a collagen-based bilayered hydrogel to mimic healthy or diseased compositions of the native fibrosa and spongiosa layers. When the gels were assembled in a VOC with VECs and VICs, the diseased VOCs revealed key insights about the CAVD initiation process. Calcific aortic valve disease (CAVD) elevates the risk of death due to cardiovascular pathophysiology by 50 %, however, prevention and mitigation strategies are lacking, clinically. Developing tools to assess early disease would significantly aid in the prevention of disease and in the development of therapeutics. Previously, studies have utilized collagen and glycosaminoglycan-based hydrogels for valve cell co-cultures, valve cell co-cultures in dynamic environments, and inorganic polymer-based multilayered hydrogels; however, these approaches have not been combined to make a physiologically relevant model for CAVD studies. We fabricated a bi-layered hydrogel that closely mimics the aortic valve and used it for valve cell co-culture in a dynamic platform to gain mechanistic insights into the CAVD initiation process using proteomic and multiphoton imaging assessment. [Display omitted] [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Bicuspid aortic valve (BAV), the most common congenital heart defect, is a major cause of aortic valve disease requiring valve interventions and thoracic aortic aneurysms predisposing to acute aortic dissections. The spectrum of BAV ranges from early onset valve and aortic complications (EBAV) to sporadic late onset disease. Rare genomic copy number variants (CNVs) have previously been implicated in the development of BAV and thoracic aortic aneurysms. We determined the frequency and gene content of rare CNVs in EBAV probands (n = 272) using genome-wide SNP microarray analysis and three complementary CNV detection algorithms (cnvPartition, PennCNV, and QuantiSNP). Unselected control genotypes from the Database of Genotypes and Phenotypes were analyzed using identical methods. We filtered the data to select large genic CNVs that were detected by multiple algorithms. Findings were replicated in a BAV cohort with late onset sporadic disease (n = 5040). We identified 3 large and rare (< 1,1000 in controls) CNVs in EBAV probands. The burden of CNVs intersecting with genes known to cause BAV when mutated was increased in case-control analysis. CNVs intersecting with GATA4 and DSCAM were enriched in cases, recurrent in other datasets, and segregated with disease in families. In total, we identified potentially pathogenic CNVs in 9% of EBAV cases, implicating alterations of candidate genes at these loci in the pathogenesis of BAV. [ABSTRACT FROM AUTHOR]

Background: Aortic valve infective endocarditis (IE) is associated with significant morbidity and mortality. We aimed to describe the clinical profile, risk factors and predictors of short- and long-term mortality in patients with aortic valve IE treated with aortic valve replacement (AVR) compared with a control group undergoing AVR for non-infectious valvular heart disease. Methods: Between January 2008 and December 2013, a total of 170 cases with IE treated with AVR (exposed cohort) and 677 randomly selected non-infectious AVR-treated patients with degenerative aortic valve disease (controls) were recruited from three tertiary hospitals with cardiothoracic facilities across Scandinavia. Crude and adjusted hazard ratios (HR) were estimated using Cox regression models. Results: The mean age of the IE cohort was 58.5 ± 15.1 years (80.0% men). During a mean follow-up of 7.8 years (IQR 5.1-10.8 years), 373 (44.0%) deaths occurred: 81 (47.6%) in the IE group and 292 (43.1%) among controls. Independent risk factors associated with IE were male gender, previous heart surgery, underweight, positive hepatitis C serology, renal failure, previous wound infection and dental treatment (all p < 0.05). IE was associated with an increased risk of both short-term (≤ 30 days) (HR 2.86, [1.36–5.98], p = 0.005) and long-term mortality (HR 2.03, [1.43–2.88], p < 0.001). In patients with IE, chronic obstructive pulmonary disease (HR 2.13), underweight (HR 4.47), renal failure (HR 2.05), concomitant mitral valve involvement (HR 2.37) and mediastinitis (HR 3.98) were independent predictors of long-term mortality. Staphylococcus aureus was the most prevalent microbe (21.8%) and associated with a 5.2-fold increased risk of early mortality, while enterococci were associated with the risk of long-term mortality (HR 1.78). Conclusions: In this multicenter case-control study, IE was associated with an increased risk of both short- and long-term mortality compared to controls. Efforts should be made to identify, and timely treat modifiable risk factors associated with contracting IE, and mitigate the predictors of poor survival in IE. [ABSTRACT FROM AUTHOR]

Bicuspid aortic valve (BAV) is the most common congenital heart malformation in adults, but it can also cause childhood-onset complications. The presentation and clinical course of young adults who present due to BAV complications are relatively uncharacterized. In a multicenter study, we found that young people who experience significant complications related to BAV disease before age 30 are distinguished from the majority of BAV cases that manifest after age 50 by a relatively severe clinical course, with higher rates of surgical interventions, more frequent second interventions, and a greater burden of congenital heart malformations. These observations highlight the need for prompt recognition, regular lifelong surveillance, and targeted interventions to address the significant health burdens of patients with early-onset BAV complications. [ABSTRACT FROM AUTHOR]

Patient-prosthesis mismatch (PPM) is the situation in which the area of an artificial valve is smaller than that of a healthy native valve it replaces. By this definition, all artificial valves demonstrate PPM, but large observational studies and several meta-analyses suggest that it is present in 30-50% of patients after surgical aortic valve replacement (SAVR). PPM has an impact on outcomes only when the indexed aortic valve area (AVAi) is ≤0.85cm2/m2 (moderate PPM) or 0.65cm2/m2 (severe PPM), particularly in patients with reduced LVEF. In transcatheter aortic valve replacement, the prevalence of PPM may be as low as 0.1%, and its impact on hard outcomes is not clear. We present a review of the relevant literature together with a framework for the differential diagnosis of increased pressure gradient and reduced area in prosthetic aortic valves and different strategies to reduce the risk of PPM with SAVR. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The association of non-alcoholic fatty liver disease (NAFLD) with aortic valve sclerosis (AVS) is gaining prominence in the context of both non-diabetic and type 2 diabetic populations. While AVS was once dismissed as an incidental echocardiographic observation, it's now recognized as a potential risk factor for adverse cardiovascular outcomes. Concurrently, NAFLD's ramifications extend beyond liver-associated complications, encompassing cardiovascular and renal anomalies. Aims & Objectives: This research aimed to unearth the correlation between NAFLD and AVS in patients with Type 2 Diabetes Mellitus, primarily focusing on the presence or absence of AVS in the context of ultrasonographically diagnosed NAFLD. Methods: A cross-sectional assessment spanning 12 months was undertaken at the Kempegowda Institute of Medical Sciences, Bangalore, including 100 patients diagnosed with both NAFLD and type 2 diabetes. Comprehensive evaluations, encompassing clinical assessments, blood tests, ultrasonography, and 2DECHO, formed the research's backbone. Findings: Among the cohort, 49% demonstrated a normal echocardiogram, while 51% exhibited signs of sclerotic aortic valve. Notably, male gender exhibited a significant correlation with 2D ECHO findings (p=0.046). Lipid profiles showed marked differences, particularly in triglycerides and LDL levels, between the two groups, with p-values less than 0.05. Other parameters showcased minimal variances, but the lipid profile variations were significantly high in the AVS group. Conclusion: The study underscores the tangible link between NAFLD and lipid irregularities in the backdrop of AVS in type 2 diabetic patients. Such findings accentuate the need for vigilant monitoring and targeted interventions for this demographic, given the overarching cardiovascular implications. [ABSTRACT FROM AUTHOR]

Background: Elevated levels of lipoprotein(a) [Lp(a)] represent a risk factor for cardiovascular disease including aortic valve stenosis, myocardial infarction and stroke. While the patho‐physiological mechanisms linking Lp(a) with atherosclerosis are not fully understood, from genetic studies that lower Lp(a) levels protect from CVD independently of other risk factors including lipids and lipoproteins. Hereby, Lp(a) has been considered an appealing pharmacological target. Results: However, approved lipid lowering therapies such as statins, ezetimibe or PCSK9 inhibitors have a neutral to modest effect on Lp(a) levels, thus prompting the development of new strategies selectively targeting Lp(a). These include antisense oligonucleotides and small interfering RNAs (siRNAs) directed towards apolipoprotein(a) [Apo(a)], which are in advanced phase of clinical development. More recently, additional approaches including inhibitors of Apo(a) and gene editing approaches via CRISPR‐Cas9 technology entered early clinical development. Conclusion: If the results from the cardiovascular outcome trials, designed to demonstrate whether the reduction of Lp(a) of more than 80% as observed with pelacarsen, olpasiran or lepodisiran translates into the decrease of cardiovascular mortality and major adverse cardiovascular events, will be positive, lowering Lp(a) will become a new additional target in the management of patients with elevated cardiovascular risk. [ABSTRACT FROM AUTHOR]

Calcific aortic valve disease (CAVD) predominantly affects the elderly and currently lacks effective medical treatments. Nesfatin-1, a peptide derived from the cleavage of Nucleobindin 2, has been implicated in various calcification processes, both physiological and pathological. This study explores the impact of Nesfatin-1 on the transformation of aortic valve interstitial cells (AVICs) in CAVD. In vitro experiments showed that Nesfatin-1 treatment mitigated the osteogenic differentiation of AVICs. Corresponding in vivo studies demonstrated a deceleration in the progression of CAVD. RNA-sequencing of AVICs treated with and without Nesfatin-1 highlighted an enrichment of the Ferroptosis pathway among the top pathways identified by the Kyoto Encyclopedia of Genes and Genomes analysis. Further examination confirmed increased ferroptosis in both calcified valves and osteoblast-like AVICs, with a reduction in ferroptosis following Nesfatin-1 treatment. Within the Ferroptosis pathway, ZIP8 showed the most notable modulation by Nesfatin-1. Silencing ZIP8 in AVICs increased ferroptosis and osteogenic differentiation, decreased intracellular Mn2+ concentration, and reduced the expression and activity of superoxide dismutase (SOD2). Furthermore, the silencing of SOD2 exacerbated ferroptosis and osteogenic differentiation. Nesfatin-1 treatment was found to elevate the expression of glutathione peroxidase 4 (GPX4) and levels of glutathione (GSH), as confirmed by Western blotting and GSH concentration assays. In summary, Nesfatin-1 effectively inhibits the osteogenic differentiation of AVICs by attenuating ferroptosis, primarily through the GSH/GPX4 and ZIP8/SOD2 pathways. A schematic model is presented to demonstrate the protective effects of Nesfatin-1 against aortic valve calcification in aortic valve interstitial cells (AVICs). This protection occurs through the regulation of ferroptosis, facilitated by the GSH/GPX4 and ZIP8/SOD2 axes. [Display omitted] • Nesfatin-1 could inhibit AVICs osteogenic differentiation in vitro. • Nesfatin-1 treatment reduces AVICs' osteogenic differentiation, a potential therapy for CAVD. • Ferroptosis is involved in Nesfatin-1 inhibiting AVICs osteogenic differentiation. • GSH/GPX4 and ZIP8/SOD2 axes mediate the reduced ferroptosis level. [ABSTRACT FROM AUTHOR]

Prosthetic heart valves (PHVs) are employed to replace the diseased native valve as a treatment of severe aortic valve disease. This study aimed to evaluate the effect of curvature of the belly curve on valve performance, so as to support a better comprehension of the relationship between valve design and its performance. Five PHV models with different curvatures of the belly curve were established. Iterative implicit fluid–structure interaction simulations were carried out, analyzing in detail the effect of belly curvature on the geometric orifice area (GOA), coaptation area (CA), regurgitant fraction (RF), leaflet kinematics and stress distribution on the leaflets. Overall, GOA and CA were negatively and positively related to the curvature of the belly curve, respectively. Nevertheless, an excessive increase in curvature can lead to incomplete sealing of free edges of the valve during its closure, which resulted in a decrease in CA and an increase in regurgitation. The moderate curvature of the belly curve contributed to reducing RF and fluttering frequency. Valves with small curvature experienced a significantly higher frequency of fluttering. Furthermore, all stress concentrations intensified with the increase in the curvature of the belly curve. The valve with moderate curvature of the belly curve strikes the best compromise between valve performance parameters, leaflet kinematics and mechanical stress. Considering the different effects of the curvature of belly curve on valve performance parameters, the PHV design with variable curvature of belly curve may be a direction towards valve performance optimization. [ABSTRACT FROM AUTHOR]

Purpose: Transcatheter aortic valve replacement (TAVR) induced coronary artery obstruction (CAO) is a rare but devastating complication. Current preventive strategies need additional procedures and may be associated with adverse events. This study aimed to evaluate the early safety and efficacy of stand-alone TAVR using the J-Valve (Jianshi JieCheng Medical Technology Co. Ltd, Shanghai, China) in patients at potential high risk for CAO. Patients and Methods: CAO was defined as coronary ostia obstruction requiring intervention. Patients at potential high risk for CAO were identified retrospectively from 673 consecutive patients who underwent TAVR from January 2015 to July 2021 at Zhongshan Hospital, Fudan University. Procedural results and early outcomes were evaluated according to Valve Academic Research Consortium-3 definitions. Results: A total of 20 consecutive patients (age 72 ± 9 years; 85% female;) were included. The Society of Thoracic Surgeons-Predicted Risk of Mortality was 5% (interquartile range, 4 to 10%). All patients (100%) had at least 2 classical risk factors for CAO by pre-procedural computed tomography analysis, and 90% patients had native aortic valve diseases. TAVR was successful in 95% of cases, with only 1 patient requiring second device implantation. Early safety at 30 days was achieved in all cases without death. All patients were free from CAO, stroke or emergency reintervention. Post-procedural mean aortic valve gradient was 7 (interquartile range, 4, 12) mmHg, and none/trace or mild aortic regurgitation was present in all patients. Conclusion: Stand-alone TAVR using the J-Valve may mitigate the risk of TAVR-induced CAO. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This document, titled "Oxidative Stress: The Hidden Catalyst Fueling Atherosclerosis and Cardiovascular Disease," explores the role of oxidative stress in the development and progression of atherosclerosis, a condition characterized by inflammation of arterial vessels that can lead to serious cardiovascular outcomes. The article discusses various risk factors for atherosclerosis, such as smoking, dyslipidemia, obesity, hypertension, and diabetes, which contribute to endothelial dysfunction and the formation of atherosclerotic plaques. It also highlights the role of oxidative stress in this process, including the production of reactive oxygen species (ROS) and the damage they can cause to cells and tissues. The document presents several studies that investigate the impact of oxidative stress on atherosclerosis and potential therapeutic approaches to modulate this pathway. However, it acknowledges that there are other mechanisms and pathways involved in atherosclerosis that were not covered in this special issue. The article concludes by emphasizing the need for further research, particularly larger human studies and randomized controlled trials, to fully understand the clinical impact of antioxidant therapies in atherosclerosis and its complications. [Extracted from the article]

Background Aim Methods Results Conclusion Infective endocarditis (IE) is a severe infection with considerable mortality. It is associated with geographical variation, complicating diagnosis and treatment of patients in a standardised manner.To evaluate the characteristics and management outcomes of patients with IE in Royal Perth Hospital (RPH).A single‐centre, retrospective cohort study. Data were collected from medical records of 131 patients with a diagnosis of IE admitted to RPH between 2016 and 2021.Eighty‐four patients with definite IE were included for analysis. The median age of patients was 51.5 years and 77.4% were male. Compared to the general Australian population, there was disproportionately greater representation of Indigenous Australians (21.4%), those with a history of injecting drug use (IDU) (27.4%), rheumatic heart disease (14.3%) and previous IE (13.1%). The most commonly affected valve was the mitral valve in 46.4% of patients, and the most common pathogen was Staphylococcus aureus in 47.6% of patients. Twelve‐month mortality was 16.7%, with significantly increased mortality in those treated non‐surgically (25.6% vs 7.3%, P = 0.025). Factors associated with undergoing surgery included the presence of aortic valve disease, perivalvular extension of infection and infection with Enterococcus faecalis, whereas IDU, tricuspid valve disease and S. aureus infection were associated with non‐surgical management. Adherence to multidisciplinary team review was 75.0%, and surgical management was performed in 70.7% of patients meeting an indication for surgery.IE mortality rates remain high, particularly in patients who do not undergo surgical management. Streamlined MDT assessment and referral for surgical management where appropriate is necessary to improve outcomes. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are the main cause of death in the world and cardiovascular imaging techniques are the mainstay of noninvasive diagnosis. Aortic stenosis is a lethal cardiac disease preceded by aortic valve calcification for several years. Data-driven tools developed with Deep Learning (DL) algorithms can process and categorize medical images data, providing fast diagnoses with considered reliability, to improve healthcare effectiveness. A systematic review of DL applications on medical images for pathologic calcium detection concluded that there are established techniques in this field, using primarily CT scans, at the expense of radiation exposure. Echocardiography is an unexplored alternative to detect calcium, but still needs technological developments. In this article, a fully automated method based on Convolutional Neural Networks (CNNs) was developed to detect Aortic Calcification in Echocardiography images, consisting of two essential processes: (1) an object detector to locate aortic valve – achieving 95% of precision and 100% of recall; and (2) a classifier to identify calcium structures in the valve – which achieved 92% of precision and 100% of recall. The outcome of this work is the possibility of automation of the detection with Echocardiography of Aortic Valve Calcification, a lethal and prevalent disease. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: Chronic kidney disease (CKD) is a risk factor for the development of cardiovascular diseases, e.g., atherosclerosis and calcific aortic valve disease, leading inevitably to valve replacement surgery. CKD patients with bioprosthetic cardiovascular grafts, in turn, have a higher risk of premature graft degeneration. Peroxisome proliferator-activated receptor gamma (PPARγ) activation by pioglitazone has cardio-renal protective properties, and research using a heterotopic valve implantation model has shown anti-degenerative effects of PPARγ activation on bioprosthetic valved grafts (BVG) in rats. The present work aims to analyze a potential protective effect of pioglitazone treatment on BVG in an adenine-induced rat model of CKD. Methods and Results: BVG of Sprague Dawley rats were heterotopically implanted in Wistar rats in an infrarenal position for 4 and 8 weeks. Animals were distributed into three groups for each time point: 1) control group receiving standard chow, 2) CKD group receiving 0.25% adenine and 3) CKD + pioglitazone group (300 mg per kg of 0.25% adenine chow). BVG function was analyzed by echocardiography. Plasma analytes were determined and explanted grafts were analyzed by semi-quantitative real-time PCR, Western blot analysis, histology and immunohistology. PPARγ activation significantly reduced CKD-induced calcification of aortic and valvular segments of BVG by 44% and 53%, respectively. Pioglitazone treatment significantly also reduced CKD-induced intima hyperplasia by 60%. Plasma analysis revealed significantly attenuated potassium and phosphate levels after pioglitazone treatment. Moreover, PPARγ activation led to significantly decreased interleukin-6 gene expression (by 57%) in BVG compared to CKD animals. Pioglitazone treatment leads to functional improvement of BVG. Conclusion: This study broadens the understanding of the potential value of PPARγ activation in cardio-renal diseases and delineates pioglitazone treatment as a valuable option to prevent bioprosthetic graft failure in CKD. Further mechanistic studies, e.g., using small molecules activating PPARγ signaling pathways, are necessary for the evaluation of involved mechanisms. Additionally, the translation into pre-clinical studies using large animals is intended as the next research project. [ABSTRACT FROM AUTHOR]

Infective endocarditis (IE) poses a significant clinical challenge, especially among patients with end-stage renal disease (ESRD) undergoing dialysis, and is associated with high morbidity and mortality rates. This review provides a contemporary discussion of the epidemiology, risk factors, diagnostic challenges, and management strategies for IE among ESRD patients, including a literature review of recent studies focused on this vulnerable population. The review highlights the multifactorial nature of IE risk in ESRD patients, emphasizing the roles of vascular access type, dialysis modality, and comorbid conditions. It also explores the diagnostic utility of different imaging modalities and the importance of a multidisciplinary approach in managing IE, including both medical and surgical interventions. The insights from this review aim to contribute to the improvement of patient outcomes through early recognition, appropriate antimicrobial therapy, and timely surgical intervention when necessary. [ABSTRACT FROM AUTHOR]

Valvular heart disease is a common cause of morbidity and mortality worldwide and has no effective medical therapy. Severe disease is managed with valve replacement procedures, which entail high health care-related costs and postprocedural morbidity and mortality. Robust ongoing research programs have elucidated many important molecular pathways contributing to primary valvular heart disease. However, there remain several key challenges inherent in translating research on valvular heart disease to viable molecular targets that can progress through the clinical trials pathway and effectively prevent or modify the course of these common conditions. In this scientific statement, we review the basic cellular structures of the human heart valves and discuss how these structures change in primary valvular heart disease. We focus on the most common primary valvular heart diseases, including calcific aortic stenosis, bicuspid aortic valves, mitral valve prolapse, and rheumatic heart disease, and outline the fundamental molecular discoveries contributing to each. We further outline potential therapeutic molecular targets for primary valvular heart disease and discuss key knowledge gaps that might serve as future research priorities. [ABSTRACT FROM AUTHOR]

Aims: Data regarding the characterization and outcomes of patients with heart failure (HF) with mildly reduced ejection fraction (HFmrEF) is scarce. This study investigates the characteristics and prognostic impact of native aortic valve diseases (AVD) in patients with HFmrEF. Methods and results: Consecutive patients hospitalized with HFmrEF (i.e. left ventricular ejection fraction 41–49% and signs and/or symptoms of HF) were retrospectively included at one institution from 2016 to 2022. The prognostic impact of native aortic valve stenosis (AS), aortic valve regurgitation (AR) and mixed AVD (MAVD) was investigated for the primary endpoint of long‐term all‐cause mortality during a median follow‐up of 30 months. Kaplan–Meier, univariable and multivariable Cox proportional analyses were applied. From a total of 2106 patients hospitalized with HFmrEF, the prevalence of AS and AR was 16.5% and 31.2%, respectively (MAVD 7.8%). The presence of moderate/severe AS was associated with a higher risk of long‐term all‐cause mortality (44.8% vs. 28.7%; p = 0.001) and HF‐related rehospitalization (18.6% vs. 12.0%; p = 0.001), even after multivariable adjustment (mortality: hazard ratio [HR] 1.320; 95% confidence interval [CI] 1.035–1.684; p = 0.025; HF‐related rehospitalization: HR 1.570; 95% CI 1.101–2.241; p = 0.013). Interestingly, even mild AS was associated with increased risk of long‐term all‐cause mortality compared to patients without AS (HR 1.477; 95% CI 1.101–1.982; p = 0.009). In contrast, the presence of AR was not associated with long‐term outcomes after multivariable adjustment. Conclusions: The presence of AS, but not AR, was independently associated with increased risk of all‐cause mortality and HF‐related rehospitalization in patients with HFmrEF. Even milder stages of AS were associated with impaired prognosis. [ABSTRACT FROM AUTHOR]

Aortic valve disease is a significant health issue. Research on the effects of aortic sinus geometry and aortic valve motion during a heartbeat is imperative, as numerous valvular diseases are associated with blood flow near the heart valve. Changes in the internal space of the sinus and the formation of blood clots have been reported after the implantation of a transcatheter aortic valve, an artificial heart valve. Although the sinus shape and leaflet motion significantly affect the hemodynamic characteristics and platelet aggregation, the blood flow behaviors near the heart valve associated with clot formation have not been fully elucidated. This study conducted in vitro experiments to investigate the flow behavior near an aortic sinus model based on the sinus shape. Additionally, hemodynamic changes associated with variations in the aortic sinus geometry and leaflet length within an aortic sinus model under pulsatile-flow conditions were elucidated. In a curved sinus model, a large single vortex formed near the center of the sinus region. Meanwhile, the center of the vortex in the sinus region shifted during a cycle in an expanded sinus model. Furthermore, a small vortex remained where the leaflet was initiated, thus increasing the likelihood of thrombus formation. Thus, the curved sinus model is advantageous for preventing material accumulation by maintaining a large vortex structure. The experimental results confirmed that the aortic sinus shape and leaflet length affect the likelihood of thrombus formation inside the aortic sinus. [ABSTRACT FROM AUTHOR]

Background Severe aortic paravalvular leaks (PVLs) after surgical mechanical aortic valve replacement (AVR) represent a high risk for congestive heart failure, haemolysis, and infective endocarditis. This is the first reported case of distal radial artery (DRA) access for severe mechanical aortic PVL closure with a sequential double vascular plug guided by computed tomography angiography (CTA), transoesophageal echocardiography (TOE), and 3D TOE in an acute setting. Case summary A 51-year-old male presented with significant mixed aortic valve disease. Aortic valve replacement was performed (Slimline Bicarbon A-25 mm) according to guidelines. Four and 16 days later, a re-exploration was carried out due to pericardial effusion. Four months after discharge from rehabilitation, the patient was readmitted due to worsening dyspnoea on exertion and then at rest. Transthoracic echocardiography, TOE, and consequently, CTA, revealed severe PVL, following which the procedure of transcatheter PVL closure was chosen, with a preference for DRA access. After a CTA scan analysis and angiographic, TOE, and 3D TOE visualization of the leak, a 14/5 mm and a 10/5 mm vascular plug (AVPIII) were deployed to achieve good results. A 9-month clinical, echocardiographic, and CTA follow-up revealed good long-term results. Discussion For transcatheter PVL closure, CTA is helpful for not only vascular access planning, but also a visualization of the magnitude of the leak, location, and device planning. This case report demonstrates that the distal radial approach is feasible in patients with severe mechanical aortic valve PVL retrograde transcatheter closure. DRA access could possibly represent less bleeding and vascular access site complications when compared with femoral access and has some potential advantages over regular radial access. [ABSTRACT FROM AUTHOR]

Aortic valve replacement (AVR) is a critical procedure for patients with aortic valve diseases. This study compares the effectiveness of three minimally-invasive surgical approaches for AVR: totally thoracoscopic (TT), right anterior mini-thoracotomy, and upper mini-sternotomy. We analyzed retrospective data from 130 patients who underwent one of these surgeries, focusing on various factors such as duration of hospital stay, operation time, times for cardiopulmonary bypass and aortic cross-clamping, postoperative complications, levels of cardiac biomarkers, pain intensity using the Visual Analog Scale, and mid-term survival rates. Results show that while the TT method had the longest operation times, it also had the shortest hospital stays and faster pain reduction post-surgery. Although the TT group initially showed higher cardiac biomarker levels after surgery, these levels normalized by the third day, similar to the other groups. There were no significant differences in mid-term survival and major adverse cardiac and cerebrovascular event (MACCE) rates among the groups. These findings suggest that the TT method, despite longer surgical times, offers a quicker initial recovery, making it a viable option for AVR. [ABSTRACT FROM AUTHOR]

This manuscript represents the official position of the Korean Society of Echocardiography on valvular heart diseases. This position paper focuses on the clinical management of valvular heart diseases with reference to the guidelines recently published by the American College of Cardiology/American Heart Association and the European Society of Cardiology. The committee tried to reflect the recently published results on the topic of valvular heart diseases and Korean data by a systematic literature search based on validity and relevance. In part I of this article, we will review and discuss the current position of aortic valve disease in Korea. [ABSTRACT FROM AUTHOR]

Background: Surgical aortic valve replacement (SAVR) currently stands as a primary surgical intervention for addressing aortic valve disease in patients. This retrospective study focused on the role of the red blood cell distribution width (RDW) in predicting adverse outcomes among SAVR patients. Methods: The subjects for this study were exclusively derived from the Medical Information Mart for Intensive Care database (MIMIC IV 2.0). Kaplan‒Meier (K-M) curves and Cox proportional hazards regression models were employed to assess the correlation between RDW, one-year mortality, and postoperative atrial fibrillation (POAF). The smooth-fitting curves were used to observe the relative risk (RR) of RDW in one-year mortality and POAF. Furthermore, time-dependent receiver operating characteristic (ROC) curves, the continuous-net reclassification index (NRI), and integrated discrimination improvement (IDI) were employed for comprehensive assessment of the prognostic value of RDW. Results: Analysis of RDW revealed a distinctive inverted U-shaped relationship with one-year mortality, while its association with POAF appeared nearly linear. Cox multiple regression models showed that RDW > 14.35%, along with preoperative potassium concentration and perioperative red blood cell transfusion, were significantly linked to one-year mortality (K-M curves, log-rank P < 0.01). Additionally, RDW was associated with both POAF and prolonged hospital stays (P < 0.05). There was no significant difference in length of stay in ICU. Notably, the inclusion of RDW in the predictive models substantially enhanced its performance. This was evidenced by the time-dependent ROC curve (AUC = 0.829), NRI (P< 0.05), IDI (P< 0.05), and K-M curves (log-rank P< 0.01). Conclusions: RDW serves as a robust prognostic indicator for SAVR patients, offering a novel means of anticipating adverse postoperative events. [ABSTRACT FROM AUTHOR]

Transcatheter technologies triggered the recent revision of the guidelines that progressively widened the indications for the treatment of aortic stenosis. On the surgical realm, a technology avoiding the need for sutures to anchor the prosthesis to the aortic annulus has been developed with the aim to reduce the duration of cardiopulmonary bypass and simplify the process of valve implantation. In addition to a transcatheter aortic valve replacement (TAVR)-like stent that exerts a radial force, these so-called "rapid deployment valves" or "sutureless valves" for aortic valve replacement also have cuffs to improve sealing and reduce the risk of paravalvular leak. Despite promising, the actual advantage of sutureless valves over traditional surgical procedures (surgical aortic valve replacement) or TAVR is still debated. This review summarizes the current comparative evidence reporting outcomes of "sutureless valves" for aortic valve replacement to TAVR and surgical aortic valve replacement in the treatment of aortic valve stenosis. • The comparative safety and efficacy of sutureless (SuAVR) vs conventional aortic valve replacement surgery is currently under investigation. • Potential candidates for SuAVR include those undergoing concomitant procedures, complex reoperations in patients with frail aortic root tissue, minimally invasive aortic valve replacement procedures, and high-risk patients for whom TAVR is not suitable. • The Heart Team should participate in shared decision making with patients in the selection of valve replacement modality for aortic stenosis. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic fatty liver disease (NAFLD) has emerged as a predominant driver of chronic liver disease globally and is associated with increased cardiovascular disease morbidity and mortality. However, the association between NAFLD and calcific aortic valve disease remains unclear. We aimed to prospectively investigate the association between NAFLD and incident aortic valve calcification (AVC), as well as its genetic relationship with incident calcific aortic valve stenosis (CAVS). Methods: A post hoc analysis was conducted on 4226 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) database. We employed the adjusted Cox models to assess the observational association between NAFLD and incident AVC. Additionally, we conducted two-sample Mendelian randomization (MR) analyses to investigate the genetic association between genetically predicted NAFLD and calcific aortic valve stenosis (CAVS), a severe form of CAVD. We repeated the MR analyses by excluding NAFLD susceptibility genes linked to impaired very low-density lipoprotein (VLDL) secretion. Results: After adjustment for potential risk factors, participants with NAFLD had a hazard ratio of 1.58 (95% CI: 1.03-2.43) for incident AVC compared to those without NAFLD. After excluding genes associated with impaired VLDL secretion, the MR analyses consistently showed the significant associations between genetically predicted NAFLD and CAVS for 3 traits: chronic elevation of alanine aminotransferase (odds ratio = 1.13 [95% CI: 1.01-1.25]), imaging-based NAFLD (odds ratio = 2.81 [95% CI: 1.66-4.76]), and biopsy-confirmed NAFLD (odds ratio = 1.12 [95% CI: 1.01-1.24]). However, the association became non-significant when considering all NAFLD susceptibility genes. Conclusions: NAFLD was independently associated with an elevated risk of incident AVC. Genetically predicted NAFLD was also associated with CAVS after excluding genetic variants related to impaired VLDL secretion. [ABSTRACT FROM AUTHOR]

Background: The current study presents a novel and precise surgical technique for complete reconstruction of the aortic valve using glutaraldehyde-treated autologous pericardium in a patient with aortic valve disease and endocarditis. The technique aims to provide a more effective and reproducible method for aortic valve repair, with the goal of improving outcomes and quality of life for patients with aortic valve disease. Case presentation: A 35-year-old Iranian male with aortic valve disease and endocarditis underwent aortic valve reconstruction surgery. Preoperative echocardiography showed a degenerative aortic valve with severe regurgitation, reduced left ventricular ejection fraction, and specific aortic root dimensions. The surgical technique involved precise measurements and calculations to design the size and shape of the new aortic valve cusps using autologous pericardium, with the goal of optimizing coaptation and function. The surgeon calculated the intercommissural distance based on the aortic annulus diameter to determine cusp size and shape. He tailored the pericardial cusps to have a height equal to 80% of the coaptation margin length. Detailed suturing techniques were used to ensure proper alignment and coaptation of the new cusps. Intraoperative evaluation of the valve function using suction and transesophageal echocardiography showed good coaptation and minimal residual regurgitation. At the 3-year follow-up, the patient had a well-functioning aortic valve with only trivial leak and was in satisfactory clinical condition. Conclusions: Glutaraldehyde-treated autologous pericardium is a validated leaflet alternative, and the causes of its failure are late annular dilatation and other technique breakdowns. Current evidence reveals that aortic valve reconstruction with glutaraldehyde-treated autologous pericardium is associated with many advantages with the potential to improve patient outcomes and quality of life. Further clinical studies are warranted to evaluate the long-term durability and efficacy of this approach. [ABSTRACT FROM AUTHOR]

Introduction: Non-invasive detection of pathological changes in thoracic aortic disease remains an unmet clinical need particularly for patients with congenital heart disease. Positron emission tomography combined with magnetic resonance imaging (PET-MRI) could provide a valuable low-radiation method of aortic surveillance in high-risk groups. Quantification of aortic microcalcification activity using sodium [18F]fluoride holds promise in the assessment of thoracic aortopathies. We sought to evaluate aortic sodium [18F]fluoride uptake in PET-MRI using three methods of attenuation correction compared to positron emission tomography computed tomography (PET-CT) in patients with bicuspid aortic valve, Methods: Thirty asymptomatic patients under surveillance for bicuspid aortic valve disease underwent sodium [18F]fluoride PET-CT and PET-MRI of the ascending thoracic aorta during a single visit. PET-MRI data were reconstructed using three iterations of attenuation correction (Dixon, radial gradient recalled echo with two [RadialVIBE-2] or four [RadialVIBE-4] tissue segmentation). Images were qualitatively and quantitatively analysed for aortic sodium [18F]fluoride uptake on PET-CT and PET-MRI. Results: Aortic sodium [18F]fluoride uptake on PET-MRI was visually comparable with PET-CT using each reconstruction and total aortic standardised uptake values on PET-CT strongly correlated with each PET-MRI attenuation correction method (Dixon R = 0.70; RadialVIBE-2 R = 0.63; RadialVIBE-4 R = 0.64; p < 0.001 for all). Breathing related artefact between soft tissue and lung were detected using Dixon and RadialVIBE-4 but not RadialVIBE-2 reconstructions, with the presence of this artefact adjacent to the atria leading to variations in blood pool activity estimates. Consequently, quantitative agreements between radiotracer activity on PET-CT and PET-MRI were most consistent with RadialVIBE-2. Conclusion: Ascending aortic microcalcification analysis in PET-MRI is feasible with comparable findings to PET-CT. RadialVIBE-2 tissue attenuation correction correlates best with the reference standard of PET-CT and is less susceptible to artefact. There remain challenges in segmenting tissue types in PET-MRI reconstructions, and improved attenuation correction methods are required. [ABSTRACT FROM AUTHOR]

OBJECTIVES The potential risk of autograft dilatation and homograft stenosis after the Ross procedure mandates lifelong follow-up. This retrospective cohort study aimed to determine long-term outcome of the Ross procedure, investigating autograft and homograft failure patterns leading to reintervention. METHODS All adults who underwent the Ross procedure between 1991 and 2018 at the University Hospitals Leuven were included, with follow-up data collected retrospectively. Autograft implantation was performed using the full root replacement technique. The primary end-point was long-term survival. Secondary end-points were survival free from any reintervention, autograft or homograft reintervention-free survival, and evolution of autograft diameter, homograft gradient and aortic regurgitation grade over time. RESULTS A total of 173 adult patients (66% male) with a median age of 32 years (range 18–58 years) were included. External support at both the annulus and sinotubular junction was used in 38.7% (67/173). Median follow-up duration was 11.1 years (IQR, 6.4–15.9; 2065 patient-years) with 95% follow-up completeness. There was one (0.6%) perioperative death. Kaplan–Meier estimate for 15-year survival was 91.1% and Ross-related reintervention-free survival was 75.7% (autograft: 83.5%, homograft: 85%). Regression analyses demonstrated progressive neoaortic root dilatation (0.56 mm/year) and increase in homograft gradient (0.72 mmHg/year). CONCLUSIONS The Ross procedure has the potential to offer excellent long-term survival and reintervention-free survival. These long-term data further confirm that the Ross procedure is a suitable option in young adults with aortic valve disease which should be considered on an individual basis. [ABSTRACT FROM AUTHOR]

The JAK2 V617F somatic variant is a well-known driver of myeloproliferative neoplasms (MPN) associated with an increased risk for athero-thrombotic cardiovascular disease. Recent studies have demonstrated its role in the development of thoracic aortic aneurysm (TAA). However, limited clinical information and level of JAK2 V617F burden have been provided for a comprehensive evaluation of potential confounders. A retrospective genotype-first study was conducted to identify carriers of the JAK2 V617F variant from an internal exome sequencing database in Yale DNA Diagnostics Lab. Additionally, the overall incidence of somatic variants in the JAK2 gene across various tissue types in the healthy population was carried out based on reanalysis of SomaMutDB and data from the UK Biobank (UKBB) cohort to compare our dataset to the population prevalence of the variant. In our database of 12,439 exomes, 594 (4.8%) were found to have a thoracic aortic aneurysm (TAA), and 12 (0.049%) were found to have a JAK2 V617F variant. Among the 12 JAK2 V617F variant carriers, five had a TAA (42%), among whom four had an ascending TAA and one had a descending TAA, with a variant allele fraction ranging from 11.2% to 20%. Among these five patients, 60% were female, and average age at diagnosis was 70 (49–79). The mean ascending aneurysm size was 5.05 cm (range 4.6–5.5 cm), and four patients had undergone surgical aortic replacement or repair. UKBB data revealed a positive correlation between the JAK2 V617F somatic variant and aortic valve disease (effect size 0.0086, p = 0.85) and TAA (effect size = 0.004, p = 0.92), although not statistically significant. An unexpectedly high prevalence of TAA in our dataset (5/594, 0.84%) is greater than the prevalence reported before for the general population, supporting its association with TAA. JAK2 V617F may contribute a meaningful proportion of otherwise unexplained aneurysm patients. Additionally, it may imply a potential JAK2-specific disease mechanism in the developmental of TAA, which suggests a possible target of therapy that warrants further investigation. [ABSTRACT FROM AUTHOR]