Abstract Background We recently demonstrated in an experimental model the expression of tissue factor (TF) in aortic valves. Thrombin, generated at the end of the TF-initiated coagulation cascade, ...has been shown to cleave the anti-calcific osteopontin (OSP) liberating the pro-inflammatory OSP N-half. Objectives We hypothesized that TF might play an important role in calcific aortic valve stenosis (AS) through thrombin generation and hence evaluated the valvular expression of TF and its inhibitor (TF pathway inhibitor), α-thrombin, OSP and its thrombin-cleaved form (OSP N-half). Methods Calcified aortic valves were obtained from patients undergoing valve replacement. Protein expression was evaluated by immunostaining and measured using ELISA kits. Transcripts were analyzed by RT-PCR. Results We included 52 patients (31 men; age 70 ± 10 years; aortic valve area index 0.35 ± 0.13 cm2 /m2 ). Immunohistochemistry revealed that TF, OSP and α-thrombin expressions were associated with calcifications at the aortic side of the leaflets. There was an overexpression in calcified regions as compared to non-calcified zones of TF (733.3 ± 70.5 pg/mg vs. 429.4 ± 73.2 pg/mg; p < 0.0001), OSP (88.9 ± 12.7 ng/mg vs. 15.0 ± 3.3 ng/mg; p < 0.0001) and OSP N-half (0.41 ± 0.06 pmol/mg vs. 0.056 ± 0.011 pmol/mg; p < 0.0001). Additionally, both TF and α-thrombin expressions were associated with OSP N-half ( r = 0.52; p < 0.0001 and r = 0.33; p = 0.019, respectively). Conclusions Aortic leaflet TF and α-thrombin expressions and their association with the thrombin-cleaved form of OSP, are a new and important feature of AS. We hypothesize that TF may be involved in the mineralization process of aortic valves by enhancing the generation of the pro-inflammatory OSP N-half through thrombin induction. This pathway deserves further studies to address its implication in the aortic valve calcification process.
Humans cannot synthesize N‐glycolylneuraminic acid (Neu5Gc) but dietary Neu5Gc can be absorbed and deposited on endothelial cells (ECs) and diet‐induced anti‐Neu5Gc antibodies (Abs) develop early in ...human life. While the interaction of Neu5Gc and diet‐induced anti‐Neu5Gc Abs occurs in all normal individuals, endothelium activation by elicited anti‐Neu5Gc Abs following a challenge with animal‐derived materials, such as following xenotransplantation, had been postulated. Ten primary human EC preparations were cultured with affinity‐purified anti‐Neu5Gc Abs from human sera obtained before or after exposure to Neu5Gc‐glycosylated rabbit IgGs (elicited Abs). RNAs of each EC preparation stimulated in various conditions by purified Abs were exhaustively sequenced. EC transcriptomic patterns induced by elicited anti‐Neu5Gc Abs, compared with pre‐existing ones, were analyzed. qPCR, cytokines/chemokines release, and apoptosis were tested on some EC preparations. The data showed that anti‐Neu5Gc Abs induced 967 differentially expressed (DE) genes. Most DE genes are shared following EC activation by pre‐existing or anti‐human T‐cell globulin (ATG)‐elicited anti‐Neu5Gc Abs. Compared with pre‐existing anti‐Neu5Gc Abs, which are normal component of ECs environment, elicited anti‐Neu5Gc Abs down‐regulated 66 genes, including master genes of EC function. Furthermore, elicited anti‐Neu5Gc Abs combined with complement‐containing serum down‐regulated most transcripts mobilized by serum alone. Both types of anti‐Neu5Gc Abs‐induced a dose‐ and complement‐dependent release of selected cytokines and chemokines. Altogether, these data show that, compared with pre‐existing anti‐Neu5Gc Abs, ATG‐elicited anti‐Neu5Gc Abs specifically modulate genes related to cytokine responses, MAPkinase cascades, chemotaxis, and integrins and do not skew the EC transcriptome toward a pro‐inflammatory profile in vitro.
Various definitions of very severe (VS) tricuspid regurgitation (TR) have been proposed based on the effective regurgitant orifice area (EROA) or tricuspid coaptation gap (TCG). Because of the ...inherent limitations associated with the EROA, we hypothesized that the TCG would be more suitable for defining VSTR and predicting outcomes.
In this French multicentre retrospective study, we included 606 patients with ≥moderate-to-severe isolated functional TR (without structural valve disease or an overt cardiac cause) according to the recommendations of the European Association of Cardiovascular Imaging. Patients were further stratified into VSTR according to the EROA (≥60 mm
) and then according to the TCG (≥10 mm). The primary endpoint was all-cause mortality and the secondary endpoint was cardiovascular mortality.
The relationship between the EROA and TCG was poor (
=
0.22), especially when the size of the defect was large. Four-year survival was comparable between patients with an EROA <60 mm
vs. ≥60 mm
(68 ± 3% vs. 64 ± 5%,
= 0.89). A TCG ≥10 mm was associated with lower four-year survival than a TCG <10 mm (53 ± 7% vs. 69 ± 3%,
< 0.001). After adjustment for covariates, including comorbidity, symptoms, dose of diuretics, and right ventricular dilatation and dysfunction, a TCG ≥10 mm remained independently associated with higher all-cause mortality (adjusted HR95% CI = 1.471.13-2.21,
= 0.019) and cardiovascular mortality (adjusted HR95% CI = 2.121.33-3.25,
= 0.001), whereas an EROA ≥60 mm
was not associated with all-cause or cardiovascular mortality (adjusted HR95% CI: 1.160.81-1.64,
= 0.416, and adjusted HR95% CI: 1.070.68-1.68,
= 0.784, respectively).
The correlation between the TCG and EROA is weak and decreases with increasing defect size. A TCG ≥10 mm is associated with increased all-cause and cardiovascular mortality and should be used to define VSTR in isolated significant functional TR.
The cause of structural valve deterioration (SVD) is unclear. Therefore, we investigated oxidative stress markers in sera from patients with bioprosthetic heart valves (BHVs) and their association ...with SVD. Blood samples were taken from SVD (Phase A) and BHV patients during the first 24 (Phase B1) and >48 months (Phase B2) after BHV implantation to assess total antioxidant capacity (TAC), malondialdehyde (MDA), and nitrotyrosine (NT). The results show that MDA levels increased significantly 1 month after surgery in all groups but were higher at 6 months only in incipient SVD patients. NT levels increased gradually for the first 24 months after implantation in the BHV group. Patients with transcatheter aortic valve implantation (TAVI) showed even higher levels of stress markers. After >48 months, MDA and NT continued to increase in BHV patients with a further elevation after 60–72 months; however, these levels were significantly lower in the incipient and established SVD groups. In conclusion, oxidative stress may play a significant role in SVD, increasing early after BHV implantation, especially in TAVI cases, and also after 48 months’ follow-up, but decreasing when SVD develops. Oxidative stress potentially represents a target of therapeutic intervention and a biomarker of BHV dysfunction.
The relative impact of comorbidities and parameters of left ventricular diastolic function on clinical outcome has not been thoroughly investigated in patients who are hospitalized for heart failure ...decompensation and found to have preserved ejection fraction. We identified 98 HFpEF patients among 1452 patients admitted with acute heart failure. Clinical characteristics, hemoglobin levels, estimated glomerular filtration rate (eGFR), B-type natriuretic peptide (BNP) and Doppler-echocardiographic parameters were analyzed. The primary end point of the study combined death and rehospitalization for decompensated heart failure after the index hospitalization. Mean age was 76 ± 9 years. LV ejection fraction,
E
/
E
a
ratio, and estimated systolic pulmonary artery pressure were 61 (55–67)%, 12.9 (9.4–15.1), 40 (32–46) mmHg, respectively. BNP values, hemoglobin and eGFR were 287 (164–562) pg/mL, 11.3 (10.4–12.4) g/dL and 45 (37–74) mL/min/m
2
, respectively. During a mean follow-up of 17 ± 11 months, 56% reached the primary endpoint of the study: 31 died and 24 were re-hospitalizated for heart failure. Diabetes HR = 1.76 (1.03–3.00),
P
= 0.039, lower systolic blood pressure HR = 0.99 (0.97–0.99),
P
= 0.016, hemoglobin HR = 0.62 (0.49–0.76),
P
< 0.0001, and eGFR HR = 0.98 (0.97–0.99),
P
= 0.004 were associated with a poor outcome. Neither BNP nor echocardiographic parameters were correlated with outcome. Comorbidities primarily correlate with outcome in patients with HFpEF.
The fibrous annulus of the mitral valve plays an important role in valvular function and cardiac physiology, while normal variation in the size of cardiovascular anatomy may share a genetic link with ...common and rare disease. We derived automated estimates of mitral valve annular diameter in the 4-chamber view from 32,220 MRI images from the UK Biobank at ventricular systole and diastole as the basis for GWAS. Mitral annular dimensions corresponded to previously described anatomical norms, and GWAS inclusive of 4 population strata identified 10 loci, including possibly novel loci (GOSR2, ERBB4, MCTP2, MCPH1) and genes related to cardiac contractility (BAG3, TTN, RBFOX1). ATAC-Seq of primary mitral valve tissue localized multiple variants to regions of open chromatin in biologically relevant cell types and rs17608766 to an algorithmically predicted enhancer element in GOSR2. We observed strong genetic correlation with measures of contractility and mitral valve disease and clinical correlations with heart failure, cerebrovascular disease, and ventricular arrhythmias. Polygenic scoring of mitral valve annular diameter in systole was predictive of risk mitral valve prolapse across 4 cohorts. In summary, genetic and clinical studies of mitral valve annular diameter revealed genetic determinants of mitral valve biology, while highlighting clinical associations. Polygenic determinants of mitral valve annular diameter may represent an independent risk factor for mitral prolapse. Overall, computationally estimated phenotypes derived at scale from medical imaging represent an important substrate for genetic discovery and clinical risk prediction.
Structural valve deterioration (SVD) of bioprosthetic heart valves (BHVs) has great clinical and economic consequences. Notably, immunity against BHVs plays a major role in SVD, especially when ...implanted in young and middle-aged patients. However, the complex pathogenesis of SVD remains to be fully characterized, and analyses of commercial BHVs in standardized-preclinical settings are needed for further advancement. Here, we studied the immune response to commercial BHV tissue of bovine, porcine, and equine origin after subcutaneous implantation into adult α1,3-galactosyltransferase-knockout (Gal KO) mice. The levels of serum anti-galactose α1,3-galactose (Gal) and -non-Gal IgM and IgG antibodies were determined up to 2 months post-implantation. Based on histological analyses, all BHV tissues studied triggered distinct infiltrating cellular immune responses that related to tissue degeneration. Increased anti-Gal antibody levels were found in serum after ATS 3f and Freedom/Solo implantation but not for Crown or Hancock II grafts. Overall, there were no correlations between cellular-immunity scores and post-implantation antibodies, suggesting these are independent factors differentially affecting the outcome of distinct commercial BHVs. These findings provide further insights into the understanding of SVD immunopathogenesis and highlight the need to evaluate immune responses as a confounding factor.
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