Aortic Wall Elastic Properties in Case of Bicuspid Aortic Valve

Purpose of the ReviewBicuspid aortic valve (BAV) is associated with a significant risk of development of aneurysm and dissection of the ascending thoracic aorta. Development of what is called BAV associated aortopathy is particularly heterogeneous with an uncertain prognosis and with no prognostic biomarkers except for the aortic diameter. This situation leads to an important variability of the therapeutic strategy of this aortopathy. By reviewing the literature on aortic stiffness in the case of BAV, we aimed at evaluating its potential prognostic role in the development of aortic dilatation.Recent FindingsStudies evaluating aortic stiffness, with ultrasound or magnetic resonance imaging, converge toward the description of an increased segmental aortic stiffness in BAV patients regardless of age, diameter or aortic level, from the root to the arch. Even though there is a lack of longitudinal studies evaluating the progression of aortic dilatation, new data have recently shown the potential prognostic role of the maximal rate of systolic distension of the aortic wall with magnetic resonance imaging.SummaryAlthough the use of aortic distensibility calculation is a simple evaluation of stiffness that could be easily transposed in daily practice, its interpretation remains uncertain. New arterial stiffening indicators seem more promising but need a stronger validation

Comparative Molecular and Microbiologic Diagnosis of Bacterial Endocarditis

Sequencing of 16S rDNA, and of sodAint and rpoBint in some cases, was applied to DNA from heart valves of 46 patients (36 with definite and 10 with possible endocarditis). Sequence-based identifications were compared with those obtained with conventional methods. Among the 36 definite cases, 30 had positive blood cultures and 6 had negative cultures. Among the 30 positive cases, sequencing of 16S rDNA permitted identification of species (18), genus (8), or neither (4); sodAint and rpoBint sequencing was necessary for species identification in 8 cases. Species identifications were identical in only 61.5%, when conventional techniques and DNA sequencing were used. In five of the six blood culture–negative endocarditis cases, sequencing identified Bartonella quintana (3), B. henselae (1), and Streptococcus gallolyticus (1). Our results demonstrate a clear benefit of molecular identification, particularly in cases of blood culture–negative endocarditis and of possible endocarditis, to confirm or invalidate the diagnosis. Moreover, in 19.4% of the definite cases, the improvement in species identification by sequencing led to improved patient management

Case report Evidence of leaflet injury during percutaneous aortic valve deployment

Abstract It has been suggested that valved stent deployment during transcatheter aortic valve implantation may be responsible for traumatic injury to pericardial leaflets, especially with balloon expandable valved stents. However, such an injury has not been described nor reported so far. We here report the microscopic analysis of 4 Sapien-Edwards prostheses, 2 of which have been implanted in humans. There was no macroscopic evidence of traumatic injury to the pericardial leaflets of the percutaneous valves. However, pathological microscopic findings were observed in all of them. These mainly consisted of collagen fibers fragmentation and disruption. Areas of non-or mildly affected tissue were adjacent to areas of severely damaged tissue. The entire thickness of the leaflets might be involved. The severity of the lesions also differed among leaflets from a same prosthesis. Areas of plasmatic insudation were identified in one case. The disruption index was significantly higher in the Sapien group in comparison to the control group: 42.4% (14-63.5%) versus 17.5% (9.2-31%) ( p < 0.001). Although of limited size sample, this study does prove that traumatic injury to leaflets occurs during percutaneous valves implantation. This should prompt physicians to wait for the long-term results of this new technology before extending the indications to low-risk patients.

Necrotic Cell Sensor Clec4e Promotes a Proatherogenic Macrophage Phenotype Through Activation of the Unfolded Protein Response.

BACKGROUND: Atherosclerotic lesion expansion is characterized by the development of a lipid-rich necrotic core known to be associated with the occurrence of complications. Abnormal lipid handling, inflammation, and alteration of cell survival or proliferation contribute to necrotic core formation, but the molecular mechanisms involved in this process are not properly understood. C-type lectin receptor 4e (Clec4e) recognizes the cord factor of Mycobacterium tuberculosis but also senses molecular patterns released by necrotic cells and drives inflammation. METHODS: We hypothesized that activation of Clec4e signaling by necrosis is causally involved in atherogenesis. We addressed the impact of Clec4e activation on macrophage functions in vitro and on the development of atherosclerosis using low-density lipoprotein receptor-deficient (Ldlr-/-) mice in vivo. RESULTS: We show that Clec4e is expressed within human and mouse atherosclerotic lesions and is activated by necrotic lesion extracts. Clec4e signaling in macrophages inhibits cholesterol efflux and induces a Syk-mediated endoplasmic reticulum stress response, leading to the induction of proinflammatory mediators and growth factors. Chop and Ire1a deficiencies significantly limit Clec4e-dependent effects, whereas Atf3 deficiency aggravates Clec4e-mediated inflammation and alteration of cholesterol efflux. Repopulation of Ldlr-/- mice with Clec4e-/- bone marrow reduces lipid accumulation, endoplasmic reticulum stress, and macrophage inflammation and proliferation within the developing arterial lesions and significantly limits atherosclerosis. CONCLUSIONS: Our results identify a nonredundant role for Clec4e in coordinating major biological pathways involved in atherosclerosis and suggest that it may play similar roles in other chronic inflammatory diseases.This work was supported by a European Research Council grant (to Z.M.), and by the British Heart Foundation (Z. M.).This is the author accepted manuscript. The final version is available from the American Heart Association via https://doi.org/10.1161/CIRCULATIONAHA.116.02266

Necrotic Cell Sensor Clec4e Promotes a Proatherogenic Macrophage Phenotype Through Activation of the Unfolded Protein Response

$\textbf{Background}$: Atherosclerotic lesion expansion is characterized by the development of a lipid-rich necrotic core known to be associated with the occurrence of complications. Abnormal lipid handling, inflammation, and alteration of cell survival or proliferation contribute to necrotic core formation, but the molecular mechanisms involved in this process are not properly understood. C-type lectin receptor 4e (Clec4e) recognizes the cord factor of Mycobacterium $\textit{tuberculosis}$ but also senses molecular patterns released by necrotic cells and drives inflammation. $\textbf{Methods}$: We hypothesized that activation of Clec4e signaling by necrosis is causally involved in atherogenesis. We addressed the impact of Clec4e activation on macrophage functions in vitro and on the development of atherosclerosis using low-density lipoprotein receptor–deficient ($\textit{Ldlr}$$^{−/−}$) mice in vivo. $\textbf{Results}$: We show that Clec4e is expressed within human and mouse atherosclerotic lesions and is activated by necrotic lesion extracts. Clec4e signaling in macrophages inhibits cholesterol efflux and induces a Syk-mediated endoplasmic reticulum stress response, leading to the induction of proinflammatory mediators and growth factors. $\textit{Chop }$and $\textit{Ire1a}$ deficiencies significantly limit Clec4e-dependent effects, whereas $\textit{Atf}$3 deficiency aggravates Clec4e-mediated inflammation and alteration of cholesterol efflux. Repopulation of $\textit{Ldlr}$$^{−/−}$ mice with $\textit{Clec4e}$$^{−/−}$ bone marrow reduces lipid accumulation, endoplasmic reticulum stress, and macrophage inflammation and proliferation within the developing arterial lesions and significantly limits atherosclerosis. $\textbf{Conclusions}$: Our results identify a nonredundant role for Clec4e in coordinating major biological pathways involved in atherosclerosis and suggest that it may play similar roles in other chronic inflammatory diseases.This work was supported by a European Research Council grant (to Z.M.), and by the British Heart Foundation (Z. M.).This is the author accepted manuscript. The final version is available from the American Heart Association via https://doi.org/10.1161/CIRCULATIONAHA.116.02266

Imaging the dynamics of cardiac fiber orientation in vivo using 3D Ultrasound Backscatter Tensor Imaging

The assessment of myocardial fiber disarray is of major interest for the study of the progression of myocardial disease. However, time-resolved imaging of the myocardial structure remains unavailable in clinical practice. In this study, we introduce 3D Backscatter Tensor Imaging (3D-BTI), an entirely novel ultrasound-based imaging technique that can map the myocardial fibers orientation and its dynamics with a temporal resolution of 10 ms during a single cardiac cycle, non-invasively and in vivo in entire volumes. 3D-BTI is based on ultrafast volumetric ultrasound acquisitions, which are used to quantify the spatial coherence of backscattered echoes at each point of the volume. The capability of 3D-BTI to map the fibers orientation was evaluated in vitro in 5 myocardial samples. The helicoidal transmural variation of fiber angles was in good agreement with the one obtained by histological analysis. 3D-BTI was then performed to map the fiber orientation dynamics in vivo in the beating heart of an open-chest sheep at a volume rate of 90 volumes/s. Finally, the clinical feasibility of 3D-BTI was shown on a healthy volunteer. These initial results indicate that 3D-BTI could become a fully non-invasive technique to assess myocardial disarray at the bedside of patients

Vascular Smooth Muscle Cell Plasticity and Autophagy in Dissecting Aortic Aneurysms.

Objective- Recent studies suggested the occurrence of phenotypic switching of vascular smooth muscle cells (VSMCs) during the development of aortic aneurysm (AA). However, lineage-tracing studies are still lacking, and the behavior of VSMCs during the formation of dissecting AA is poorly understood. Approach and Results- We used multicolor lineage tracing of VSMCs to track their fate after injury in murine models of Ang II (angiotensin II)-induced dissecting AA. We also addressed the direct impact of autophagy on the response of VSMCs to AA dissection. Finally, we studied the relevance of these processes to human AAs. Here, we show that a subset of medial VSMCs undergoes clonal expansion and that VSMC outgrowths are observed in the adventitia and borders of the false channel during Ang II-induced development of dissecting AA. The clonally expanded VSMCs undergo phenotypic switching with downregulation of VSMC differentiation markers and upregulation of phagocytic markers, indicative of functional changes. In particular, autophagy and endoplasmic reticulum stress responses are activated in the injured VSMCs. Loss of autophagy in VSMCs through deletion of autophagy protein 5 gene ( Atg5) increases the susceptibility of VSMCs to death, enhances endoplasmic reticulum stress activation, and promotes IRE (inositol-requiring enzyme) 1α-dependent VSMC inflammation. These alterations culminate in increased severity of aortic disease and higher incidence of fatal AA dissection in mice with VSMC-restricted deletion of Atg5. We also report increased expression of autophagy and endoplasmic reticulum stress markers in VSMCs of human dissecting AAs. Conclusions- VSMCs undergo clonal expansion and phenotypic switching in Ang II-induced dissecting AAs in mice. We also identify a critical role for autophagy in regulating VSMC death and endoplasmic reticulum stress-dependent inflammation with important consequences for aortic wall homeostasis and repair

Genetic Depletion or Hyperresponsiveness of Natural Killer Cells Do Not Affect Atherosclerosis Development.

RATIONALE: Chronic inflammation is central in the development of atherosclerosis. Both innate and adaptive immunities are involved. Although several studies have evaluated the functions of natural killer (NK) cells in experimental animal models of atherosclerosis, it is not yet clear whether NK cells behave as protective or proatherogenic effectors. One of the main caveats of previous studies was the lack of specificity in targeting loss or gain of function of NK cells. OBJECTIVES: We used 2 selective genetic approaches to investigate the role of NK cells in atherosclerosis: (1) Ncr1iCre/+R26lsl-DTA/+ mice in which NK cells were depleted and (2) Noé mice in which NK cells are hyperresponsive. METHODS AND RESULTS: No difference in atherosclerotic lesion size was found in Ldlr-/- (low-density lipoprotein receptor null) mice transplanted with bone marrow (BM) cells from Ncr1iCreR26Rlsl-DTA , Noé, or wild-type mice. Also, no difference was observed in plaque composition in terms of collagen content, macrophage infiltration, or the immune profile, although Noé chimera had more IFN (interferon)-γ-producing NK cells, compared with wild-type mice. Then, we investigated the NK-cell selectivity of anti-asialoganglioside M1 antiserum, which was previously used to conclude the proatherogenicity of NK cells. Anti-asialoganglioside M1 treatment decreased atherosclerosis in both Ldlr-/- mice transplanted with Ncr1iCreR26Rlsl-DTA or wild-type bone marrow, indicating that its antiatherogenic effects are unrelated to NK-cell depletion, but to CD8+ T and NKT cells. Finally, to determine whether NK cells could contribute to the disease in conditions of pathological NK-cell overactivation, we treated irradiated Ldlr-/- mice reconstituted with either wild-type or Ncr1iCreR26Rlsl-DTA bone marrow with the viral mimic polyinosinic:polycytidylic acid and found a significant reduction of plaque size in NK-cell-deficient chimeric mice. CONCLUSIONS: Our findings, using state-of-the-art mouse models, demonstrate that NK cells have no direct effect on the natural development of hypercholesterolemia-induced atherosclerosis, but may play a role when an additional systemic NK-cell overactivation occurs

Imaging the dynamics of cardiac fiber orientation in vivo using 3D Ultrasound Backscatter Tensor Imaging

ABSTRACT: The assessment of myocardial fiber disarray is of major interest for the study of the progression of myocardial disease. However, time-resolved imaging of the myocardial structure remains unavailable in clinical practice. In this study, we introduce 3D Backscatter Tensor Imaging (3D-BTI), an entirely novel ultrasound-based imaging technique that can map the myocardial fibers orientation and its dynamics with a temporal resolution of 10 ms during a single cardiac cycle, non-invasively and in vivo in entire volumes. 3D-BTI is based on ultrafast volumetric ultrasound acquisitions, which are used to quantify the spatial coherence of backscattered echoes at each point of the volume. The capability of 3D-BTI to map the fibers orientation was evaluated in vitro in 5 myocardial samples. The helicoidal transmural variation of fiber angles was in good agreement with the one obtained by histological analysis. 3D-BTI was then performed to map the fiber orientation dynamics in vivo in the beating heart of an open-chest sheep at a volume rate of 90 volumes/s. Finally, the clinical feasibility of 3D-BTI was shown on a healthy volunteer. These initial results indicate that 3D-BTI could become a fully non-invasive technique to assess myocardial disarray at the bedside of patients

In Utero Exposure to Maternal Diabetes Impairs Vascular Expression of Prostacyclin Receptor in Rat Offspring

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