Autotaxin inhibition attenuates the aortic valve calcification by suppressing inflammation-driven fibro-calcific remodeling of valvular interstitial cells.

BACKGROUND: Patients with fibro-calcific aortic valve disease (FCAVD) have lipid depositions in their aortic valve that engender a proinflammatory impetus toward fibrosis and calcification and ultimately valve leaflet stenosis. Although the lipoprotein(a)-autotaxin (ATX)-lysophosphatidic acid axis has been suggested as a potential therapeutic target to prevent the development of FCAVD, supportive evidence using ATX inhibitors is lacking. We here evaluated the therapeutic potency of an ATX inhibitor to attenuate valvular calcification in the FCAVD animal models. METHODS: ATX level and activity in healthy participants and patients with FCAVD were analyzed using a bioinformatics approach using the Gene Expression Omnibus datasets, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and western blotting. To evaluate the efficacy of ATX inhibitor, interleukin-1 receptor antagonist-deficient (Il1rn-/-) mice and cholesterol-enriched diet-induced rabbits were used as the FCAVD models, and primary human valvular interstitial cells (VICs) from patients with calcification were employed. RESULTS: The global gene expression profiles of the aortic valve tissue of patients with severe FCAVD demonstrated that ATX gene expression was significantly upregulated and correlated with lipid retention (r = 0.96) or fibro-calcific remodeling-related genes (r = 0.77) in comparison to age-matched non-FCAVD controls. Orally available ATX inhibitor, BBT-877, markedly ameliorated the osteogenic differentiation and further mineralization of primary human VICs in vitro. Additionally, ATX inhibition significantly attenuated fibrosis-related factors' production, with a detectable reduction of osteogenesis-related factors, in human VICs. Mechanistically, ATX inhibitor prohibited fibrotic changes in human VICs via both canonical and non-canonical TGF-ß signaling, and subsequent induction of CTGF, a key factor in tissue fibrosis. In the in vivo FCAVD model system, ATX inhibitor exposure markedly reduced calcific lesion formation in interleukin-1 receptor antagonist-deficient mice (Il1rn-/-, P = 0.0210). This inhibition ameliorated the rate of change in the aortic valve area (P = 0.0287) and mean pressure gradient (P = 0.0249) in the FCAVD rabbit model. Moreover, transaortic maximal velocity (Vmax) was diminished with ATX inhibitor administration (mean Vmax = 1.082) compared to vehicle control (mean Vmax = 1.508, P = 0.0221). Importantly, ATX inhibitor administration suppressed the effects of a high-cholesterol diet and vitamin D2-driven fibrosis, in association with a reduction in macrophage infiltration and calcific deposition, in the aortic valves of this rabbit model. CONCLUSIONS: ATX inhibition attenuates the development of FCAVD while protecting against fibrosis and calcification in VICs, suggesting the potential of using ATX inhibitors to treat FCAVD.

Andrographolide regulates H3 histone lactylation by interfering with p300 to alleviate aortic valve calcification.

BACKGROUND AND PURPOSE: Our previous studies have found that andrographolide (AGP) alleviates calcific aortic valve disease (CAVD), but the underlying mechanism is unclear. This study explores the molecular target and signal mechanisms of AGP in inhibiting CAVD. EXPERIMENTAL APPROACH: The anti-calcification effects of the aortic valve with AGP treatment were evaluated by alizarin red staining in vitro and ultrasound and histopathological assessment of a high-fat (HF)-fed ApoE-/- mouse valve calcification model. A correlation between the H3 histone lactylation (H3Kla) and calcification was detected. Molecular docking and surface plasmon resonance (SPR) experiments were further used to confirm p300 as a target for AGP. Overexpression (oe) and silencing (si) of p300 were used to verify the inhibitory effect of AGP targeting p300 on the H3Kla in vitro and ex vivo. KEY RESULTS: AGP significantly inhibited calcium deposition in valve interstitial cells (VICs) and ameliorated aortic valve calcification. The multi-omics analysis revealed the glycolysis pathway involved in CAVD, indicating that AGP interfered with lactate production by regulating lactate dehydrogenase A (LDHA). In addition, lactylation, a new post-translational modification, was shown to have a role in promoting aortic valve calcification. Furthermore, H3Kla and H3K9la site were shown to correlate with Runx2 expression inhibition by AGP treatment. Importantly, we found that p300 transferase was the molecular target of AGP in inhibiting H3Kla. CONCLUSIONS AND IMPLICATIONS: Our findings, for the first time, demonstrated that AGP alleviates calcification by interfering with H3Kla via p300, which might be a powerful drug to prevent CAVD.

Enhancing aortic valve drug delivery with PAR2-targeting magnetic nano-cargoes for calcification alleviation.

Calcific aortic valve disease is a prevalent cardiovascular disease with no available drugs capable of effectively preventing its progression. Hence, an efficient drug delivery system could serve as a valuable tool in drug screening and potentially enhance therapeutic efficacy. However, due to the rapid blood flow rate associated with aortic valve stenosis and the lack of specific markers, achieving targeted drug delivery for calcific aortic valve disease has proved to be challenging. Here we find that protease-activated-receptor 2 (PAR2) expression is up-regulated on the plasma membrane of osteogenically differentiated valvular interstitial cells. Accordingly, we develop a magnetic nanocarrier functionalized with PAR2-targeting hexapeptide for dual-active targeting drug delivery. We show that the nanocarriers effectively deliver XCT790-an anti-calcification drug-to the calcified aortic valve under extra magnetic field navigation. We demonstrate that the nano-cargoes consequently inhibit the osteogenic differentiation of valvular interstitial cells, and alleviate aortic valve calcification and stenosis in a high-fat diet-fed low-density lipoprotein receptor-deficient (Ldlr-/-) mouse model. This work combining PAR2- and magnetic-targeting presents an effective targeted drug delivery system for treating calcific aortic valve disease in a murine model, promising future clinical translation.

Renin-angiotensin system inhibition after surgical aortic valve replacement for aortic stenosis.

OBJECTIVE: The optimal medical therapy after surgical aortic valve replacement (SAVR) for aortic stenosis remains unknown. Renin-angiotensin system (RAS) inhibitors could potentially improve cardiac remodelling and clinical outcomes after SAVR. METHODS: All patients undergoing SAVR due to aortic stenosis in Sweden 2006-2020 and surviving 6 months after surgery were included. The primary outcome was major adverse cardiovascular events (MACEs; all-cause mortality, stroke or myocardial infarction). Secondary endpoints included the individual components of MACE and cardiovascular mortality. Time-updated adjusted Cox regression models were used to compare patients with and without RAS inhibitors. Subgroup analyses were performed, as well as a comparison between angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs). RESULTS: A total of 11 894 patients (mean age, 69.5 years, 40.4% women) were included. Median follow-up time was 5.4 (2.7-8.5) years. At baseline, 53.6% of patients were dispensed RAS inhibitors, this proportion remained stable during follow-up. RAS inhibition was associated with a lower risk of MACE (adjusted hazard ratio (aHR) 0.87 (95% CI 0.81 to 0.93), p<0.001), mainly driven by a lower risk of all-cause death (aHR 0.79 (0.73 to 0.86), p<0.001). The lower MACE risk was consistent in all subgroups except for those with mechanical prostheses (aHR 1.07 (0.84 to 1.37), p for interaction=0.040). Both treatment with ACE inhibitors (aHR 0.89 (95% CI 0.82 to 0.97)) and ARBs (0.87 (0.81 to 0.93)) were associated with lower risk of MACE. CONCLUSION: The results of this study suggest that medical therapy with an RAS inhibitor after SAVR is associated with a 13% lower risk of MACE and a 21% lower risk of all-cause death.

Major Facilitator Superfamily Domain Containing 5 Inhibition Reduces Lipoprotein(a) Uptake and Calcification in Valvular Heart Disease.

BACKGROUND: High circulating levels of Lp(a) (lipoprotein[a]) increase the risk of atherosclerosis and calcific aortic valve disease, affecting millions of patients worldwide. Although atherosclerosis is commonly treated with low-density lipoprotein-targeting therapies, these do not reduce Lp(a) or risk of calcific aortic valve disease, which has no available drug therapies. Targeting Lp(a) production and catabolism may provide therapeutic benefit, but little is known about Lp(a) cellular uptake. METHODS: Here, unbiased ligand-receptor capture mass spectrometry was used to identify MFSD5 (major facilitator superfamily domain containing 5) as a novel receptor/cofactor involved in Lp(a) uptake. RESULTS: Reducing MFSD5 expression by a computationally identified small molecule or small interfering RNA suppressed Lp(a) uptake and calcification in primary human valvular endothelial and interstitial cells. MFSD5 variants were associated with aortic stenosis (P=0.027 after multiple hypothesis testing) with evidence suggestive of an interaction with plasma Lp(a) levels. CONCLUSIONS: MFSD5 knockdown suppressing human valvular cell Lp(a) uptake and calcification, along with meta-analysis of MFSD5 variants associating with aortic stenosis, supports further preclinical assessment of MFSD5 in cardiovascular diseases, the leading cause of death worldwide.

Metformin ameliorates valve interstitial cell calcification by promoting autophagic flux.

Calcific aortic valve disease (CAVD) is the most common heart disease of the developed world. It has previously been established that metformin administration reduces arterial calcification via autophagy; however, whether metformin directly regulates CAVD has yet to be elucidated. In the present study we investigated whether metformin alleviates valvular calcification through the autophagy-mediated recycling of Runx2. Calcification was reduced in rat valve interstitial cells (RVICs) by metformin treatment (0.5-1.5 mM) (P < 0.01), with a marked decrease in Runx2 protein expression compared to control cells (P < 0.05). Additionally, upregulated expression of Atg3 and Atg7 (key proteins required for autophagosome formation), was observed following metformin treatment (1 mM). Blocking autophagic flux using Bafilomycin-A1 revealed colocalisation of Runx2 with LC3 puncta in metformin treated RVICs (P < 0.001). Comparable Runx2 accumulation was seen in LC3 positive autolysosomes present within cells that had been treated with both metformin and hydroxychloroquine in combination (P < 0.001). Mechanistic studies employing three-way co-immunoprecipitation with Runx2, p62 and LC3 suggested that Runx2 binds to LC3-II upon metformin treatment in VICs. Together these studies suggest that the utilisation of metformin may represent a novel strategy for the treatment of CAVD.

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.

Rationale and design of Non-antithrombotic Therapy After Transcatheter Aortic Valve Implantation (NAPT) Trial.

BACKGROUND: Despite the wide implementation of transcatheter aortic valve implantation (TAVI), the optimal antithrombotic therapy after TAVI has not been established yet. Owing to the accumulating evidence supporting the efficacy and safety of single antiplatelet therapy (SAPT) over dual antiplatelet therapy, the latest guideline recommends life-long SAPT. However, there is scarce evidence supporting SAPT compared with non-antithrombotic therapy. Given the vulnerability of patients undergoing TAVI in terms of high bleeding risk, the benefit of SAPT may be canceled out by its potential increased bleeding risk. STUDY DESIGN AND OBJECTIVES: Non-antithrombotic Therapy After Transcatheter Aortic Valve Implantation (NAPT) Trial is a prospective, randomized controlled, open-label blinded endpoint multicenter trial conducted in Japan, testing the non-inferiority of non-antithrombotic therapy compared with aspirin monotherapy in patients who underwent TAVI and had no indications for long-term oral anticoagulation therapy (OAC). Patients who successfully underwent trans-femoral TAVI for severe aortic stenosis with either balloon-expandable or self-expandable valves are eligible for inclusion. Key exclusion criteria are (i) occurrence of perioperative complications (ii) indications of taking antithrombotic drugs for other reasons; (iii) eGFR <30 ml/min/1.73 m2 or hemodialysis or peritoneal dialysis. A total of 360 patients will be randomized (1:1) to aspirin monotherapy vs. non-antithrombotic therapy. The primary outcome is a composite of all-cause mortality, myocardial infarction, stroke, and bleeding. All bleeding events based on the Valve Academic Research Consortium 3 are included as a component of the primary outcome. CONCLUSION: The NAPT trial will determine the non-inferiority of a non-antithrombotic therapy compared with aspirin monotherapy after TAVI.

Antithrombotic therapy following transcatheter aortic valve intervention.

Transcatheter aortic valve replacement (TAVR) is increasingly being performed to treat symptomatic patients with aortic stenosis and annual procedure volume has overtaken surgical aortic valve replacement in the United States. However, current international guidelines were written prior to the publication of several important recent studies. Furthermore, European and American guidelines differ in their recommendations of antithrombotic therapy following TAVR. Consequently, there is a need to examine the literature to provide clinicians guidance on the optimum antithrombotic strategy, particularly as different patient populations exist. In this review, we examine the data for antiplatelet and anticoagulation therapy post-TAVR.

Targeted inhibition of PTPN22 is a novel approach to alleviate osteogenic responses in aortic valve interstitial cells and aortic valve lesions in mice.

BACKGROUND: Calcific aortic valve disease (CAVD) is the most prevalent valvular disease and has high morbidity and mortality. CAVD is characterized by complex pathophysiological processes, including inflammation-induced osteoblastic differentiation in aortic valve interstitial cells (AVICs). Novel anti-CAVD agents are urgently needed. Protein tyrosine phosphatase nonreceptor type 22 (PTPN22), an intracellular nonreceptor-like protein tyrosine phosphatase, is involved in several chronic inflammatory diseases, including rheumatoid arthritis and diabetes. However, it is unclear whether PTPN22 is involved in the pathogenesis of CAVD. METHODS: We obtained the aortic valve tissue from human and cultured AVICs from aortic valve. We established CAVD mice model by wire injury. Transcriptome sequencing, western bolt, qPCR, and immunofluorescence were performed to elucidate the molecular mechanisms. RESULTS: Here, we determined that PTPN22 expression was upregulated in calcific aortic valve tissue, AVICs treated with osteogenic medium, and a mouse model of CAVD. In vitro, overexpression of PTPN22 induced osteogenic responses, whereas siRNA-mediated PTPN22 knockdown abolished osteogenic responses and mitochondrial stress in the presence of osteogenic medium. In vivo, PTPN22 ablation ameliorated aortic valve lesions in a wire injury-induced CAVD mouse model, validating the pathogenic role of PTPN22 in CAVD. Additionally, we discovered a novel compound, 13-hydroxypiericidin A 10-O-α-D-glucose (1 → 6)-ß-D-glucoside (S18), in a marine-derived Streptomyces strain that bound to PTPN22 with high affinity and acted as a novel inhibitor. Incubation with S18 suppressed osteogenic responses and mitochondrial stress in human AVICs induced by osteogenic medium. In mice with aortic valve injury, S18 administration markedly alleviated aortic valve lesions. CONCLUSION: PTPN22 plays an essential role in the progression of CAVD, and inhibition of PTPN22 with S18 is a novel option for the further development of potent anti-CAVD drugs. Therapeutic inhibition of PTPN22 retards aortic valve calcification through modulating mitochondrial dysfunction in AVICs.

Platelet membrane-coated alterbrassicene A nanoparticle inhibits calcification of the aortic valve by suppressing phosphorylation P65 NF-κB.

Rationale: Calcific aortic valve disease (CAVD) is a leading cause of cardiovascular mortality and morbidity with increasing prevalence and incidence. The pathobiology of CAVD involves valvular fibrocalcification, and osteogenic and fibrogenic activities are elevated in aortic valve interstitial cells (VICs) from diseased valves. It has been demonstrated that activated NF-κB pathway was present in the early stage of CAVD process. There is currently no effective clinical drugs targeting NF-κB pathway for CAVD treatment. Therefore, it is of great clinical significance to seek effective treatments for valve calcification. Methods: In this study, we established immortal human valve interstitial cells (im-hVICs) with pGMLV-SV40T-puro lentivirus. Alizarin red staining and western blotting were performed to evaluate the calcification of immortal VICs supplemented with different compounds. The natural fusicoccane diterpenoid alterbrassicene A (ABA) was found to have potential therapeutic functions. Ribonucleic acid sequencing was used to identify the potential target of ABA. Platelet membrane-coated nanoparticle of ABA (PNP-ABA) was fabricated and the IBIDI pump was used to evaluate the adhesion ability of PNP-ABA. Murine wire-induced aortic valve stenosis model was conducted for in vivo study of PNP-ABA. Results: The natural fusicoccane diterpenoid ABA was found to significantly reduce the calcification of human VICs during osteogenic induction via inhibiting the phosphorylation P65. Runt-related transcription factor 2 (Runx2) and bone morphogenetic protein-2 (BMP2) were down regulated with the treatment of ABA in human VICs. Additionally, molecular docking results revealed that ABA bound to RelA (P65) protein. Phosphorylation of P65 (Ser536) was alleviated by ABA treatment, as well as the nuclear translocation of P65 during osteogenic induction in human VICs. Alizarin red staining showed that ABA inhibited osteogenic differentiation of VICs in a dose-dependent manner. PNP-ABA attenuated aortic valve calcification in murine wire-induced aortic valve stenosis model in vivo. Conclusions: The establishment of im-hVICs provides a convenient cell line for the study of CAVD. Moreover, our current research highlights a novel natural compound, ABA, as a promising candidate to prevent the progression of CAVD.

Comparison of oral anticoagulation by vitamin-K antagonists and non-vitamin-K antagonists for treatment of leaflet thickening after transcatheter aortic valve implantation (TAVI).

INTRODUCTION: Hypoattenuated leaflet thickening (HALT), as identified by CT imaging, is not infrequent after transcatheter aortic valve implantation (TAVI). The best choice of oral anticoagulation is unknown. We compared the effectiveness of Direct Oral AntiCoagulants (DOAC) and Vitamin-K Antagonists (VKA) to resolve HALT in patients with serial CT aquisitions. METHODS: A total of 46 consecutive TAVI patients in whom anticoagulation had been initiated because of HALT and who underwent follow-up CT were identified. Indication and type of anticoagulation was according to physician discretion. Patients on DOAC were compared to VKA therapy regarding resolution of HALT. RESULTS: Mean age of the 46 patients was 80 ± 6 years (59% men), and the mean duration of anticoagulation was 156 days. Overall, 41 patients (89%) showed resolution of HALT with anticoagulation therapy, whereas HALT persisted in 5 patients (11%). Resolution of HALT was seen in 26 out of 30 (87%) patients receiving VKA and in 15 out of 16 (94%) patients receiving DOAC, respectively. Groups did not differ regarding age, cardiovascular risk factors, TAVI prosthesis type and size or duration of anticoagulation (all p > 0.05). CONCLUSION: Anticoagulation therapy resolves leaflet thickening after TAVI in most patients. Non-Vitamin-K antagonists seem to be an effective alternative to Vitamin-K antagonists. This finding needs to be confirmed in larger prospective trials.

Medium-Term Outcomes of the Different Antithrombotic Regimens After Transcatheter Aortic Valve Implantation.

Bioprosthetic valve thrombosis is associated with accelerated bioprosthesis degeneration and valve re-replacement. Whether 3-month warfarin use after transcatheter aortic valve implantation (TAVI) protects against such consequences is unknown. We aimed to investigate if 3-month warfarin treatment after TAVI is associated with better outcomes than dual antiplatelet therapy (DAPT) and single antiplatelet therapy (SAPT) at medium-term follow-up. Adults who underwent TAVI were identified retrospectively (n = 1,501) and classified into warfarin, DAPT, and SAPT groups based on antithrombotic regimen received. Patients with atrial fibrillation were excluded. Outcomes and valve hemodynamics were compared between the groups. Annualized change from baseline in mean gradients and effective orifice area at last follow-up echocardiography was calculated. Overall, 844 patients were included (mean age: 80 ± 9 years, 43% women; 633 receiving warfarin, 164 DAPT, and 47 SAPT). Median time to follow-up was 2.5 (interquartile range 1.2 to 3.9) years. There were no differences in the adjusted outcome end points of ischemic stroke, death, valve re-replacement/intervention, structural valve degeneration, or their composite end point at follow-up. Annualized change in aortic valve area was significantly higher in DAPT (-0.11 [0.19] cm2/year) than warfarin (-0.06 [0.25] cm2/y, p = 0.03), but annualized change in mean gradients was not different (p >0.05). In conclusion, antithrombotic regimen, including warfarin, after TAVI was associated with marginally lower decrease in aortic valve area but no difference in medium-term clinical outcomes compared with DAPT and SAPT.

Capsaicin inhibits aortic valvular interstitial cell calcification via the redox-sensitive NFκB/AKT/ERK1/2 pathway.

Calcific aortic valve stenosis (CAVS), the third most prevalent cardiovascular disorder is known to impose a huge social and economic burden on patients. However, no pharmacotherapy has yet been established. Aortic valve replacement is the only treatment option, although its lifelong efficacy is not guaranteed and involves inevitable complications. So, there is a crucial need to find novel pharmacological targets to delay or prevent CAVS progression. Capsaicin is well known for its anti-inflammatory and antioxidant properties and has recently been revealed to inhibit arterial calcification. We thus investigated the effect of capsaicin in attenuating aortic valve interstitial cells (VICs) calcification induced by pro-calcifying medium (PCM). Capsaicin reduced the level of calcium deposition in calcified VICs, along with reductions in gene and protein expression of the calcification markers Runx2, osteopontin, and BMP2. Based on Gene Ontology biological process and Kyoto Encyclopedia of Genes and Genomes pathway analysis oxidative stress, AKT and AGE-RAGE signaling pathways were selected. The AGE-RAGE signaling pathway activates oxidative stress and inflammation-mediated pathways including ERK and NFκB signaling pathways. Capsaicin successfully inhibited oxidative stress- and reactive oxygen species-related markers NOX2 and p22phox. The markers of the AKT, ERK1/2, and NFκB signaling pathways, namely, phosphorylated AKT, ERK1/2, NFκB, and IκBα were upregulated in calcified cells, while being significantly downregulated upon capsaicin treatment. Capsaicin attenuates VICs calcification in vitro by inhibition of redox-sensitive NFκB/AKT/ERK1/2 signaling pathway, indicating its potential as a candidate to alleviate CAVS.

Diuretic treatment before and after transcatheter aortic valve implantation: A Danish nationwide study.

OBJECTIVES: We examined loop diuretic treatment before and 1-year after transcatheter aortic valve implantation (TAVI), as a proxy for changes in symptom severity and secondly assessed how changes in loop diuretics related to mortality risk. BACKGROUND: Randomized clinical trials suggest that approximately one third of patients undergoing TAVI do not achieve symptom relief, but "all-comer" data are lacking. METHODS: Using Danish nationwide registries, we identified all citizens, who underwent TAVI from 2008 to 2019 and were alive at 1-year post-discharge. Loop diuretic treatment pre-TAVI and at 1-year post-TAVI were assessed and grouped as receiving 1) no-loop diuretics; 2) low: 1-40 mg of furosemide (or equivalent bumetanide) daily; 3) intermediate: 41-120 mg of furosemide daily; or 4) high: >120 mg furosemide daily. RESULTS: Among the 4431 patients undergoing TAVI, 2173 (49%) patients were not treated with loop diuretics at the time of TAVI, 918 (21%) had low-loop diuretics, 881 (20%) had intermediate-loop diuretics, and 459 (10%) had high-loop diuretics. At 1-year post-TAVI, 893 (20%) patients had increased, 1010 (23%) had reduced, and 2528 (57%) had unchanged loop diuretic treatment. The cumulative 5-year risk of death in patients surviving one year, was 61% (95% CI: 56.4% to 65.3%) in patients with increased and 47% (95% CI: 44.9% to 49.9%) in patients with reduced/unchanged loop diuretic treatment, respectively. In multivariable Cox proportional hazard analysis, increased loop diuretic treatment was associated with a higher risk of death compared with reduced/unchanged loop diuretic treatment (Hazard ratio: 1.4; 95% CI: 1.22 to 1.52). CONCLUSIONS: Among patients undergoing TAVI, surviving one year, one fifth of patients had increased loop diuretic treatment, and a little over one fifth had reduced loop diuretic treatment 1-year post-procedure. In patients with increased diuretic treatment, the risk of death was higher compared to those with reduced/unchanged loop diuretic treatment.

Bleeding Events After Transcatheter Aortic Valve Replacement: JACC State-of-the-Art Review.

Transcatheter aortic valve replacement (TAVR) has gained over time a major reduction in procedural complications. Despite this, clinically relevant bleeding still occurs in a non-negligible proportion of patients and adversely affects prognosis. Patients with severe aortic stenosis are at heightened risk for spontaneous bleeding due to advanced age and a high comorbidity burden. Also, procedural factors and antithrombotic management contribute to define individual bleeding susceptibility. Bleeding prevention represents an emerging area for improving patient care. Because of the tight hemorrhagic/ischemic balance, a tailored approach based on individual bleeding-risk profile, such as a less invasive antithrombotic regimen or appropriate diagnostic preprocedural evaluation, should be pursued to avoid bleeding events. This review aims to provide an in-depth overview of bleeding events in the TAVR field, including definitions, timing and the extent of risk, and clinical impact, as well as updates on antithrombotic management and its potential influence on bleeding complications.

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.

Subclinical leaflet thrombosis and antithrombotic therapy post-TAVI: An LRT substudy.

BACKGROUND: Subclinical leaflet thrombosis (SLT) is characterized on computed tomography (CT) imaging as hypoattenuated leaflet thickening (HALT), reduced leaflet motion (RELM), and hypoattenuation affecting motion (HAM). How antithrombotic regimen type impacts SLT remains poorly understood. We evaluated how antithrombotic regimen type impacts SLT in low-risk subjects following transcatheter aortic valve implantation (TAVI). METHODS: This substudy is a post hoc analysis of the LRT 1.0 and 2.0 trials to assess SLT in subjects who underwent CT or transoesophageal echocardiogram (TOE) imaging at 30 days, stratified by antithrombotic regimen received (single antiplatelet therapy [SAPT], dual antiplatelet therapy [DAPT], or oral anticoagulation). We also utilized univariable logistic regression modelling to identify echocardiographic predictors of HALT. RESULTS: Rates of HALT, RELM, and HAM were all significantly lower with oral anticoagulation compared to SAPT or DAPT at 30 days (HALT: 2.6% vs 14.3% vs 17.2%, respectively, with p < 0.001; RELM: 1.8% vs 9.6% vs 13.1%, respectively, with p = 0.004; and HAM: 0.9% vs 8.5% vs 9.8%, respectively, with p = 0.011). Additionally, short-term oral anticoagulation was not associated with higher bleeding rates compared to SAPT or DAPT (0.8% vs. 1.8% vs. 3.6%, p = 0.291). The presence of HALT did not significantly impact echocardiographic haemodynamic parameters at 30 days. CONCLUSION: This is the largest study to date that evaluated the impact of different antithrombotic regimens on SLT in low-risk TAVI patients. Oral anticoagulation was associated with significantly lower rates of SLT at 30 days compared to DAPT or SAPT, and there was no apparent benefit of DAPT over SAPT.

Remimazolam Requires Less Vasopressor Support during Induction and Maintenance of General Anesthesia in Patients with Severe Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement: A Retrospective Analysis from a Single Center.

Introduction: We compared the hemodynamics during general anesthesia with remimazolam and conventional anesthetics in patients with severe aortic stenosis (AS). Methods: This was a retrospective single-center analysis. We reviewed the records of 42 patients who underwent transcatheter aortic valve implantation with a transfemoral artery approach under general anesthesia from January to December 2020. Patients were divided into three groups based on the general anesthetic used for (induction/maintenance) remimazolam/remimazolam (Group R/R), propofol/sevoflurane (Group P/S), and midazolam/propofol (Group M/P). Vasopressor use (ephedrine, phenylephrine, and noradrenaline) was compared among the groups. Results: The number of patients in each group was 15 (Group R/R), 13 (Group P/S), and 14 (Group M/P), with no significant difference in background characteristics and intraoperative vital signs. For anesthesia induction, doses of ephedrine and phenylephrine used were significantly lower in Group R/R (ephedrine [mg]: Group R/R 2 [0-4] vs. Group P/S 8 [8-12], P < 0.001, Group R/R vs. Group M/P 5 [0-15], P = 0.39; phenylephrine (mg): Group R/R 0 [0-0.08] vs. Group P/S 0.15 [0.10-0.20], P = 0.03, Group M/P 0.21 [0.04-0.40], P = 0.08). For anesthesia maintenance, the noradrenaline dose used was low in the Group R/R (noradrenaline [µg/kg/min]: Group R/R 0.019 [0.015-0.039], Group P/S 0.042 [0.035-0.045], P = 0.02, Group M/P 0.048 [0.040-0.059], P < 0.01). Conclusion: In patients with severe AS, induction and maintenance of anesthesia with remimazolam resulted in less overall vasopressor use than conventional general anesthetics.