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Carcinoid heart disease, a severe complication of neuroendocrine tumors, affects up to 50% of patients and is challenging to treat due to a limited understanding of its mechanisms. The disease is characterized by structural remodeling and thickening of the right heart valves, associated with elevated levels of serotonin (5-HT) released from tumor cells that have spread to the liver. Existing animal models have limitations as they either use mice with compromised immune systems or employ methods that don’t consistently evaluate valve changes. We developed an improved experimental model by implanting syngeneic liver-targeted melanoma cells that were genetically engineered to produce 5-HT through the expression of the enzyme tryptophan hydroxylase type 1 (Tph1) in wild-type C57BL/6 mice. We introduced high-resolution episcopic microscopy (HREM) for comprehensive assessment of valve pathology and morphometry. Five weeks after implantation, mice exhibited increased 5-HT/creatinine urinary level ratios and HREM imaging showed selective thickening and structural remodeling of right heart valves (tricuspid and pulmonary), correlating with 5-HT/creatinine urinary level ratio, while left heart valves remained unaffected. Our data suggest that this non-immunosuppressed, right-heart valve restricted model reproduces key features of human carcinoid heart disease and, combined with HREM analysis, provides a valuable platform for studying disease mechanisms and testing potential therapies.

The accumulation of calcified material in cardiovascular tissue is thought to involve cytochemical, extracellular matrix and systemic signals; however, its precise composition and nanoscale architecture remain largely unexplored. Using nano-analytical electron microscopy techniques, we examined valves, aortae and coronary arteries from patients with and without calcific cardiovascular disease and detected spherical calcium phosphate particles, regardless of the presence of calcific lesions. We also examined lesions after sectioning with a focused ion beam and found that the spherical particles are composed of highly crystalline hydroxyapatite that crystallographically and structurally differs from bone mineral. Taken together, these data suggest that mineralized spherical particles may play a fundamental role in calcific lesion formation. Their ubiquitous presence in varied cardiovascular tissues and from patients with a spectrum of diseases further suggests that lesion formation may follow a common process. Indeed, applying materials science techniques to ectopic and orthotopic calcification has great potential to lend critical insights into pathophysiological processes underlying calcific cardiovascular disease. Analytical techniques reveal that spherical calcium phosphate particles are the first mineralized structures to be formed in the calcification process in cardiovascular tissues. Furthermore, the inner sections of calcified lesions in patients with various cardiovascular diseases are identified as highly crystalline, spherical hydroxyapatite particles that differ in structure from bone mineral.

Cardiovascular magnetic resonance (CMR) phase contrast imaging has undergone a wide range of changes with the development and availability of improved calibration procedures, visualization tools, and analysis methods. This article provides a comprehensive review of the current state-of-the-art in CMR phase contrast imaging methodology, clinical applications including summaries of past clinical performance, and emerging research and clinical applications that utilize today’s latest technology.

Valvular heart disease (VHD) is a highly prevalent age‐associated cardiovascular pathology. VHD can be characterised by stenosis, an increase in valve stiffening commonly due to leaflet calcification, or regurgitation, where backflow of blood can occur as a result of valve remodelling. At present, there is a paucity of spontaneous animal models of valve disease which would aid mechanistic investigations and allow therapeutic screening. Here, we report a spontaneously occurring zebrafish valve disease model, which is associated with natural ageing. Using 2D and 3D morphometric approaches, we identify that aged zebrafish (> 2.5 years old) show greater valve volume and leaflet width/area when compared to young fish (< 1.5 years old). Size and shape changes occur in both the atrioventricular (AV) and bulboventricular valves (BV). Immunofluorescence and histological analyses reveal cellular changes, increased immune cell infiltration and altered distribution of elastin and collagen in aged leaflets, similar to that observed in mammalian clinical samples. Finally, we show that aged zebrafish exhibit cardiac dysfunction associated with valve degeneration. We have demonstrated that this novel zebrafish model of spontaneously occurring age‐related valve degeneration may have utility as a human disease model and could be used to determine mechanistic insights in the future. Natural ageing in zebrafish results in spontaneous development of valvular degeneration in both the atrioventricular (AV) and bulboventricular (BV) valves. Aged zebrafish valves are larger and exhibit cystic regions, immune cell infiltration, early osteoblast differentiation and increased regurgitation. Zebrafish represent a new valve disease model.

Potential applications of tissue engineering in regenerative medicine range from structural tissues to organs with complex function. This review focuses on the engineering of heart valve tissue, a goal which involves a unique combination of biological, engineering, and technological hurdles. We emphasize basic concepts, approaches and methods, progress made, and remaining challenges. To provide a framework for understanding the enabling scientific principles, we first examine the elements and features of normal heart valve functional structure, biomechanics, development, maturation, remodeling, and response to injury. Following a discussion of the fundamental principles of tissue engineering applicable to heart valves, we examine three approaches to achieving the goal of an engineered tissue heart valve: (1) cell seeding of biodegradable synthetic scaffolds, (2) cell seeding of processed tissue scaffolds, and (3) in-vivo repopulation by circulating endogenous cells of implanted substrates without prior in-vitro cell seeding. Lastly, we analyze challenges to the field and suggest future directions for both preclinical and translational (clinical) studies that will be needed to address key regulatory issues for safety and efficacy of the application of tissue engineering and regenerative approaches to heart valves. Although modest progress has been made toward the goal of a clinically useful tissue engineered heart valve, further success and ultimate human benefit will be dependent upon advances in biodegradable polymers and other scaffolds, cellular manipulation, strategies for rebuilding the extracellular matrix, and techniques to characterize and potentially non-invasively assess the speed and quality of tissue healing and remodeling.

Background. Coxiella burnetii endocarditis is considered to be a late complication of Q fever in patients with preexisting valvular heart disease (VHD). We observed a large transient aortic vegetation in a patient with acute Q fever and high levels of IgG anticardiolipin antibodies (IgG aCL). Therefore, we sought to determine how commonly acute Q fever could cause valvular vegetations associated with antiphospholipid antibody syndrome, which would be a new clinical entity. Methods. We performed a consecutive case series between January 2007 and April 2014 at the French National Referral Center for Q fever. Age, sex, history of VHD, immunosuppression, and IgG aCL assessed by enzyme-linked immunosorbent assay were tested as potential predictors. Results. Of the 759 patients with acute Q fever and available echocardiographic results, 9 (1.2%) were considered to have acute Q fever endocarditis, none of whom had a previously known VHD. After multiple adjustment, very high IgG aCL levels (>100 immunoglobulin G–type phospholipid units; relative risk [RR], 24.9 [95% confidence interval {CI}, 4.5–140.2]; P = .002) and immunosuppression (RR, 10.1 [95% CI, 3.0–32.4]; P = .002) were independently associated with acute Q fever endocarditis. Conclusions. Antiphospholipid antibody syndrome with valvular vegetations in acute Q fever is a new clinical entity. This would suggest the value of systematically testing for C. burnetii in antiphospholipid-associated cardiac valve disease, and performing early echocardiography and antiphospholipid dosages in patients with acute Q fever.

Endothelial cells are critical mediators of haemodynamic forces and as such are important foci for initiation of vascular pathology. Valvular leaflets are also lined with endothelial cells, though a similar role in mechanosensing has not been demonstrated. Recent evidence has shown that valvular endothelial cells respond morphologically to shear stress, and several studies have implicated valvular endothelial dysfunction in the pathogenesis of disease. This review seeks to combine what is known about vascular and valvular haemodynamics, endothelial response to mechanical stimuli and the pathogenesis of valvular diseases to form a hypothesis as to how mechanical stimuli can initiate valvular endothelial dysfunction and disease progression. From this analysis, it appears that inflow surface-related bacterial/thrombotic vegetative endocarditis is a high shear-driven endothelial denudation phenomenon, while the outflow surface with its related calcific/atherosclerotic degeneration is a low/oscillatory shear-driven endothelial activation phenomenon. Further understanding of these mechanisms may help lead to earlier diagnostic tools and therapeutic strategies.

[...]the prevalence of prior myocardial infarction might alter the impact of beta-blocker therapy on clinical outcomes in different study populations. [...]the observations in this study may shed light on valve and coronary artery embryology, as pointed out in an accompanying editorial. 5 \"The genetic underpinning of abnormal coronary development is not well understood and identifying association with congenital left heart disease and aortic root abnormalities may shed some light on a potential common developmental landscape. In the Cardiology in Focus section, Tom Treasure provides a synopsis of the early days in cardiac surgery in the UK which started by treating congenital heart disease with systemic to pulmonary shunts, followed by later development of intracardiac procedures to relieve pulmonic and mitral valve stenosis. 7 The Image Challenge in this issue shows a photograph and ultrasound image of impressive right wrist swelling 4 months after coronary angiography in a 93-year-old woman being considered for transcatheter aortic valve implantation. 8 How would you manage this finding?

Immune privilege is an evolutionary adaptation that protects vital tissues with limited regenerative capacity from collateral damage by the immune response. Classical examples include the anterior chamber of the eye and the brain. More recently, the placenta, testes and articular cartilage were found to have similar immune privilege. What all of these tissues have in common is their vital function for evolutionary fitness and a limited regenerative capacity. Immune privilege is clinically relevant, because corneal transplantation and meniscal transplantation do not require immunosuppression. The heart valves also serve a vital function and have limited regenerative capacity after damage. Moreover, experimental and clinical evidence from heart valve transplantation suggests that the heart valves are spared from alloimmune injury. Here we review this evidence and propose the concept of heart valves as immune privileged sites. This concept has important clinical implications for heart valve transplantation.

Heart valve disease affects up to 30% of the population and has been shown to have origins during embryonic development. Valvulogenesis begins with formation of endocardial cushions in the atrioventricular canal and outflow tract regions. Subsequently, endocardial cushions remodel, elongate and progressively form mature valve structures composed of a highly organized connective tissue that provides the necessary biomechanical function throughout life. While endocardial cushion formation has been well studied, the processes required for valve remodeling are less well understood. The transcription factor Scleraxis (Scx) is detected in mouse valves from E15.5 during initial stages of remodeling, and expression remains high until birth when formation of the highly organized mature structure is complete. Heart valves from Scx-/- mice are abnormally thick and develop fibrotic phenotypes similar to human disease by juvenile stages. These phenotypes begin around E15.5 and are associated with defects in connective tissue organization and valve interstitial cell differentiation. In order to understand the etiology of this phenotype, we analyzed the transcriptome of remodeling valves isolated from E15.5 Scx-/- embryos using RNA-seq. From this, we have identified a profile of protein and non-protein mRNAs that are dependent on Scx function and using bioinformatics we can predict the molecular functions and biological processes affected by these genes. These include processes and functions associated with gene regulation (methyltransferase activity, DNA binding, Notch signaling), vitamin A metabolism (retinoic acid biosynthesis) and cellular development (cell morphology, cell assembly and organization). In addition, several mRNAs are affected by alternative splicing events in the absence of Scx, suggesting additional roles in post-transcriptional modification. In summary, our findings have identified transcriptome profiles from abnormal heart valves isolated from E15.5 Scx-/- embryos that could be used in the future to understand mechanisms of heart valve disease in the human population.