The prognostic value of automated coronary calcium derived by a deep learning approach on non-ECG gated CT images from ⁸²Rb-PET/CT myocardial perfusion imaging

Background: Assessment of both coronary artery calcium(CAC) scores and myocardial perfusion imaging(MPI) in patients suspected of coronary artery disease(CAD) provides incremental prognostic information. We used an automated method to determine CAC scores on low-dose attenuation correction CT(LDACT) images gathered during MPI in one single assessment. The prognostic value of this automated CAC score is unknown, we therefore investigated the association of this automated CAC scores and major adverse cardiovascular events(MACE) in a large chest-pain cohort. Method: We analyzed 747 symptomatic patients referred for 82RubidiumPET/CT, without a history of coronary revascularization. Ischemia was defined as a summed difference score≥2. We used a validated deep learning(DL) method to determine CAC scores. For survival analysis CAC scores were dichotomized as low(90 days after scanning) or nonfatal myocardial infarction. Cox proportional hazard analysis were performed to identify predictors of MACE. Results: During 4 years follow-up, 115 MACEs were observed. High CAC scores showed higher cumulative event rates, irrespective of ischemia (nonischemic: 25.8% vs 11.9% and ischemic: 57.6% vs 23.4%, P-values <0.001). Multivariable cox regression revealed both high CAC scores (HR 2.19 95%CI 1.43–3.35) and ischemia (HR 2.56 95%CI 1.71–3.35) as independent predictors of MACE. Addition of automated CAC scores showed a net reclassification improvement of 0.13(0.022–0.245). Conclusion: Automatically derived CAC scores determined during a single imaging session are independently associated with MACE. This validated DL method could improve risk stratification and subsequently lead to more personalized treatment in patients suspected of CAD

IgM antibody level against proinflammatory bacterial peptidoglycan is inversely correlated with extent of atherosclerotic disease

Objective: Atherosclerosis may lead to acute clinical events by rupture of a vulnerable atherosclerotic plaque. Previously, we demonstrated that peptidoglycan (PGN), a major cell wall component of gram-positive bacteria that induces production of proinflammatory cytokines through TLR2 and CD14, is prevalent in atherosclerotic lesions with histological features associated with plaque vulnerability. We hypothesized that in atherosclerotic patients antibody levels against PGN may differ compared with matched controls. Methods and results: ELISA was performed to measure immunoglobulin levels against PGN in sera of 80 atherosclerotic patients versus 77 control patients with an increased cardiovascular risk, frequency-matched for age, sex and risk factors for atherosclerotic disease. In all patients and controls, intima-media (IMT) thickness was assessed using an array transducer. Significantly lower levels of IgM directed against PGN were found in atherosclerotic patients compared with the control patients without clinically manifested disease (P=0.02). The IgM levels against PGN decreased with increasing mean common carotid IMT thickness (P=0.006). Conclusions: These results show that patients suffering from atherosclerotic disease have decreased IgM levels against PGN. The data suggest that an antibody response against PGN could have a protective effect against the development or activity of atherosclerotic disease

Mast cell distribution in human carotid atherosclerotic plaque differs significantly by histological segment

Mast cells (MCs) are important contributors to atherosclerotic plaque progression. For prospective studies on mast cell contributions to plaque instability, the distribution of intraplaque MCs needs to be elucidated. Plaque stability is generally histologically assessed by dividing the plaque specimen into segments to be scored on an ordinal scale. However, owing to competitive use, studies may have to deviate to adjacent segments, yet intersegment differences of plaque characteristics, especially MCs, are largely unknown. Therefore, the hypothesis that there is no segment to segment difference in MC distribution between atherosclerotic plaque segments was tested, and intersegment associations between MCs and other plaque characteristics was investigated.\nTwenty-six carotid atherosclerotic plaques from patients undergoing carotid endarterectomy included in the Athero-Express Biobank were analysed. The plaque was divided in 5 mm segments, differentiating between the culprit lesion (segment 0), adjacent segments (-1/+1) and more distant segments (-2/+2) for the presence of MCs. The associations between the intersegment distribution of MCs and smooth muscle cells, macrophage content, and microvessel density in the culprit lesion were studied.\nA statistically significant difference in MCs/mm2 between the different plaque segments (p 2 between the culprit and adjacent segment (p = .037) and between the culprit lesion and the more distant segment (p 2 in multiple different segments were positively correlated with microvessel density and macrophage content in the culprit lesion.\nMC numbers reveal significant intersegment differences in human carotid plaques. Future histological studies on MCs should use a standardised segment for plaque characterisation as plaque segments cannot be used interchangeably for histological MC analyses.Biopharmaceutic

Shear-stress and wall-stress regulation of vascular remodeling after balloon angioplasty: effect of matrix metalloproteinase inhibition

BACKGROUND: Constrictive vascular remodeling (VR) is the most significant component of restenosis after balloon angioplasty (PTA). Whereas in physiologi

Intersecting single-cell transcriptomics and genome-wide association studies identifies crucial cell populations and candidate genes for atherosclerosis

Genome-wide association studies (GWASs) have discovered hundreds of common genetic variants for atherosclerotic disease and cardiovascular risk factors. The translation of susceptibility loci into biological mechanisms and targets for drug discovery remains challenging. Intersecting genetic and gene expression data has led to the identification of candidate genes. However, previously studied tissues are often non-diseased and heterogeneous in cell composition, hindering accurate candidate prioritization. Therefore, we analysed single-cell transcriptomics from atherosclerotic plaques for cell-type-specific expression to identify atherosclerosis-associated candidate gene-cell pairs.\nWe applied gene-based analyses using GWAS summary statistics from 46 atherosclerotic and cardiovascular disease, risk factors, and other traits. We then intersected these candidates with single-cell RNA sequencing (scRNA-seq) data to identify genes specific for individual cell (sub)populations in atherosclerotic plaques. The coronary artery disease (CAD) loci demonstrated a prominent signal in plaque smooth muscle cells (SMCs) (SKI, KANK2, and SORT1) P-adj. = 0.0012, and endothelial cells (ECs) (SLC44A1, ATP2B1) P-adj. = 0.0011. Finally, we used liver-derived scRNA-seq data and showed hepatocyte-specific enrichment of genes involved in serum lipid levels.\nWe discovered novel and known gene-cell pairs pointing to new biological mechanisms of atherosclerotic disease. We highlight that loci associated with CAD reveal prominent association levels in mainly plaque SMC and EC populations. We present an intuitive single-cell transcriptomics-driven workflow rooted in human large-scale genetic studies to identify putative candidate genes and affected cells associated with cardiovascular traits. Collectively, our workflow allows for the identification of cell-specific targets relevant for atherosclerosis and can be universally applied to other complex genetic diseases and traits.Biopharmaceutic

Associations of autozygosity with a broad range of human phenotypes

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p <0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding.Peer reviewe

Cloning, sequence analysis and expression of the hyperglycemic neurohormone family in crustaceans

Contains fulltext : mmubn000001_202171221.pdf (publisher's version ) (Open Access)Promotores : G. Martens, J. Denucé en F. Van Herp132 p

Innate immune signaling in cardiac ischemia

Despite advances in treatment of patients who suffer from ischemic heart disease, morbidity related to myocardial infarction is increasing in Western societies. Acute and chronic immune responses elicited by myocardial ischemia have an important role in the functional deterioration of the heart. Research on modulation of the inflammatory responses was focused on effector mediators such as leukocytes. However, increasing evidence indicates that various endogenous ligands that act as 'danger signals', also called danger-associated molecular patterns (DAMPs), are released upon injury and modulate inflammation. Originally described as part of the first-line defense against invading microorganisms, several Toll-like receptors (TLRs) on leukocytes and parenchymal cells have now been shown to respond to such signals and to have a pivotal role in noninfectious pathological cardiovascular conditions, such as ischemia-reperfusion injury and heart failure. From a therapeutic perspective, DAMPs are attractive targets owing to their specific induction after injury. In this Review, we will discuss innate immune activation through TLRs in cardiac ischemia mediated by DAMPs