Sex differences in calcific aortic valve disease (CAVD) progressing to aortic valve stenosis have been documented clinically, but the underlying cellular mechanisms that drive sex-dependent fibrocalcification in aortic valve tissue remain poorly understood. Human aortic valve tissues were analyzed via histological techniques and scanning electron microscopy to visualize and quantify sites of calcification. Single-cell and spatial transcriptomics were used to investigate mechanisms that drive sex-dependent spatial organization of valvular interstitial cell (VIC) and macrophage gene expression near calcification sites in human male and female aortic valve tissues. RNA in situ hybridization was used to validate sex-dependent gene expression near sites of calcification, and cell communication analyses were performed using bioinformatics tools to determine sex-dependent pathological cell-cell interactions. Histological analyses of aortic valve tissues from healthy patients and patients with CAVD reveal increased valve calcification area in CAVD male aortic valves relative to female valves. Single-cell sequencing analysis of heterogeneous VIC populations reveals male-biased gene expression of the AP-1 (activator protein 1) transcription factor complex and female-biased ECM (extracellular matrix) remodeling genes. Spatial transcriptomics analyses of VIC populations near histologically defined calcification sites revealed male-dependent localization of COMP or cartilage oligomeric matrix protein, as opposed to nonlocalized COMP expression in female VICs. Female CAVD tissues with increased fibrotic density had elevated expression of SERPINE1, encoding PAI-1 (plasminogen activator inhibitor-1), relative to male tissues. Female CAVD tissues also exhibited increased macrophage count heterogeneity relative to male tissues. Candidate ligand-receptor interactions, including osteopontin (SPP1) interacting with CD44, which encodes a cell-surface glycoprotein, were identified as contributors to inflammation-mediated CAVD. Our results reveal sex differences in VIC and macrophage heterogeneity and functions near sites of calcification in aortic valve tissue. Our results highlight the importance of sex-based transcriptomics analyses to understand the cellular phenotypes responsible for causing sex differences in aortic valve fibrocalcification.

Postoperative high-grade atrioventricular block is prevalent following congenital aortic valve, root and left ventricular outflow tract (LVOT) surgery. We aimed to evaluate the application of presurgical cardiac computed tomography (CT) estimation of the conduction axis in mitigating this issue. Patients with congenital aortic valve, root and LVOT disease evaluated and operated in our center from February 2022 to August 2025 who underwent presurgical CT with intact central fibrous body were included. Anatomical landmarks were used to estimate the atrioventricular node (point A), His bundle course (point B), and left bundle branch origin (point C) relative to the aortic virtual basal ring plane, and guide avoidance during cardiac surgery. Fifty-three patients were included (mean age, 32 years [range, 2-68 years]; 72% male). The most common diagnoses were bileaflet (70%) and unileaflet (10%) aortic valves, and LVOT obstruction (7%). Points A, B, and C were located at a mean depth of +11.8 ± 4.8 mm, +3.3 ± 3.2 mm, and +1.5 ± 2.7 mm inferior to the aortic virtual basal ring plane, respectively. Some form of aortic valve repair was performed in 38 patients (72%). The remaining 15 patients (28%) underwent some form of aortic valve replacement. One patient (1.9%) developed high-grade atrioventricular block with permanent pacemaker insertion, with subsequent spontaneous resolution. This incidence compared favorably to our prior report of 10% in a similar cohort without pre-surgical CT conduction system estimation. This CT-based conduction axis estimation may mitigate conduction damage risk during congenital LVOT, aortic valve, and root surgery. Further prospective multisurgeon, multicenter studies are necessary to validate this approach.

Calcific aortic valve disease, commonly manifesting as aortic stenosis, is a leading cause of mortality with no effective therapy. We previously identified CROT (carnitine O-octanoyltransferase) as a mediator of mitochondrial dysfunction and vascular calcification; however, its role in calcific aortic valve disease is unknown. We investigated whether CROT promotes calcific aortic valve disease progression through the release of procalcific mitochondria-derived extracellular vesicles (mitoEVs). Human valvular interstitial cells were isolated from aortic valves of patients with aortic stenosis (n=49; n=34 males, n=15 females). Calcification was induced with osteogenic medium and assessed by Alizarin red. Proteomics compared valvular interstitial cells cultured in normal medium or osteogenic medium following scramble or CROT siRNA to define CROT-dependent pathways. Mitochondrial function was evaluated by Seahorse XF analysis (oxygen consumption rate) and morphology by MitoTracker staining. Extracellular vesicles were isolated by ultracentrifugation and characterized using NanoSight Pro. In vivo, aortic stenosis was induced by aortic valve wire injury in Ldlr-/-Crot+/+ (Sham, n=12; aortic valve wire injury, n=19) and Ldlr-/-Crot-/- (aortic valve wire injury, n=23) mice. Disease progression was monitored by echocardiography, and calcification was visualized using OsteoSense680EX imaging. CROT silencing significantly reduced osteogenic medium-induced calcification in valvular interstitial cells (P<0.05). Proteomics revealed alterations in mitochondria-associated proteins following siCROT. Osteogenic medium-induced mitochondrial fragmentation and increased mitoEV release were attenuated by CROT silencing. Immunofluorescence revealed mitoEVs localized to calcified extracellular regions. In vivo, CROT deficiency reduced valvular calcification and attenuated aortic stenosis progression. Osteogenic stress drives mitochondrial fragmentation and procalcific mitoEV release. CROT inhibition restores mitochondrial homeostasis, reduces mitoEV release and calcification, identifying CROT as a potential therapeutic strategy for calcific aortic valve disease.

Despite the technically challenging nature of valve-sparing root replacement, restoration of aortic valve competence can be achieved through a complete understanding of the aortic root anatomy and pathophysiology. In this review, we discuss the physiology of normal aortic root function as well as pathophysiologic mechanisms contributing to aortic valve incompetence. Preoperative planning for valve-sparing root replacement is discussed, including the use of imaging to guide surgical decision-making. Pitfalls and pearls of the critical technical steps for both valve-sparing root replacement and repair of both tricuspid and bicuspid aortic valves are provided. Finally, current evidence guiding best practices in valve-sparing root replacement and aortic valve repair is presented to support decision-making for patient selection.

The internal geometric annuloplasty ring is the only commercially available aortic annuloplasty ring designed to reduce and prevent annular dilatation during aortic valve repair; however, data regarding its long-term durability remain limited. Here we present our mid-term outcomes. A retrospective review was conducted of all adult patients who underwent aortic valve repair using the internal geometric annuloplasty ring between January 2017 and May 2025. Patients requiring valve reintervention were included in the analysis. Eighteen aortic valve repairs were performed in 17 patients (mean age, 54 ± 15 years; 16 males; 14 tricuspid valves, 2 bicuspid valves, 1 unicuspid valve), including 1 redo repair. Ten cases (56%) involved concomitant aortic root remodeling. Tricuspid 21-mm rings were used most frequently (61%). During a mean follow-up of 3.7 ± 1.7 years, 8 reinterventions were required in 7 patients (44%) owing to severe aortic insufficiency (AI; n = 7) or endocarditis with moderate AI (n = 1). The 5-year estimated reintervention rate was 40.8% (95% confidence interval, 20.0%-70.5%). Reinterventions included surgical aortic valve replacement (n = 5), redo internal geometric annuloplasty (n = 1), aortic root replacement (n = 1), and valve-in-ring transcatheter aortic valve replacement (n = 1). In surgical cases, postexplantation annular dimensions of the ring consistently returned to their preimplantation sizes. In our experience, 44% of patients receiving the internal geometric annuloplasty ring required aortic valve reintervention. Although effective in reducing annular size, the ring's rigid intra-annular design and the potential for excessive annular downsizing may predispose to recurrent insufficiency and limit future transcatheter options, prompting careful consideration of its broad application.

From the first aortic valve replacement (AVR) in 1960, surgical approaches evolved toward reduction of surgical invasiveness and enhanced recovery. Conventional minimally invasive approaches still require postoperative opioid use and chest restrictions. To further minimize aortic valve surgery, a robotic technique for transcervical AVR (TC-AVR) was developed to avoid major chest wall incisions and to facilitate expedited recovery. Following extensive cadaver simulations, the TC-AVR was performed in 7 patients between March and July 2025. The procedure includes cervical incision, similar to a thyroidectomy approach, representing a working port for robotic AVR. Cardiopulmonary bypass is established with femoral cannulation. After native valve excision, a conventional prosthetic valve is implanted with a running suture technique. Patients (mean age, 66 ± 8 years; 71% male) presented mostly with severe aortic stenosis, whereas a bicuspid aortic valve was present in 57%. Mean aortic cross-clamp and cardiopulmonary bypass times were 118 and 218 minutes, respectively, with reductions observed in later cases. There was no postimplantation aortic regurgitation, and intraoperative peak and mean gradients were 10 ± 5 mm Hg and 5 ± 2 mm Hg, respectively. There were no deaths. Postoperatively, no opioids were required for patients not needing reoperation (uncomplicated cases; n = 5), with mean in-hospital stay of 3.2 days (2-4 days). Patients resumed daily activities soon after discharge, unrestricted by chest precautions. Robotic TC-AVR is feasible, with the potential to offer superior patient recovery compared with traditional approaches. Accordingly, continued development of this technique and specialized instrumentation along with further safety evaluation are warranted and should be actively pursued.

Sex-specific gene expression signatures of calcific aortic valve stenosis in a large collection of human tissues.

Sutureless aortic valves, such as the Perceval (Corcym) valve, provide important procedural advantages and favorable mid- to long-term outcomes; however, potentially serious aortic complications related to their self-expanding stent structure remain incompletely understood. Thus, we report the case of an 85-year-old woman who developed early-onset localized ascending aortic dissection after aortic valve replacement with a sutureless valve. The entry tear was located at the level of the stent edge, slightly proximal to the aortotomy suture line, and the dissection extended only between these two points, suggesting a localized stent-aortic wall interaction with external mechanical stress as a potential trigger.

Isolated Transcatheter and Surgical Aortic Valve Replacement in the Evolut Low-Risk Trial: 5-Year Comparative Outcomes.

Left ventricular (LV) hypertrophy and dysfunction secondary to aortic stenosis (AS) are key components of the disease's underlying pathophysiology. Previous trials suggest that up to 1/3 of patients do not benefit symptomatically after aortic valve replacement (AVR), which could be explained by insufficient LV remodeling. Sodium‒glucose cotransporter-2 (SGLT2) inhibitors are effective in heart failure (HF) and have been shown to improve LV remodeling (change in LV mass). The EMPAVR study is an investigator-initiated, randomized, placebo-controlled, and double-blinded trial comparing the effect of empagliflozin to placebo in patients with severe and symptomatic AS undergoing transcatheter aortic valve implantation (TAVI). The primary outcome for the EMPAVR trial is the difference in LV mass indexed to body surface area (measured by cardiac CT) from pre-AVR to 6 months post-AVR. Patients are randomized in a 1:1 ratio to 180 days of treatment. To the best of our knowledge, the EMPAVR study is the first placebo-controlled trial investigating the effects of SGLT2 inhibition in patients following TAVI because of AS. The EMPAVR study has the potential to pave the way for treatment of the LV in valvular heart disease and may help patients worldwide and expand our understanding of aortic stenosis. The EMPAVR study was registered in December 2024 (Clinical Trial Registration number: NCT06171802) before enrollment of the first patient. All patients will provide oral and written informed consent. The EMPAVR study is approved by the Regional Committee on Health Research Ethics and the Danish Medicines Agency.

The LYSET gene encodes the LYSET transmembrane protein, which regulates lysosome biogenesis by activating the mannose-6-phosphate (M6P) pathway. This is an autosomal recessive, ultrarare, and severe progressive skeletal dysplasia with coarse facies, distended abdomen, short stature, and severe physical disability. In a diagnostic odyssey, we report a female patient, born in 2008, daughter of consanguineous parents, with hand contractures and a typical facial appearance since 5 months old. She was clinically diagnosed at 2 years old with contractures and severe dysplasia. Systolic murmur, thickening of mitral and aortic valves, and tricuspid regurgitation were observed. Nine enzymes showed increased levels in plasma, and seven showed decreased levels in fibroblasts. Abnormal sialic acid profile and GAGs (glycosaminoglycans) were detected in urine. No variants were identified during more than a decade of investigation. A whole-genome analysis identified the homozygous nonsense variant NM_001098621.4:c.112C>T (p.Gln38Ter) in the LYSET gene. The patient had not been diagnosed before due to the recent association of the gene with the lysosomal hydrolase labeling pathway. She died in 2018 from respiratory causes. The discovery of the relationship between the LYSET gene and lysosomal biogenesis was determinative of the diagnostic conclusion. Cases of dysostosis multiplex can be highly challenging due to the rarity of the disease and its clinical similarity to mucopolysaccharidosis (MPS) and mucolipidosis II/III (MLII/III). This is the first western report of a challenging case of an extensive diagnostic odyssey and demonstrates that the LYSET gene must be considered in the differential diagnosis when M6P-labeled lysosomal enzymes are altered.

Experimental Evaluation of a Large Fenestrated Physician-Modified Endo-Wheat Using a Cadaveric Model.

Percutaneous cardiac interventions in neonates and young infants have fundamentally altered the management paradigm of critical congenital heart disease, offering minimally invasive alternatives to surgery as definitive therapies or as bridges to later repair. Advances in catheter technology, device miniaturization, and imaging have enabled increasingly complex interventions to be performed safely in this highly vulnerable population. This review provides a comprehensive overview of commonly performed neonatal cardiac interventions, including balloon atrial septostomy, balloon dilatation of the aortic and pulmonary valves, ductal stenting, transcatheter patent ductus arteriosus closure in preterm infants, coarctation interventions, pulmonary valve perforation, right ventricular outflow tract stenting, pulmonary vein interventions, and emerging techniques such as percutaneous pulmonary artery banding. For each intervention, the authors outline indications, technical considerations, procedural outcomes, and limitations, with emphasis on neonatal-specific anatomical and physiological challenges. Neonatal cardiac interventions are inherently unforgiving, mandating meticulous patient selection and a structured multidisciplinary heart team approach to ensure ethical, evidence-based decision-making. The review also addresses unique challenges relevant to low- and middle-income settings, particularly India, including disparities in access to specialized care, affordability, reliance on off-label device use, and the critical role of fetal diagnosis. In conclusion, neonatal transcatheter interventions continue to expand in scope and efficacy, driven by technological innovation and collaborative care models. Addressing systemic barriers and strengthening fetal and neonatal cardiac services are essential to optimizing outcomes and ensuring equitable access to these life-saving therapies in resource-limited settings.

Long-Term Outcomes After Aortic Mechanical Valve Closure During Left Ventricular Assist Device Implantation: Comparison of "Gap-Filler" and “Sandwich” Techniques After over Six Years of Support

Fractional flow reserve-guided percutaneous coronary intervention for transcatheter aortic valve implantation: a FAITAVI accompli for better outcomes?

Design and rationale of the Impella®-protected cardiac surgery trial (IMPACT): A multicenter, single-arm pilot study in high-risk cardiac surgery patients.

Postoperative pulmonary decline is an established complication of open-heart surgery extending beyond the immediate postoperative phase. Inflammation-mediated lung damage and ischaemia-reperfusion injury secondary to extracorporeal circulation is a proposed pathophysiological driver. GLP-1 receptor agonists (GLP-1RA) have emerged as promising protective agents in this setting. Investigate whether infusion of the GLP-1RA, exenatide during cardiopulmonary bypass and weaning thereof, can mitigate the decline in diffusing capacity and ventilatory performance 3 months postoperative, compared to placebo. In this predefined explorative substudy of the randomised, clinical GLORIOUS trial, 878 adult patients undergoing non-emergent coronary artery bypass grafting (CABG) and/or surgical aortic valve replacement (SAVR) were randomised to a continuous infusion of the GLP-1RA, exenatide or placebo during cardiopulmonary bypass, extending into the early postoperative period. Diffusing capacity of the lung for carbon monoxide (DLCO) and ventilatory performance (FEV1/FVC) were measured preoperatively and 3 months postoperatively. Median DLCO (% predicted corrected) declined from 80% preoperative to 72% 3 months postoperative, corresponding to a -7.7 percentage point (pp) difference (95% CI 6.2 to 9.1; p < 0.001). FEV1/FVC declined from 0.75 preoperative to 0.73 postoperative, corresponding to a -1.6 difference (95% CI 1.0 to 2.1; p < 0.001). However, there were no significant differences in decline between the exenatide and placebo groups (all p > 0.3). Findings were consistent across subgroup analyses. While both diffusing capacity and ventilatory performance exhibited a mild-to-moderate decline 3 months after open-heart surgery, the GLP-1RA exenatide did not mitigate this decline compared with placebo. Pulmonary dysfunction is one of the most common complications to open-heart surgery. The present study confirms a decline in diffusing capacity of the lung for carbon monoxide (DLCO) and in ventilatory performance measured as FEV1/FVC at 3 months postoperatively compared to preoperative measurements. Infusion of GLP-1 receptor antagonist during cardiopulmonary bypass and weaning did not mitigate the pulmonary decline compared to placebo.

Aortic Root Thrombus Following Transcatheter Aortic Valve Replacement in a Patient with HeartMate 3 Left Ventricular Assist Device Support

Design and rationale of the prospective, randomized, controlled trial to assess the management of moderate aortic stenosis by clinical surveillance or transcatheter aortic valve replacement: The PROGRESS Trial.

Aortic stenosis (AS) may lead to left ventricular (LV) hypertrophy (LVH). After aortic valve replacement (AVR), LVH often does not regress fully. This has been associated with a worse prognosis. This study aimed at comparing LVH regression between male and female patients and to discover cardiac molecular factors associated with it. Myocardial samples were collected from 18 patients (50% female) who underwent surgical AVR. Preoperative and postoperative LV mass indices (LVMi) were compared between male and female patients. Expression of ADGRL4 and AQP7 was quantified by PCR and assessed with relative regression of LVMi. High-depth RNA-sequencing data from LV free-wall tissues of subjects with heart failure were employed for RNA editing analysis. Male patients had significant LVH regression (P < 0.05) after AVR, while female patients did not (P = 0.116). In male patients, a significant relationship was found between the expression of ADGRL4 (P < 0.05, R2 = 0.497) and AQP7 (P < 0.05, R2 = 0.576) and LVMi regression after AVR. This relationship was insignificant for ADGRL4 (P = 0.704, R2 = 0.0220) and AQP7 (P = 0.860, R2 = 0.00477) in female patients. RNA editing analysis revealed significant sex-biased differences in intronic adenosine-to-inosine (A-to-I) editing of AQP7, with five positions, particularly within Alu elements, along with sex-biased predicted RBP binding motifs. Recognizing patients at risk of defective LVH regression using molecular factors could lead to more intensive postoperative follow-up and earlier treatment, consequently improving reverse remodeling and prognosis. The present findings warrant further research in a larger study.NEW & NOTEWORTHY Regression of left ventricular hypertrophy is associated with better long-term outcome. This study demonstrates a significant relationship between ADGRL4 and AQP7 gene expression in perioperatively collected myocardial tissues and the regression of left ventricular mass postoperatively in male patients with aortic stenosis only. This could contribute to the development of a sex-based tool to predict the extent of postoperative hypertrophy regression.