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BACKGROUND: Calcific aortic valve disease (CAVD) is characterized by a phenotypic switch of valvular interstitial cells to bone-forming cells. Toll-like receptors (TLRs) are evolutionarily conserved pattern recognition receptors at the interface between innate immunity and tissue repair. Type I interferons (IFNs) are not only crucial for an adequate antiviral response but also implicated in bone formation. We hypothesized that the accumulation of endogenous TLR3 ligands in the valvular leaflets may promote the generation of osteoblast-like cells through enhanced type I IFN signaling. METHODS: Human valvular interstitial cells isolated from aortic valves were challenged with mechanical strain or synthetic TLR3 agonists and analyzed for bone formation, gene expression profiles, and IFN signaling pathways. Different inhibitors were used to delineate the engaged signaling pathways. Moreover, we screened a variety of potential lipids and proteoglycans known to accumulate in CAVD lesions as potential TLR3 ligands. Ligand-receptor interactions were characterized by in silico modeling and verified through immunoprecipitation experiments. Biglycan (Bgn), Tlr3, and IFN-α/β receptor alpha chain (Ifnar1)-deficient mice and a specific zebrafish model were used to study the implication of the biglycan (BGN)-TLR3-IFN axis in both CAVD and bone formation in vivo. Two large-scale cohorts (GERA [Genetic Epidemiology Research on Adult Health and Aging], n=55 192 with 3469 aortic stenosis cases; UK Biobank, n=257 231 with 2213 aortic stenosis cases) were examined for genetic variation at genes implicated in BGN-TLR3-IFN signaling associating with CAVD in humans. RESULTS: Here, we identify TLR3 as a central molecular regulator of calcification in valvular interstitial cells and unravel BGN as a new endogenous agonist of TLR3. Posttranslational BGN maturation by xylosyltransferase 1 (XYLT1) is required for TLR3 activation. Moreover, BGN induces the transdifferentiation of valvular interstitial cells into bone-forming osteoblasts through the TLR3-dependent induction of type I IFNs. It is intriguing that Bgn-/-, Tlr3-/-, and Ifnar1-/- mice are protected against CAVD and display impaired bone formation. Meta-analysis of 2 large-scale cohorts with >300 000 individuals reveals that genetic variation at loci relevant to the XYLT1-BGN-TLR3-interferon-α/β receptor alpha chain (IFNAR) 1 pathway is associated with CAVD in humans. CONCLUSIONS: This study identifies the BGN-TLR3-IFNAR1 axis as an evolutionarily conserved pathway governing calcification of the aortic valve and reveals a potential therapeutic target to prevent CAVD.

The impact of sex-differences on the release of cardiac biomarkers after coronary artery bypass grafting (CABG) remains unknown. The aim of our study was to (1) investigate the impact of sex-differences in cardiac biomarker release after CABG and (2) determine sex-specific thresholds for high-sensitivity cardiac troponin (hs-cTn) and creatine kinase-myocardial band (CK-MB) associated with 30-day major adverse cardiovascular events (MACE) and mortality. A consecutive cohort of 3687 patients, comprising 643 women (17.4%) and 3044 men (82.6%), undergoing CABG from 2008 to 2021 in 2 tertiary university centers with serial postoperative cTn and CK-MB measurement was analyzed. The composite primary outcome was MACE at 30 days. Secondary end points were 30-day mortality and 5-year mortality and MACE. Sex-specific thresholds for cTn and CK-MB were determined. Lower levels of cTn were found in women after CABG (69.18 vs 77.57 times the upper reference limit [URL]; P <.001). The optimal threshold value for cTn was calculated at 94.36 times the URL for female patients and 206.07 times the URL for male patients to predict 30-day MACE. Female patients missed by a general threshold had increased risk for MACE or death within 30 days (cTn: MACE: odds ratio [OR], 3.78; 95% CI, 1.03-13.08; P =.035; death: OR, 4.98; 95% CI, 1.20-20.61; P =.027; CK-MB: MACE: OR, 10.04; 95% CI, 2.07-48.75; P <.001; death: OR 13.59; 95% CI, 2.66-69.47; P =.002). We provide evidence for sex-specific differences in the outcome and biomarker release after CABG. Sex-specific cutoffs are necessary for the diagnosis of perioperative myocardial injury to improve outcomes of women after CABG. [Display omitted] [ABSTRACT FROM AUTHOR]

Background and Aims In chronic ischaemic heart failure, revascularisation strategies control symptoms but are less effective in improving left ventricular ejection fraction (LVEF). The aim of this trial is to investigate the safety of cardiac shockwave therapy (SWT) as a novel treatment option and its efficacy in increasing cardiac function by inducing angiogenesis and regeneration in hibernating myocardium. Methods In this single-blind, parallel-group, sham-controlled trial (cardiac shockwave therapy for ischemic heart failure, CAST-HF; NCT03859466) patients with LVEF ≤40% requiring surgical revascularisation were enrolled. Patients were randomly assigned to undergo direct cardiac SWT or sham treatment in addition to coronary bypass surgery. The primary efficacy endpoint was the improvement in LVEF measured by cardiac magnetic resonance imaging from baseline to 360 days. Results Overall, 63 patients were randomized, out of which 30 patients of the SWT group and 28 patients of the Sham group attained 1-year follow-up of the primary endpoint. Greater improvement in LVEF was observed in the SWT group (Δ from baseline to 360 days: SWT 11.3%, SD 8.8; Sham 6.3%, SD 7.4, P =.0146). Secondary endpoints included the 6-minute walking test, where patients randomized in the SWT group showed a greater Δ from baseline to 360 days (127.5 m, SD 110.6) than patients in the Sham group (43.6 m, SD 172.1) (P =.028) and Minnesota Living with Heart Failure Questionnaire score on day 360, which was 11.0 points (SD 19.1) for the SWT group and 17.3 points (SD 15.1) for the Sham group (P =.15). Two patients in the treatment group died for non-device-related reasons. Conclusions In conclusion, the CAST-HF trial indicates that direct cardiac SWT, in addition to coronary bypass surgery improves LVEF and physical capacity in patients with ischaemic heart failure. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES Myocardial ischaemia following coronary artery bypass grafting (CABG) is a potentially devastating complication. Nevertheless, the incidence, aetiology and prognostic relevance of unplanned coronary angiography (uCAG) remain understudied. We aimed to investigate the prevalence and outcome of patients undergoing urgent, uCAG in the postoperative period following CABG. METHODS We screened all patients undergoing isolated elective CABG in an academic referral centre between 2016 and 2021 and identified patients undergoing uCAG within 30 days of surgery. For uCAG patients, a distinction was made between patients undergoing re-revascularization (REV) and patients receiving conservative management (CON). The primary outcomes were 30-day mortality and unadjusted and adjusted long-term survival. Secondary outcomes were the indication for and prevalence of uCAG and urgent revascularization. RESULTS Of the 1918 patients undergoing isolated CABG, 78 individuals needed uCAG (4.1%), of whom 45 underwent immediate revascularization (REV group; 2.3% overall, 57% within the uCAG group, median age 69.9 years) and 33 were treated conservatively (CONS group; 1.7% overall, 42% within the uCAG group, median age 69.1 years). Patients undergoing uCAG (n  = 78) had a higher 30-day mortality than patients not undergoing uCAG (n  = 1840, 30-day mortality: 9.0% vs 0.4%, P  < 0.001). Long-term survival was significantly decreased in patients undergoing uCAG in both unadjusted (hazard ratio 2.20, 95% confidence interval 1.30–3.73) and EuroSCORE-, age- and sex-adjusted models (hazard ratio uCAG 2.03, 95% confidence interval 1.16–3.56). CONCLUSIONS Unplanned postoperative coronary angiography is performed in 4.1% of isolated CABG procedures, and patients in need of such urgent invasive evaluation are subjected to decreased short- and long-term survival. [ABSTRACT FROM AUTHOR]

OBJECTIVES Restrictive cardiomyopathy is rare and is generally associated with worse clinical outcomes compared to other cardiomyopathies. Ventricular assist device (VAD) support for these children is seldom applied and often hampered by the surgical difficulties. METHODS All paediatric (<19 years) patients with a restricted cardiomyopathy supported by a VAD from the EUROMACS database were included and compared to patients with a dilated cardiomyopathy (retrospective database analyses). Participating centres were retrospectively contacted to provide additional detailed echo and Swan Ganz measurements to analyse the effect of VAD support on pulmonary artery pressure and right ventricular function. RESULTS Forty-four paediatric VAD-supported patients diagnosed with restricted cardiomyopathy were included, with a median age at implantation of 5.0 years. Twenty-six of the 44 patient with a restricted cardiomyopathy survived to transplantation (59.1%), 16 died (36.4%) and 2 are still on ongoing VAD support (4.5%) after a median duration of support of 95.5 days (interquartile range 33.3–217.8). Transplantation probability after 1 and 2 years of VAD support in patients with a restricted cardiomyopathy were comparable to patients with a dilated cardiomyopathy (52.3% vs 51.4% and 59.5% vs 60.1%, P  = 0.868). However, mortality probability was higher in the restricted cardiomyopathy cohort (35.8% vs 17.0% and 35.8% vs 19.0%, P  = 0.005). Adverse event rates were high (cerebrovascular accident in 31.8%, pump thrombosis in 29.5%, major bleeding 25.0%, eventual biventricular support in 59.1%). In the atrially cannulated group, cerebrovascular accident and pump thrombosis occurred in twice as much patients (21.1% vs 40.0%, P  = 0.595 and 15.8% vs 40.0%, P  = 0.464; probably non-significant due to the small numbers). Pulmonary arterial pressures improved after implantation of a VAD, and 6 patients who were initially labelled as ineligible due to pulmonary hypertension could eventually be transplanted. CONCLUSIONS VAD support in children with a restricted cardiomyopathy is rarely performed. Mortality and adverse event rates are high. On the other hand, survival to cardiac transplantation was 59.1% with all patients surviving the 1st 30 days after cardiac transplantation. Pulmonary arterial pressures improved while on support, potentially making cardiac transplantation a viable option for previously ineligible children. [ABSTRACT FROM AUTHOR]

OBJECTIVES The use of ventricular assist devices (VADs) in children is increasing. However, absolute numbers in individual centres and countries remain small. Collaborative efforts such as the Paedi-European Registry for Patients with Mechanical Circulatory Support (EUROMACS) are therefore essential for combining international experience with paediatric VADs. Our goal was to present the results from the fourth Paedi-EUROMACS report. METHODS All paediatric (<19 years) patients from the EUROMACS database supported by a VAD were included. Patients were stratified into a congenital heart disease (CHD) group and a group with a non-congenital aetiology. End points included mortality, a transplant and recovery. Cox proportional hazard models were used to explore associated factors for mortality, cerebrovascular accident and pump thrombosis. RESULTS A total of 590 primary implants were included. The congenital group was significantly younger (2.5 vs 8.0 years, respectively, P  < 0.001) and was more commonly supported by a pulsatile flow device (73.5% vs 59.9%, P  < 0.001). Mortality was significantly higher in the congenital group (30.8% vs 20.4%, P  = 0.009) than in the non-congenital group. However, in multivariable analyses, CHD was not significantly associated with mortality [hazard ratio (HR) 1.285; confidence interval (CI) 0.8111–2.036, P  = 0.740]. Pump thrombosis was the most frequently reported adverse event (377 events in 132 patients; 0.925 events per patient-year) and was significantly associated with body surface area (HR 0.524, CI 0.333–0.823, P  = 0.005), CHD (HR 1.641, CI 1.054–2.555, P  = 0.028) and pulsatile flow support (HR 2.345, CI 1.406–3.910, P  = 0.001) in multivariable analyses. CONCLUSIONS This fourth Paedi-EUROMACS report highlights the increasing use of paediatric VADs. The patient populations with congenital and non-congenital aetiologies exhibit distinct characteristics and clinical outcomes. [ABSTRACT FROM AUTHOR]

The article discusses the importance of timely surgical intervention for severe tricuspid regurgitation, emphasizing the need for better risk stratification and patient selection. It highlights the benefits of tricuspid valve surgery, especially in patients with low to intermediate risk scores, and the advancements in surgical techniques that have improved outcomes. The authors stress the significance of early treatment to prevent irreversible damage and emphasize that conservative approaches may not be effective in advanced cases of tricuspid valve disease. [Extracted from the article]

Background Failing bioprosthesis is an emerging issue due to (i) a shift towards liberal bioprosthesis implantation instead of mechanical prosthesis and (ii) an ageing population. Management of high-risk patients with bioprosthesis degeneration remains challenging. Case summary An 82-year-old patient with history of aortic and mitral valve replacement six years before presents with severe dyspnoea. Echocardiograpic assessment reveals (i) structural valve degeneration of the mitral prosthesis (severe stenosis and regurgitation) with concomitant major annular calcifications and (ii) structural valve degeneration of the aortic prosthesis with low-flow, low-gradient restenosis. Due to mitral annular calcifications, the risk of double valve re-replacement and the age of the patient conventional reoperation was deemed very high. The patient is evaluated for transapical double valve implantation. This option is rejected due to the high risk of left ventricular outflow obstruction. The patient is treated with an open transcatheter double valve-in-valve procedure at the following sequence: leaflet resection of the mitral bioprosthesis, mitral valve implantation and fixation under direct view, leaflet resection of the aortic bioprosthesis, and valve frame cracking and aortic valve implantation under direct view. Post-bypass echocardiography shows neither left ventricular outflow tract obstruction nor paravalvular leak or prosthesis dysfunction. The patient is extubated on the first post-operative day and transferred to normal care unit. Discussion Open transcatheter double valve-in-valve replacement for degenerated bioprostheses on the arrested heart might be a valuable alternative to treat selected high-risk patients with bioprosthetic valve degeneration. [ABSTRACT FROM AUTHOR]