Type 2 Myocardial Infarction Caused by Orthostatic Hypotension With Post-transcatheter Aortic Valve Implantation: A Case Report.

This case report delineates the occurrence and management of type 2 myocardial infarction (MI) in an 89-year-old woman following transcatheter aortic valve implantation (TAVI). The patient, with a history of severe aortic stenosis, hypertension, dyslipidemia, and colorectal cancer, presented with nausea and significant hypotension. Initial assessments revealed elevated troponin levels, atrial fibrillation, and ST-segment depression, leading to a diagnosis of type 2 MI. This condition was attributed to the interplay between left ventricular hypertrophy, hypotension-induced dehydration, and increased myocardial oxygen demand. The patient with post-TAVI exhibited dynamic changes in cardiac hemodynamics, with improvements in left ventricular function but persistent hypertrophy and diastolic dysfunction. This state, combined with hypotension due to diuretic-induced dehydration and atrial fibrillation, precipitated a mismatch in myocardial oxygen supply and demand. The cessation of diuretics and initiation of rehydration therapy stabilized her condition, with subsequent normalization of troponin levels and blood pressure. This case highlights the complexity of managing type 2 MI in elderly patients post-TAVI. It underscores the importance of holistic consideration of both myocardial oxygen supply and demand factors, particularly in left ventricular hypertrophy and diastolic dysfunction. The multifactorial nature of type 2 MI necessitates a tailored approach to diagnosis and management, emphasizing the need for comprehensive post-procedural care in patients undergoing TAVI.

The gut microbe-derived metabolite trimethylamine-N-oxide induces aortic valve fibrosis via PERK/ATF-4 and IRE-1α/XBP-1s signaling in vitro and in vivo.

BACKGROUND AND AIMS: The gut microbe-derived metabolite trimethylamine-N-oxide (TMAO) has been implicated in the development of cardiovascular fibrosis. Endoplasmic reticulum (ER) stress occurs after the dysfunction of ER and its structure. The three signals PERK/ATF-4, IRE-1α/XBP-1s and ATF6 are activated upon ER stress. Recent reports have suggested that the activation of PERK/ATF-4 and IRE-1α/XBP-1s signaling contributes to cardiovascular fibrosis. However, whether TMAO mediates aortic valve fibrosis by activating PERK/ATF-4 and IRE-1α/XBP-1s signaling remains unclear. METHODS: Human aortic valve interstitial cells (AVICs) were isolated from aortic valve leaflets. PERK IRE-1α, ATF-4, XBP-1s and CHOP expression, and production of collagen Ⅰ and TGF-ß1 were analyzed following treatment with TMAO. The role of PERK/ATF-4 and IRE-1α/XBP-1s signaling pathways in TMAO-induced fibrotic formation was determined using inhibitors and small interfering RNA. RESULTS: Diseased valves produced greater levels of ATF-4, XBP-1, collagen Ⅰ and TGF-ß1. Interestingly, diseased cells exhibited augmented PERK/ATF-4 and IRE-1α/XBP-1s activation after TMAO stimulation. Inhibition and silencing of PERK/ATF-4 and IRE-1α/XBP-1s each resulted in enhanced suppression of TMAO-induced fibrogenic activity in diseased cells. Mice treated with dietary choline supplementation had substantially increased TMAO levels and aortic valve fibrosis, which were reduced by 3,3-dimethyl-1-butanol (DMB, an inhibitor of trimethylamine formation) treatment. Moreover, a high-choline and high-fat diet remodeled the gut microbiota in mice. CONCLUSIONS: TMAO promoted aortic valve fibrosis through activation of PERK/ATF-4 and IRE-1α/XBP-1s signaling pathways in vitro and in vivo. Modulation of diet, gut microbiota, TMAO, PERK/ATF-4 and IRE1-α/XBP-1s may be a promising approach to prevent aortic valve fibrosis.

Impact of the COVID-19 pandemic on provision of interventional cardiology and cardiac surgery services in Australia: a review of Medicare claims data.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has significantly impacted healthcare service provision worldwide. There is limited information on changes in invasive cardiovascular services during the pandemic, particularly in Australia. AIM: We sought to assess temporal trends on the use of interventional cardiology and cardiac surgery services before and following the COVID-19 pandemic in Australia. METHODS: Medicare Benefits Schedule items data from the Australian Government Services Australia on outpatient and private hospital interventional cardiology procedures (coronary angiogram, percutaneous coronary intervention and transcatheter aortic valve implantation) and cardiac surgery procedures (coronary artery bypass grafting [CABG] and surgical valve replacement, repair and annuloplasty) were analysed from March 2019 to 2021. This was superimposed on monthly COVID-19 case data obtained from the Australian Department of Health and Aged Care epidemiology reports. RESULTS: A sustained reduction in CABG (-10.1%) and surgical valve intervention (-11.1%) was appreciated from March 2019-2020 to March 2020-2021, in the first year of the COVID-19 pandemic. During this period, an overall increase (+25.9%) in the use of transcatheter aortic valve implantation was observed. Following the initial period of mandated isolation in March-April 2020, a reduction in coronary angiography (-29.1%) and percutaneous coronary intervention (-19.5%) was observed in comparison to March-April 2019; however, this was largely attenuated over time. CONCLUSIONS: The COVID-19 pandemic has resulted in reductions in the use of interventional cardiology and cardiac surgery services, with cardiac surgery most affected. However, an increase in uptake of transcatheter aortic valve implantation has been observed during the pandemic. This may have implications for future planning and resource allocation in the aftermath of the pandemic.

Considering alternatives to transcatheter heart valves for managing patients with severe aortic valve stenosis.

INTRODUCTION: Transcatheter aortic valve implantation (TAVI) is becoming the standard of care for severe symptomatic aortic stenosis (AS). Yet, some patients with AS are not indicated/eligible for TAVI. Several noninvasive, catheter-based or surgical alternatives exist, and other therapeutic options are emerging. AREAS COVERED: This review provides an overview of non-TAVI options for severe AS. Non-invasive, transcatheter, and alternative surgical strategies are discussed, emphasizing their backgrounds, techniques, and outcomes. EXPERT OPINION: Alternative therapies to TAVI, whether device-based or non-device-based, continue to evolve or emerge and provide either alternative treatments or a bridge to TAVI, for patients not meeting indications for, or having contraindications to TAVI.Although TAVI and SAVR are the current dominant therapies, there are still some patients that could benefit in the future from other alternatives.Data on alternative options for such patients are scarce. Many advantages and disadvantages arise when selecting a specific treatment strategy for individual patients.Head-to-head comparison studies could guide physicians toward better patient selection and procedural planning. Awareness of therapeutic options, indications, techniques, and outcomes should enable heart teams to achieve optimized patient selection. Furthermore, it can increase the use of these alternatives to optimize the management of AS among different patient populations.

Prevalence of Aortic Valve Calcium and the Long-Term Risk of Incident Severe Aortic Stenosis.

BACKGROUND: Aortic valve calcification (AVC) is a principal mechanism underlying aortic stenosis (AS). OBJECTIVES: This study sought to determine the prevalence of AVC and its association with the long-term risk for severe AS. METHODS: Noncontrast cardiac computed tomography was performed among 6,814 participants free of known cardiovascular disease at MESA (Multi-Ethnic Study of Atherosclerosis) visit 1. AVC was quantified using the Agatston method, and normative age-, sex-, and race/ethnicity-specific AVC percentiles were derived. The adjudication of severe AS was performed via chart review of all hospital visits and supplemented with visit 6 echocardiographic data. The association between AVC and long-term incident severe AS was evaluated using multivariable Cox HRs. RESULTS: AVC was present in 913 participants (13.4%). The probability of AVC >0 and AVC scores increased with age and were generally highest among men and White participants. In general, the probability of AVC >0 among women was equivalent to men of the same race/ethnicity who were approximately 10 years younger. Incident adjudicated severe AS occurred in 84 participants over a median follow-up of 16.7 years. Higher AVC scores were exponentially associated with the absolute risk and relative risk of severe AS with adjusted HRs of 12.9 (95% CI: 5.6-29.7), 76.4 (95% CI: 34.3-170.2), and 380.9 (95% CI: 169.7-855.0) for AVC groups 1 to 99, 100 to 299, and ≥300 compared with AVC = 0. CONCLUSIONS: The probability of AVC >0 varied significantly by age, sex, and race/ethnicity. The risk of severe AS was exponentially higher with higher AVC scores, whereas AVC = 0 was associated with an extremely low long-term risk of severe AS. The measurement of AVC provides clinically relevant information to assess an individual's long-term risk for severe AS.

Local versus General Anaesthesia for Transcatheter Aortic Valve Implantation (TAVI): A Systematic Review, Meta-Analysis, and Trial Sequential Analysis of Randomised and Propensity-Score Matched Studies.

Transcatheter aortic valve implantation (TAVI) is a common practice for severe aortic stenosis, but the choice between general (GA) and local anesthesia (LA) remains uncertain. We conducted a comprehensive literature review until April 2023, comparing the safety and efficacy of LA versus GA in TAVI procedures. Our findings indicate significant advantages of LA, including lower 30-day mortality rates (RR: 0.69; 95% CI [0.58, 0.82]; p < 0.001), shorter in-hospital stays (mean difference: -0.91 days; 95% CI [-1.63, -0.20]; p = 0.01), reduced bleeding/transfusion incidents (RR: 0.64; 95% CI [0.48, 0.85]; p < 0.01), and fewer respiratory complications (RR: 0.56; 95% CI [0.42, 0.76], p<0.01). Other operative outcomes were comparable. Our findings reinforce prior evidence, presenting a compelling case for LA's safety and efficacy. While patient preferences and clinical nuances must be considered, our study propels the discourse towards a more informed anaesthesia approach for TAVI procedures.

Improved Reversion of Calcifications in Porcine Aortic Heart Valves Using Elastin-Targeted Nanoparticles.

Calcified aortic valve disease in its final stage leads to aortic valve stenosis, limiting cardiac function. To date, surgical intervention is the only option for treating calcific aortic valve stenosis. This study combined controlled drug delivery by nanoparticles (NPs) and active targeting by antibody conjugation. The chelating agent diethylenetriaminepentaacetic acid (DTPA) was covalently bound to human serum albumin (HSA)-based NP, and the NP surface was modified using conjugating antibodies (anti-elastin or isotype IgG control). Calcification was induced ex vivo in porcine aortic valves by preincubation in an osteogenic medium containing 2.5 mM sodium phosphate for five days. Valve calcifications mainly consisted of basic calcium phosphate crystals. Calcifications were effectively resolved by adding 1-5 mg DTPA/mL medium. Incubation with pure DTPA, however, was associated with a loss of cellular viability. Reversal of calcifications was also achieved with DTPA-coupled anti-elastin-targeted NPs containing 1 mg DTPA equivalent. The addition of these NPs to the conditioned media resulted in significant regression of the valve calcifications compared to that in the IgG-NP control without affecting cellular viability. These results represent a step further toward the development of targeted nanoparticular formulations to dissolve aortic valve calcifications.

Comparison of post-operative pain and quality of life between total thoracoscopic surgery and conventional full-sternotomy for aortic valve replacement.

BACKGROUND: To compare the post-operative pain and quality of life of patients who underwent total thoracoscopic surgery (TTS) or conventional full-sternotomy (CFS) for aortic valve replacement (AVR). METHODS: We reviewed the records of 223 consecutive AVR patients with either TTS or CFS from January 2018 to December 2022. We used a visual analogue scale (VAS) and the Short Form-36 Health Survey (SF-36) to measure the post-operative pain and quality of life, respectively. We also compared the operative data and clinical outcomes between the two groups. RESULTS: The TTS group had lower adjusted mean VAS scores than the CFS group at all time points after surgery (at 1 to 3 days and at 3 and 6 months, p < .001 for all comparisons), indicating less pain. The TTS group also had higher mean SF-36 scores than the CFS group up to 6 months after surgery (p < .001 for all comparisons), indicating better quality of life. The operative time was similar between the two groups (p = .224), but the TTS group had longer cardiopulmonary bypass time and aortic cross-clamp time than the CFS group (p < .001). The TTS group had more pulmonary complications than the CFS group (p = .023). However, there were no significant differences in other major complications or mortality between the two groups. CONCLUSIONS: TTS is a safe and effective alternative to CFS for AVR. TTS resulted in less pain and better quality of life, especially in the early recovery period. However, further prospective randomized controlled studies are needed to confirm our findings.

Cardiac Virtual Noncontrast Images for Calcium Quantification with Photon-counting Detector CT.

Purpose: To assess the accuracy of aortic valve calcium (AVC), mitral annular calcium (MAC), and coronary artery calcium (CAC) quantification and risk stratification using virtual noncontrast (VNC) images from late enhancement photon-counting detector CT as compared with true noncontrast images. Materials and Methods: This retrospective, institutional review board-approved study evaluated patients undergoing photon-counting detector CT between January and September 2022. VNC images were reconstructed from late enhancement cardiac scans at 60, 70, 80, and 90 keV using quantum iterative reconstruction (QIR) strengths of 2-4. AVC, MAC, and CAC were quantified on VNC images and compared with quantification of AVC, MAC, and CAC on true noncontrast images using Bland-Altman analyses, regression models, intraclass correlation coefficients (ICC), and Wilcoxon tests. Agreement between severe aortic stenosis likelihood categories and CAC risk categories determined from VNC and true noncontrast images was assessed by weighted κ analysis. Results: Ninety patients were included (mean age, 80 years ± 8 [SD]; 49 male patients). Scores were similar on true noncontrast images and VNC images at 80 keV for AVC and MAC, regardless of QIR strengths, and VNC images at 70 keV with QIR 4 for CAC (all P > .05). The best results were achieved using VNC images at 80 keV with QIR 4 for AVC (mean difference, 3; ICC = 0.992; r = 0.98) and MAC (mean difference, 6; ICC = 0.998; r = 0.99), and VNC images at 70 keV with QIR 4 for CAC (mean difference, 28; ICC = 0.996; r = 0.99). Agreement between calcification categories was excellent on VNC images at 80 keV for AVC (κ = 0.974) and on VNC images at 70 keV for CAC (κ = 0.967). Conclusion: VNC images from cardiac photon-counting detector CT enables patient risk stratification and accurate quantification of AVC, MAC, and CAC.Keywords: Coronary Arteries, Aortic Valve, Mitral Valve, Aortic Stenosis, Calcifications, Photon-counting Detector CT Supplemental material is available for this article © RSNA, 2023.

Single-Stage Procedure of Transcatheter Aortic Valve Replacement and Endovascular Aneurysm Repair Under Local Anaesthesia and Percutaneous Access.

PURPOSE: Abdominal aortic aneurysms (AAA) are observed in 6% of patients with concomitant aortic valve stenosis (AS) requiring aortic valve replacement. Optimal management of these concomitant pathologies is still debated. CASE REPORT: An 80-year-old man presented with acute heart failure due to a severe AS. Past medical history included AAA under regular surveillance. A thoracic and abdominal computed tomography angiography (CTA) confirmed a 6 mm increase of AAA over an 8-month period (max 55 mm). A multidisciplinary team prescribed a simultaneous endovascular approach of transcatheter aortic valve implantation (TAVI) followed by endovascular aneurysm repair (EVAR) under local anaesthesia with bilateral femoral percutaneous access. No intra or post-procedural complications were registered; technical success was confirmed by completion angiography and post-operative ultrasound. The patient was discharged on postoperative day 5. A 2-month post-operative CTA confirmed ongoing technical success. CONCLUSION: Combined TAVI and EVAR under local anaesthesia for AS and AAA was associated with reduced hospital stay and technical success at 2 months from intervention in this case report.

Structural Heart Interventions in the Elderly Population.

Aortic stenosis is the most common valvular heart disease in the elderly population. Since the advent of transcatheter aortic valve implantation (TAVI) in 2002, the clinical indications for this alternative to a surgical replacement have continually expanded. While the treatment of octo- and nonagenarians can present significant challenges, here we present a case of TAVI in an elderly patient. Given her suitable anatomy and active lifestyle that had been limited by her disease state, the patient successfully underwent TAVI 3 weeks later and was discharged post-operative day 1. This case is the basis for providing five key points to remember about the work-up for TAVI for severe aortic stenosis in the elderly population.

Transcatheter aortic valve intervention in patients with cancer.

The prevalence of concurrent cancer and severe aortic stenosis (AS) is increasing due to an ageing population. In addition to shared traditional risk factors for AS and cancer, patients with cancer may be at increased risk for AS due to off-target effects of cancer-related therapy, such as mediastinal radiation therapy (XRT), as well as shared non-traditional pathophysiological mechanisms. Compared with surgical aortic valve replacement, major adverse events are generally lower in patients with cancer undergoing transcatheter aortic valve intervention (TAVI), especially in those with history of mediastinal XRT. Similar procedural and short-to-intermediate TAVI outcomes have been observed in patients with cancer as compared with no cancer, whereas long-term outcomes are dependent on cancer survival. Considerable heterogeneity exists between cancer subtypes and stage, with worse outcomes observed in those with active and advanced-stage disease as well as specific cancer subtypes. Procedural management in patients with cancer poses unique challenges and thus requires periprocedural expertise and close collaboration with the referring oncology team. The decision to ultimately pursue TAVI involves a multidisciplinary and holistic approach in assessing the appropriateness of intervention. Further clinical trial and registry studies are needed to better appreciate outcomes in this population.

Shockwaves delivery for aortic valve therapy-Realistic perspective for clinical translation?

Calcific aortic valve disease (CAVD) is the most frequent valvular heart disorder, and the one with the highest impact and burden in the elderly population. While the quality and standardization of the current aortic valve replacements has reached unprecedented levels with the commercialization of minimally-invasive implants and the design of procedures for valve repair, the need of supplementary therapies able to block or retard the course of the pathology before patients need the intervention is still awaited. In this contribution, we will discuss the emerging opportunity to set up devices to mechanically rupture the calcium deposits accumulating in the aortic valve and restore, at least in part, the pliability and the mechanical function of the calcified leaflets. Starting from the evidences gained by mechanical decalcification of coronary arteries in interventional cardiology procedures, a practice already in the clinical setting, we will discuss the advantages and the potential drawbacks of valve lithotripsy devices and their potential applicability in the clinical scenario.

Network-Guided Multiomic Mapping of Aortic Valve Calcification.

Despite devastating clinical sequelae of calcific aortic valve disease that range from left ventricular remodeling to arrhythmias, heart failure, and early death, the molecular insights into disease initiation and progression are limited and pharmacotherapies remain unavailable. The pathobiology of calcific aortic valve disease is complex and comprehensive studies are challenging valvular calcification is heterogeneous and occurs preferentially on the aortic surface, along a fibrocalcific spectrum. Here, we review efforts to study (epi-)genomic, transcriptomic, proteomic, and metabolomic aspects of aortic valve calcification in combination with network medicine-/systems biology-based strategies to integrate multilayered omics datasets and prioritize druggable targets for experimental validation studies. Ultimately, such holistic approach efforts may open therapeutic avenues that go beyond invasive and costly valve replacement therapy.

Antithrombotic therapy and cardiovascular outcomes after transcatheter aortic valve implantation in patients without indications for chronic oral anticoagulation: a systematic review and network meta-analysis of randomized controlled trials.

AIMS: As the antithrombotic regimen that may best prevent ischaemic complications along with the lowest bleeding risk offset following transcatheter aortic valve implantation (TAVI) remains unclear, we aimed to compare the safety and efficacy of antithrombotic regimens in patients without having an indication for chronic oral anticoagulation. METHODS AND RESULTS: We conducted a PROSPERO-registered (CRD42021247924) systematic review and network meta-analysis of randomized controlled trials evaluating post-TAVI antithrombotic regimens up to April 2022. We estimated the relative risk (RR) and 95% confidence intervals (95% CIs) using a random-effects model in a frequentist pairwise and network metanalytic approach. We included seven studies comprising 4006 patients with a mean weighted follow-up of 12.9 months. Risk of all-cause death was significantly reduced with dual antiplatelet therapy (DAPT) compared with low-dose rivaroxaban + 3-month single antiplatelet therapy (SAPT) (RR 0.60, 95% CI 0.41-0.88), while no significant reduction was observed with SAPT vs. DAPT (RR 1.02, 95% CI 0.67-1.58) and SAPT and DAPT compared with apixaban or edoxaban (RR 0.60, 95% CI 0.32-1.14 and RR 0.59, 95% CI 0.34-1.02, respectively). SAPT was associated with a significant reduction of life-threatening, disabling, or major bleeding compared with DAPT (RR 0.45, 95% CI 0.29-0.70), apixaban or edoxaban alone (RR 0.45, 95% CI 0.25-0.79), and low-dose rivaroxaban + 3-month SAPT (RR 0.30, 95% CI 0.16-0.57). There were no differences between the various regimens with respect to myocardial infarction, stroke, or systemic embolism. CONCLUSION: Following TAVI in patients without an indication for chronic oral anticoagulant, SAPT more than halved the risk of bleeding compared with DAPT and direct oral anticoagulant-based regimens without significant ischaemic offset.

Mixed aortic stenosis and regurgitation: a clinical conundrum.

Mixed aortic stenosis (AS) and aortic regurgitation (AR) is the most frequent concomitant valve disease worldwide and represents a heterogeneous population ranging from mild AS with severe AR to mild AR with severe AS. About 6.8% of patients with at least moderate AS will also have moderate or greater AR, and 17.9% of patients with at least moderate AR will suffer from moderate or greater AS. Interest in mixed AS/AR has increased, with studies demonstrating that patients with moderate mixed AS/AR have similar outcomes to those with isolated severe AS. The diagnosis and quantification of mixed AS/AR severity are predominantly echocardiography-based, but the combined lesions lead to significant limitations in the assessment. Aortic valve peak velocity is the best parameter to evaluate the combined haemodynamic impact of both lesions, with a peak velocity greater than 4.0 m/s suggesting severe mixed AS/AR. Moreover, symptoms, increased left ventricular wall thickness and filling pressures, and abnormal left ventricular global longitudinal strain likely identify high-risk patients who may benefit from closer follow-up. Although guidelines recommend interventions based on the predominant lesion, some patients could potentially benefit from earlier intervention. Once a patient is deemed to require intervention, for patients receiving transcatheter valves, the presence of mixed AS/AR could confer benefit to those at high risk of paravalvular leak. Overall, the current approach of managing patients based on the dominant lesion might be too reductionist and a more holistic approach including biomarkers and multimodality imaging cardiac remodelling and inflammation data might be more appropriate.

Inspiratory muscle training improves cardiopulmonary function in patients after transcatheter aortic valve replacement: a randomized clinical trial.

AIMS: Inspiratory muscle training (IMT) can increase the strength or endurance of the diaphragm and accessory muscles of inspiration, yet there is no evidence that endorses the role of IMT in patients of transcatheter aortic valve replacement (TAVR). This study for the first time tested the effects of IMT plus usual cardiac rehabilitation (CR) function in patients after TAVR. METHODS AND RESULTS: A double-blinded, randomized controlled, single-centre clinical trial was undertaken. Participants who had a confirmed diagnosis of valve heart disease and were clinically stable after TAVR were recruited and received a CR programme during the hospital stay. A total of 96 patients were recruited and randomly assigned to the IMT + CR group (n = 48) or the CR group (n = 48) in a 1:1 ratio. The group difference in the primary outcome, the 6-min walk distance at the discharge of the hospital, significantly favoured the IMT + CR group (mean difference -33.52, 95% CI: -64.42 to -2.62, P = 0.034). The significant difference was maintained at the 1-month and 3-month follow-ups (mean difference: 41.51, 95% CI: 1.82-81.21, P = 0.041). In addition, the mean hospital stays of subjects in the IMT + CR group was 11 days, which was significantly shorter than the 12.5 days in the CR group (P = 0.016). Sensitivity analysis using per-protocol analysis supported these findings. No adverse treatment-related events were reported. CONCLUSION: Compared with usual CR, IMT plus CR can effectively improve exercise endurance, pulmonary ventilation function, and inspiratory muscle strength in patients after TAVR and shorten the length of hospital stay.

Dihydromyricetin ameliorates osteogenic differentiation of human aortic valve interstitial cells by targeting c-KIT/interleukin-6 signaling pathway.

Aims: Calcific aortic valve disease (CAVD) is a chronic cardiovascular disease with high morbidity that lacks effective pharmacotherapeutics. As a natural flavonoid extracted from Ampelopsis grossedentata, dihydromyricetin (DHM) has been shown to be effective in protecting against atherosclerosis; yet, the therapeutic role of DHM in CAVD remains poorly understood. Herein, we aimed to clarify the therapeutic implications of DHM in CAVD and the underlying molecular mechanisms in human valvular interstitial cells (hVICs). Methods and Results: The protein levels of two known osteogenesis-specific genes (alkaline phosphatase, ALP; runt-related transcription factor 2, Runx2) and calcified nodule formation in hVICs were detected by Western blot and Alizarin Red staining, respectively. The results showed that DHM markedly ameliorated osteogenic induction medium (OM)-induced osteogenic differentiation of hVICs, as evidenced by downregulation of ALP and Runx2 expression and decreased calcium deposition. The SwissTargetPrediction database was used to identify the potential AVC-associated direct protein target of DHM. Protein-protein interaction (PPI) analysis revealed that c-KIT, a tyrosine-protein kinase, can act as a credible protein target of DHM, as evidenced by molecular docking. Mechanistically, DHM-mediated inhibition of c-KIT phosphorylation drove interleukin-6 (IL-6) downregulation in CAVD, thereby ameliorating OM-induced osteogenic differentiation of hVICs and aortic valve calcification progression. Conclusion: DHM ameliorates osteogenic differentiation of hVICs by blocking the phosphorylation of c-KIT, thus reducing IL-6 expression in CAVD. DHM could be a viable therapeutic supplement to impede CAVD.

S2 Heart Sound Detects Aortic Valve Calcification Independent of Hemodynamic Changes in Mice.

Background: Calcific aortic valve disease (CAVD) is often undiagnosed in asymptomatic patients, especially in underserved populations. Although artificial intelligence has improved murmur detection in auscultation exams, murmur manifestation depends on hemodynamic factors that can be independent of aortic valve (AoV) calcium load and function. The aim of this study was to determine if the presence of AoV calcification directly influences the S2 heart sound. Methods: Adult C57BL/6J mice were assigned to the following 12-week-long diets: (1) Control group (n = 11) fed a normal chow, (2) Adenine group (n = 4) fed an adenine-supplemented diet to induce chronic kidney disease (CKD), and (3) Adenine + HP (n = 9) group fed the CKD diet for 6 weeks, then supplemented with high phosphate (HP) for another 6 weeks to induce AoV calcification. Phonocardiograms, echocardiogram-based valvular function, and AoV calcification were assessed at endpoint. Results: Mice on the Adenine + HP diet had detectable AoV calcification (9.28 ± 0.74% by volume). After segmentation and dimensionality reduction, S2 sounds were labeled based on the presence of disease: Healthy, CKD, or CKD + CAVD. The dataset (2,516 S2 sounds) was split subject-wise, and an ensemble learning-based algorithm was developed to classify S2 sound features. For external validation, the areas under the receiver operating characteristic curve of the algorithm to classify mice were 0.9940 for Healthy, 0.9717 for CKD, and 0.9593 for CKD + CAVD. The algorithm had a low misclassification performance of testing set S2 sounds (1.27% false positive, 1.99% false negative). Conclusion: Our ensemble learning-based algorithm demonstrated the feasibility of using the S2 sound to detect the presence of AoV calcification. The S2 sound can be used as a marker to identify AoV calcification independent of hemodynamic changes observed in echocardiography.