Differential Requirement of DICER1 Activity during Development of Mitral and Tricuspid Valves

Mitral and tricuspid valves are essential for unidirectional blood flow in the heart. They are derived from similar cell sources, and yet congenital dysplasia affecting both valves is clinically rare, suggesting the presence of differential regulatory mechanisms underlying their development. We specifically inactivated Dicer1 in the endocardium during cardiogenesis, and unexpectedly found that Dicer1-deletion caused congenital mitral valve stenosis and regurgitation, while it had no impact on other valves. We showed that hyperplastic mitral valves were caused by abnormal condensation and extracellular matrix (ECM) remodeling. Our single-cell RNA Sequencing analysis revealed impaired maturation of mesenchymal cells and abnormal expression of ECM genes in mutant mitral valves. Furthermore, expression of a set of miRNAs that target ECM genes was significantly lower in tricuspid valves compared to mitral valves, consistent with the idea that the miRNAs are differentially required for mitral and tricuspid valve development. Our study thus reveals miRNA-mediated gene regulation as a novel molecular mechanism that differentially regulates mitral and tricuspid valve development, thereby enhancing our understanding of the non-association of inborn mitral and tricuspid dysplasia observed clinically.

In Vitro Mitral Valve Model with Unrestricted Ventricular Access: Using Vacuum to Close the Valve and Enable Static Trans-Mitral Pressure

Current in vitro models of the left heart establish the pressure difference required to close the mitral valve by sealing and pressurizing the ventricular side of the valve, limiting important access to the subvalvular apparatus. This paper describes and evaluates a system that establishes physiological pressure differences across the valve using vacuum on the atrial side. The subvalvular apparatus is open to atmospheric pressure and accessible by tools and sensors, establishing a novel technique for experimentation on atrioventricular valves. Porcine mitral valves were excised and closed by vacuum within the atrial chamber. Images were used to document and analyze closure of the leaflets. Papillary muscle force and regurgitant flow rate were measured to be 4.07 N at 120 mmHg and approximately 12.1 ml/s respectively, both of which are within clinically relevant ranges. The relative ease of these measurements demonstrates the usefulness of improved ventricular access at peak pressure/force closure. Graphical abstract

Case Report: Marantic Endocarditis in Renal Cell Carcinoma: Nephrectomy a Treatment

Background Marantic endocarditis (non-bacterial thrombotic endocarditis) is a rare condition that involves non-infectious thrombotic lesions typically of the aortic and mitral valves. It is predominantly associated with malignancy and less-commonly systemic lupus erythematosus. In this case, we report a patient with marantic endocarditis secondary to a renal cell carcinoma that was successfully treated with nephrectomy and anticoagulation. Case Summary A 65-year-old male patient with embolic signs and symptoms was found to have non-infective thrombotic vegetations on three cardiac valves through transoesophageal echocardiography. Computed tomography (CT) revealed a 70 mm renal mass that confirmed to be a grade two clear-cell renal cell carcinoma. Nephrectomy and anti-coagulation led to resolution of the embolic symptoms and of the valvular vegetations. Discussion The diagnosis of marantic endocarditis requires high clinical suspicion in a patient who presents with features of embolisation. Incidence is highest in patients with an underlying malignancy, particularly adenocarcinoma. This case highlights the importance of echocardiography in diagnosis, removal of the source of thrombus, and prompt treatment with anti-coagulation.

Erythema marginatum: an uncommon presentation of acute rheumatic fever in a Nigerian adolescent girl—a case report

Background Erythema marginatum is an uncommon presentation in children with acute rheumatic fever and it is one of the major criteria needed to make a diagnosis. It is seen in less than 10% of cases. It is also reported to be difficult to detect in black-skinned children. This is the first and only patient to present with the above since the inception of the unit about 14 years ago and also the first to be reported in Nigeria as far as the authors are aware, after a careful literature search; hence, we report this case based on the rarity of this symptom of acute rheumatic fever. Case presentation This is a case report of O.E, a 12-year-old Nigerian girl who presented with features of acute rheumatic fever, and these features included the rare manifestation of erythema marginatum. She presented with generalized skin eruptions on the trunk and extremities, sparing the face, migratory polyarthritis, features of congestive heart failure and high grade continuous fever. The skin lesions consisted of papules, patches, plaques and polycycles with a reticular pattern having serpiginous and raised borders. Diagnostic investigations revealed elevated erythrocyte sedimentation rate of 83mm/h, anti-streptolysin O titer of 2020IU/L and echocardiography which showed thickened mitral valves with grade II mitral regurgitation and a mild pulmonary artery hypertension. The patient was treated with anti-inflammatory and anti-failure drugs and commenced secondary prophylaxis with benzathine penicillin. Skin eruptions resolved within 3 weeks of management and are currently on follow up. Conclusions We present the above to increase awareness on the possibility of acute rheumatic fever presenting with erythema marginatum in our region, to encourage early diagnosis of acute rheumatic fever to reduce morbidity and mortality from its sequel, rheumatic heart disease.

Monoamine oxidase contributes to the valvular oxidative stress in patients with mitral valve regurgitation

Background Oxidative stress plays a central role in the pathogenesis of cardiovascular diseases but the role of enzymatic sources of reactive oxygen species (ROS) remains elusive. There is scarce information in the literature regarding valvular oxidative stress. Monoamine oxidases (MAOs), with 2 isoforms, A and B, have emerged as important sources of oxidative stress in the cardiovascular system. Purpose To assess whether MAOs-related oxidative stress occurs in the pathological valves in patients with severe mitral regurgitation (due to valve degeneration and chordae rupture) and surgical indication and its interference with the activation of the renin-angiotensin aldosterone (RAAS) system. Material and methods Samples of mitral valve (n=17) were harvested during the valvular replacement procedure and used for reactive oxygen species (ROS) assessment (immune-fluorescence, spectrophotometry) and MAO mRNA and protein expression (qPCR and immune-fluorescence) measurement. Inflammatory markers, biochemical parameters and echocardiography (GE, Vivid 9, Vivid E95) data were also collected. Results Both MAO isoforms are expressed in the diseased mitral valves, with a predominance of MAO-A isoform. Ex vivo incubation with angiotensin 2 (12 h, 100 nM) of samples obtained from patients without RAAS medication lead to MAO upregulation and high ROS production. MAO-related oxidative stress was mitigated by MAO inhibition with clorgyline (MAO-A inhibitor, 10 microM) and selegyline (MAO-B inhibitor, 10 microM) and also by the angiotensin II receptor type 1 (AT1) antagonist, irbersartan (10 microM). Conclusions Monoamine oxidase is expressed in the pathological mitral valves, regardless the etiology. Its expression and the related-oxidative stress are modulated by angiotensin 2, irbesartan. Whether the latter effect is present in valvular patients treated with RAAS inhibitors is currently under investigation. FUNDunding Acknowledgement Type of funding sources: None.

Uniformity in bioprosthetic mitral valve sizing -- when will we get there?

Much has changed since the introduction of surgical valve repair in the 1950s, from the introduction bioprosthetic valves to percutaneous approaches to valve repair. Yet, despite substantial advancements in bioprosthetic valve technology, there has been a lack of direct, independent comparison between bioprosthetic mitral valve devices, accompanied by a marked heterogeneity in approaches to the sizing and selection thereof. Wang et al. have hence endeavoured to evaluate, head-to-head, the technical successes and biomechanical outcomes associated with three different bioprosthetic mitral valves (Epic, Abbott, IL; Mosaic, Medtronic, MN; Mitris Resilia, Edwards Lifesciences, CA) in a porcine model, under standardised haemodynamic and anatomical conditions. With a robust experimental technique, they have made clear the heterogeneity in both sizing and biomechanical properties between bioprosthetic mitral valves, and have further emphasised the need for a uniform approach to the manufacturing and sizing of bioprosthetic valves.

TRPV1 Receptor Identification in Bovine and Canine Mitral Valvular Interstitial Cells

Myxomatous mitral valve degeneration (MMVD) is the most common acquired cardiac disease in canine species, and valvular interstitial cells (VICs) are considered the main responsible for the development of this pathology. The scientific interest is focused on isolating and characterizing these cells. The aims of the present study were to verify a novel VICs mechanical isolation method and to characterize isolated cells using immunocytochemistry and immunofluorescence, with parallel histological and immunohistochemistry assays on bovine and canine healthy and MMVD mitral valves. Antibodies against vimentin (VIM), smooth muscle actin (SMA), von Willebrand (vW) factor, Transforming Growth Factor (TGF) β1, and Transient Receptor Potential Vanilloid 1 (TRPV1) were used. The isolation method was considered reliable and able to isolate only VICs. The different assays demonstrated a different expression of SMA in healthy and MMVD mitral valves, and TRPV1 was isolated for the first time from bovine and canine VICs and the correspondent mitral valve leaflets. The novelties of the present study are the new isolation method, that may allow correlations between laboratory and clinical conditions, and the identification of TRPV1, which will lead to further investigations to understand its function and possible role in the etiology of MMVD and to the design of new therapeutic strategies.