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.

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.

Lipoprotein (a) is a risk factor of aortic valve calcification in patients with a risk of atherosclerosis.

Aortic valve calcification (AVC), which causes aortic stenosis (AS), is more common in elderly persons. Controlling for conventional risk variables did not, however, reduce the incidence of AS. Thus, residual risk factors of AS should be identified. We enrolled 513 patients who underwent coronary angiography with computed tomography because of suspicion of coronary artery disease (CAD) or ruling out of CAD before aortic valve replacement. Calcium volume was calculated with a commercially available application. Conventional and lipid-related risk factors including serum levels of Lp(a) were evaluated for all patients. Calcium volume and Lp(a) levels were significantly higher in patients who underwent aortic valve replacement than in those who did not. A single regression analysis showed that the calcium volume was positively associated with age and the Lp(a) levels and negatively associated with the estimated glomerular filtration rate. No statistical significance was observed for other risk factors, including oxidized low-density lipoprotein, omega-3 fatty acids levels. The multiple regression analysis revealed that age (P<0.001), female sex (P<0.05), Lp(a) (P<0.01), and hemoglobin A1c (P<0.01) were determinants of the calcium volume. The area under the curve in receiver operating characteristic analysis of Lp(a) for implementation of AVR was 0.65 at an Lp(a) cut-off level of 16 mg/dL. In conclusion, the serum Lp(a) level is a potent risk factor of AVC in patients with high risk of atherosclerosis. J. Med. Invest. 70 : 450-456, August, 2023.

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.

[Emergent Transcatheter Aortic Valve Implantation for Degenerated Surgical Aortic Valve Under Local Anesthesia:Report of a Case].

An 89-year-old man who had undergone aortic valve replacement with a 21 mm Mosaic bioprosthetic valve at another hospital 14 years ago was admitted to the emergency room for a sudden respiratory distress two days prior and was diagnosed with severe aortic regurgitation( AR) caused by valve insufficiency and acute heart failure secondary to low cardiac function. Upon admission, he was found to have severe hypoxia with PaO2 of 40 mmHg range, and transcatheter aortic valve replacement (TAVI, TAV in SAV) with a 20 mm SAPIEN3 was performed under local anesthesia for fear of hypotension while under general anesthesia. After confirming that AR had completely disappeared, the patient was intubated and discharged from the operating room on a mechanical ventilator. The patient was weaned from the ventilator on the second postoperative day and was transferred to the other hospital for rehabilitation, 48 days postoperatively. Although there is no report on the comparative study of anesthesia methods for emergency transcatheter aortic valve implantation( TAVI), TAVI under regional anesthesia is minimally invasive with a lower risk for hypotension than general anesthesia. Therefore, we believe it is useful for patients with acute heart failure and hypotension. In addition, it is important to use a balloon expandable valve with excellent implantability to complete the procedure in a short time.

Virtual reality-assisted distraction during transcatheter aortic valve implantation under local anaesthesia: A randomised study.

BACKGROUND: A minimal approach, using local anaesthesia alone, has been advocated to promote faster transcatheter aortic valve replacement (TAVR) procedures in intermediate-risk patients. Pre- and periprocedural anxiety and pain remain a concern. Virtual reality (VR) is a form of non-pharmacological distraction that can potentially modulate pain and anxiety. This randomised study explored whether VR reduces pain and anxiety during TAVR without sedation and compared the effects of VR with those of standard care. METHODS AND RESULTS: Between June 2022 and March 2023, 207 patients underwent transfemoral TAVR (TF-TAVR). Of these, 117 (56.5%) patients were willing to participate in the study and met the educational background and mental status criteria for assessment. Fifty-nine patients underwent TF-TAVR with VR glasses (VR group). Fifty-eight patients underwent standard TF-TAVR without VR (control group; CG). Post-interventional anxiety scores (STAI-S) (31.5 ± 13.4 vs. 38.5 ± 19.2, p = 0.02) and the perceived duration of the procedure (60.1 ± 32.3 vs. 73.0 ± 32.4, p = 0.04) were lower in the VR than in the CG. Procedure time, pain, and anxiety scores (visual analogue scale) were similar between the groups. The complication rate was low and not associated with VR. Post-interventional delirium occurred in nine patients, and was similar between the groups (VR: 4 [6.8%] vs. CG: 5 [8.6%], p = 0.71). No periprocedural strokes were observed. CONCLUSION: VR for TAVR is feasible and safe and expands the non-drug spectrum of therapy for anxiety and pain in patients undergoing TAVR with a minimalistic approach.

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.

General Anesthesia Versus Local Anesthesia in Patients Undergoing Transcatheter Aortic Valve Replacement: An Updated Meta-Analysis and Systematic Review.

OBJECTIVES: For patients with aortic stenosis, transcatheter aortic valve replacement (TAVR) offers a less invasive treatment modality than conventional surgical valve replacement. Although the surgery is performed traditionally under general anesthesia (GA), recent studies have described success with TAVR using local anesthesia (LA) and/or conscious sedation. The study authors performed a pairwise meta-analysis to compare the clinical outcomes of TAVR based on operative anesthesia management. DESIGN: A random effects pairwise meta-analysis via the Mantel-Haenszel method. SETTING: Not applicable, as this is a meta-analysis. PARTICIPANTS: No individual patient data were used. INTERVENTIONS: Not applicable, as this is a meta-analysis. MEASUREMENTS AND MAIN RESULTS: The authors comprehensively searched the PubMed, Embase, and Cochrane databases to identify studies comparing TAVR performed using LA or GA. Outcomes were pooled as risk ratios (RR) or standard mean differences (SMD) and their 95% CIs. The authors' pooled analysis included 14,388 patients from 40 studies (7,754 LA; 6,634 GA). Compared to GA TAVR, LA TAVR was associated with significantly lower rates of 30-day mortality (RR 0.69; p < 0.01) and stroke (RR 0.78; p = 0.02). Additionally, LA TAVR patients had lower rates of 30-day major and/or life-threatening bleeding (RR 0.64; p = 0.01), 30-day major vascular complications (RR 0.76; p = 0.02), and long-term mortality (RR 0.75; p = 0.009). No significant difference was seen between the 2 groups for a 30-day paravalvular leak (RR 0.88, p = 0.12). CONCLUSIONS: Transcatheter aortic valve replacement performed using LA is associated with lower rates of adverse clinical outcomes, including 30-day mortality and stroke. No difference was seen between the 2 groups for a 30-day paravalvular leak. These results support the use of minimally invasive forms of TAVR without GA.

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.

Kidney function, bone-mineral metabolism markers, and calcification of coronary arteries, aorta, and cardiac valves in older adults.

BACKGROUND AND AIMS: The contribution of kidney dysfunction, especially at mild-to-moderate stages, and bone-mineral metabolism (BMM) markers to vascular calcification remains controversial or unclear. We comprehensively evaluated the association of kidney and BMM markers with coronary artery calcification (CAC) and extra-coronary calcification (ECC). METHODS: In 1931 ARIC participants (age 73-95 years) without coronary heart disease at visit 7 (2018-19), we investigated the associations of estimated glomerular filtration rate (eGFR) (with creatinine, cystatin C, and both) and five serum BMM markers (calcium, fibroblast growth factor 23, magnesium, parathyroid hormone, and phosphorus) with high CAC and ECC (sex-race specific ≥75th vs. <75th percentile Agatston score) or any vs. zero CAC and ECC using multivariable logistic regression. For eGFR and BMM markers, we took their weighted cumulative averages from visit 1 (1987-89) to visit 5 (2011-13). RESULTS: Lower eGFR, regardless of equations used, was not robustly associated with high CAC or ECC. Among BMM markers, only higher phosphorus levels, even within the normal range, showed robust associations with high CAC (only when modeled continuously) and ECC, independently of kidney function (e.g., odds ratio 1.94 [95%CI 1.38-2.73] for high aortic valve calcification, in the highest vs. lowest quartile). Results were generally consistent when analyzing any CAC or ECC, although cystatin C-based eGFR <60 mL/min/1.73 m2 became significantly associated with mitral valve calcification (odds ratio 1.69 [1.10-2.60]). CONCLUSIONS: Among kidney and BMM measures tested, only serum phosphorus demonstrated robust associations with both CAC and ECC, supporting a key role of phosphorus in the pathophysiology of vascular calcification.

Choosing transcatheter aortic valve replacement in porcelain aorta: outcomes versus surgical replacement.

OBJECTIVES: Porcelain aorta complicates aortic valve replacement and is an indication for transcatheter approaches. No study has compared surgical and transcatheter valve replacement in the setting of porcelain aorta. We characterize porcelain aorta patients undergoing aortic valve replacement and the association of aortic calcification and outcomes. METHODS: Patients undergoing aortic valve replacement with porcelain aorta were identified. Aortic calcium volume was determined using 3D computed tomography thresholding techniques. Propensity scoring was performed to assess the effect of surgical versus transcatheter approaches. Risk factors for composite major hospital complications (death, stroke and dialysis) were identified using random forest machine learning. RESULTS: From January 2006 to January 2015, 164 patients with porcelain aorta underwent aortic valve replacement [105 (64%) surgical replacement, 59 (36%) transcatheter replacement]. Propensity scoring matched 29 pairs (49% of transcatheter patients). Before matching, 5-year survival was 41% [(43% surgical, 35% transcatheter, P(log-rank) = 0.9]. After matching, mortality for surgical versus transcatheter replacement was 3.4% (n = 1) vs 10% (n = 3), stroke 14% (n = 4) vs 3.4% (n = 1) and dialysis 6.9% (n = 2) versus 11% (n = 3). Matched 5-year survival was 40% after surgical replacement and 29% after transcatheter replacement [P(log-rank) = 0.4]. Total aortic calcium volume was greater in transcatheter than surgical patients [18 (8.0) vs 17 (7.7) ml] and was associated with more major hospital complications after either approach. CONCLUSIONS: Surgical and transcatheter approaches are complementary options for aortic stenosis with porcelain aorta. Surgical valve replacement remains an effective treatment for patients requiring concomitant procedures. Quantifying aortic calcium volume is a helpful risk predictor in all patients with porcelain aorta.

ALP Inhibitors Inhibit Inflammatory Responses and Osteoblast Differentiation in hVIC via AKT-ERK Pathways.

Objective: The aim of this study was to explore the calcification process of aortic valve interstitial cells and its potential association with osteogenic differentiation and alkaline phosphatase (ALP) activity. Methods: The study patients were divided into 3 groups: the control group, the osteogenic induction medium (OM) group and the OM+ALP inhibitor group. Cell calcification was measured by alizarin red S staining and alizarin red S dye released by extracellular matrix (ECM) was quantified by spectrophotometry. Immunohistochemical staining was performed on valve tissues of patients harboring calcified and non-calcified aortic valve disease. Expression of bone morphogenetic protein (BMP), runt related transcription factor 2 (RUNX2), osteocalcin and osteopontin (OPN), was evaluated using immunohistochemistry¸and expression of osteogenic specific markers (BMP, RUNX2 and OPN) was detected using Wesern blot analysis. RNA sequencing was analyzed to further study the exact mechanism of ALP inhibitors in terms of inhibiting the osteogenic differentiation of valvular interstitial cells (VIC). The mRNA levels of tumor necrosis factor alpha (TNF-α), Toll-like receptor 4 (TLR4) and NOD-like receptor thermal protein domain associated protein 3 (NLRP3), were detected using reverse-transcription quantitative polymerase chain reaction (RT-qPCR). In addition, Western blot analysis was performed to evaluate the expression of phosphorylated extracellular regulated protein kinases (ERK), nuclear factor κ B inhibitor α (IκBα) and protein kinase B (AKT) in protein. Results: Alizarin red staining was positive in the OM and OM+ALP inhibitor groups, and calcified nodules were formed in VIC, which showed a significant difference compared with the control group (P < .05). The semi-quantitative level of calcification in the OM group was higher than in the control group (P < .05), and the semi-quantitative level of calcification in the OM+ALP inhibitor group was lower than in the OM group (P < .05). ALP staining intensity, ALP activity and messenger RNA (mRNA) levels of BMP, RUNX2, osteocalcin, OPN, ERK, IκBα, AKT, TNF-α, Toll-like receptor 4 (TLR4) and NLRP3 inflammasome (NLRP3) in the OM group were higher than in the control group (P < .05). ALP staining intensity, ALP activity and mRNA expressions of BMP, RUNX2, osteocalcin, OPN, phosphorylated ERK, IκBα, AKT, TNF-α and NLRP3 in the OM+ALP inhibitor group were lower than in the OM group (P < .05). Compared with the control group, 723 genes were upregulated and 248 genes were downregulated in the OM group. Compared with the OM group, 352 genes were upregulated and 586 genes were downregulated in the OM+ALP inhibitor group. Conclusion: We suggest that ALP inhibitors have potential in terms of inhibiting the inflammatory response and osteoblast differentiation of human VIC (hVIC) via the TLR4, AKT, ERK and NLRP3 pathways.

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.

Atractylodin targets GLA to regulate D-mannose metabolism to inhibit osteogenic differentiation of human valve interstitial cells and ameliorate aortic valve calcification.

Atractylodin (ATL) has been reported to exert anti-inflammatory effects. Osteogenic changes induced by inflammation in valve interstitial cells (VICs) play a key role in the development of calcified aortic valve disease (CAVD). This study aimed to investigate the anti-calcification effects of ATL on aortic valves. Human VICs (hVICs) were exposed to osteogenic induction medium (OM) containing ATL to investigate cell viability, osteogenic gene and protein expression, and anti-calcification effects. Gas chromatography-mass spectroscopy (GC-MS) metabolomics analysis was used to detect changes in the metabolites of hVICs stimulated with OM before and after ATL administration. The compound-reaction-enzyme-gene network was used to identify drug targets. Gene interference was used to verify the targets. ApoE-/- mice fed a high-fat (HF) diet were used to evaluate the inhibition of aortic valve calcification by ATL. Treatment with 20 µM ATL in OM prevented calcified nodule accumulation and decreases in the gene and protein expression levels of ALP, RUNX2, and IL-1ß. Differential metabolite analysis showed that D-mannose was highly associated with the anti-calcification effect of ATL. The addition of D-mannose prevented calcified nodule accumulation and inhibited succinate-mediated HIF-1α activation and IL-1ß production. The target of ATL was identified as GLA. Silencing of the GLA gene (si-GLA) reversed the anti-osteogenic differentiation of ATL. In vivo, ATL ameliorated aortic valve calcification by preventing decreases in GLA expression and the up-regulation of IL-1ß expression synchronously. In conclusion, ATL is a potential drug for the treatment of CAVD by targeting GLA to regulate D-mannose metabolism, thereby inhibiting succinate-mediated HIF-1α activation and IL-1ß production.

Predicting short-term outcomes after transcatheter aortic valve replacement for aortic stenosis.

BACKGROUND: The approved use of transcatheter aortic valve replacement (TAVR) for aortic stenosis has expanded substantially over time. However, gaps remain with respect to accurately delineating risk for poor clinical and patient-centered outcomes. Our objective was to develop prediction models for 30-day clinical and patient-centered outcomes after TAVR within a large, diverse community-based population. METHODS: We identified all adults who underwent TAVR between 2013-2019 at Kaiser Permanente Northern California, an integrated healthcare delivery system, and were monitored for the following 30-day outcomes: all-cause death, improvement in quality of life, all-cause hospitalizations, all-cause emergency department (ED) visits, heart failure (HF)-related hospitalizations, and HF-related ED visits. We developed prediction models using gradient boosting machines using linked demographic, clinical and other data from the Society for Thoracic Surgeons (STS)/American College of Cardiology (ACC) TVT Registry and electronic health records. We evaluated model performance using area under the curve (AUC) for model discrimination and associated calibration plots. We also evaluated the association of individual predictors with outcomes using logistic regression for quality of life and Cox proportional hazards regression for all other outcomes. RESULTS: We identified 1,565 eligible patients who received TAVR. The risks of adverse 30-day post-TAVR outcomes ranged from 1.3% (HF hospitalizations) to 15.3% (all-cause ED visits). In models with the highest discrimination, discrimination was only moderate for death (AUC 0.60) and quality of life (AUC 0.62), but better for HF-related ED visits (AUC 0.76). Calibration also varied for different outcomes. Importantly, STS risk score only independently predicted death and all-cause hospitalization but no other outcomes. Older age also only independently predicted HF-related ED visits, and race/ethnicity was not significantly associated with any outcomes. CONCLUSIONS: Despite using a combination of detailed STS/ACC TVT Registry and electronic health record data, predicting short-term clinical and patient-centered outcomes after TAVR remains challenging. More work is needed to identify more accurate predictors for post-TAVR outcomes to support personalized clinical decision making and monitoring strategies.

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.