MicroRNAs in Valvular Heart Diseases: Biological Regulators, Prognostic Markers and Therapeutical Targets

miRNAs have recently attracted investigators’ interest as regulators of valvular diseases pathogenesis, diagnostic biomarkers, and therapeutical targets. Evidence from in-vivo and in-vitro studies demonstrated stimulatory or inhibitory roles in mitral valve prolapse development, aortic leaflet fusion, and calcification pathways, specifically osteoblastic differentiation and transcription factors modulation. Tissue expression assessment and comparison between physiological and pathological phenotypes of different disease entities, including mitral valve prolapse and mitral chordae tendineae rupture, emerged as the best strategies to address miRNAs over or under-representation and thus, their impact on pathogeneses. In this review, we discuss the fundamental intra- and intercellular signals regulated by miRNAs leading to defects in mitral and aortic valves, congenital heart diseases, and the possible therapeutic strategies targeting them. These miRNAs inhibitors are comprised of antisense oligonucleotides and sponge vectors. The miRNA mimics, miRNA expression vectors, and small molecules are instead possible practical strategies to increase specific miRNA activity. Advantages and technical limitations of these new drugs, including instability and complex pharmacokinetics, are also presented. Novel delivery strategies, such as nanoparticles and liposomes, are described to improve knowledge on future personalized treatment directions.

MicroRNAs in Valvular Heart Diseases: Biological Regulators, Prognostic Markers and Therapeutical Targets

miRNAs have recently attracted investigators' interest as regulators of valvular diseases pathogenesis, diagnostic biomarkers, and therapeutical targets. Evidence from in-vivo and in-vitro studies demonstrated stimulatory or inhibitory roles in mitral valve prolapse development, aortic leaflet fusion, and calcification pathways, specifically osteoblastic differentiation and transcription factors modulation. Tissue expression assessment and comparison between physiological and pathological phenotypes of different disease entities, including mitral valve prolapse and mitral chordae tendineae rupture, emerged as the best strategies to address miRNAs over or under-representation and thus, their impact on pathogeneses. In this review, we discuss the fundamental intra- and intercellular signals regulated by miRNAs leading to defects in mitral and aortic valves, congenital heart diseases, and the possible therapeutic strategies targeting them. These miRNAs inhibitors comprise of antisense oligonucleotides and sponge vectors. The miRNA mimics, miRNA expression vectors, and small molecules are instead possible practical strategies to increase specific miRNA activity. Advantages and technical limitations of these new drugs, including instability and complex pharmacokinetics, are also presented. Novel delivery strategies, such as nanoparticles and liposomes, are described to improve knowledge on future personalized treatment directions.

Totally endoscopic aortic valve replacement with concomitant trans-aortic mitral valve repair for mitral regurgitation

Background Minimally invasive aortic valve procedures through a hemi-sternotomy or a right anterior mini-thoracotomy have gained popularity over the last several years. Totally endoscopic aortic valve replacement (TEAVR) is an innovative and a less invasive (incision-wise) surgical aortic valve replacement technique. The operative steps of TEAVR have been reported previously from our group. Mitral regurgitation (MR) frequently accompanies aortic valve disease that at times may also require repair. Totally endoscopic surgery in such cases has not been tested. Presentation of the technique We present a surgical technique for a totally endoscopic approach to aortic valve replacement and concomitant mitral valve repair for primary and secondary MR. An aortotomy incision was used avoiding an atriotomy, which results in an increase in cross-clamp (XC) and cardiopulmonary bypass (CPB) times that could be associated with higher mortality and morbidity. Neochords (artificial chordae tendineae) were used for primary MR and an edge-to-edge approach for secondary MR. Conclusion TEAVR and concomitant mitral valve repair can be performed successfully with reasonable XC and CPB times with excellent short-term results.

Comprehensive left ventricular outflow tract management beyond septal reduction to relieve obstruction

The surgical management of patients with hypertrophic obstructive cardiomyopathy can be extremely challenging. Relieving the left ventricular outflow tract obstruction in these patients is often achieved by performing a septal myectomy. However, in many instances, septal reduction alone is not enough to relieve the obstruction. Interventions on the sub-valvular apparatus, including the anomalous chordae tendineae and the abnormal papillary muscles, are often required. In this review, we summarize the embryology and the pathophysiology of the different elements that may contribute to the left ventricular outflow tract obstruction in the setting of hypertrophic obstructive cardiomyopathy. In addition, we highlight the different surgical procedures that a surgeon may adopt to relieve the left ventricular outflow tract obstruction, beyond the septal myectomy.

Frameshift Mutation in Polar Rich Domain (PRD) of PQBP1 Gene Associated with Asymmetric Cerebellar Hemispheres: A Case Report of Renpenning Syndrome

Introduction: In 1962, Renpenning et al. published an article with 20 male patients from three generations with mental retardation. Scientists suggested that the syndrome with mutation mapped to the locus Xp11.2-p11.4 should be called Renpenning syndrome. The deletion/duplication of an AG dinucleotide on proximal Xp in the polyglutamine tract-binding protein 1 (PQBP1) gene causing frameshift in the fourth coding exon was identified as the most frequent mutation in this syndrome. Renpenning syndrome with asymmetric cerebellar hemispheres has not been reported previously. Case Presentation: In this case report, we presented an 11-year-old male with mild developmental delay and mild intellectual disability, microcephaly, dysmorphic face, short stature, and seizures. The following morphological abnormalities were detected: a wide nasal bridge, midfacial hypoplasia, short philtrum, low-set ears, low hanging columella, high palate, and narrow face. Neurological examination showed upper and lower extremities hypotonia with joint hypermobility. The patient had his first seizure at the age of seven, and he experienced a total of 10 seizures by the age 11. A systolic murmur of intensity 2/6 was present, and echocardiography showed chordae tendineae abnormalities in the left ventricle. Brain magnetic resonance imaging (MRI) showed asymmetric cerebellar hemispheres (mild right cerebellar hemisphere hypoplasia). A frameshift mutation in the polar reach domain (PRD) of the PQBP1 gene (c.459-462 delAGAG) was detected by exome sequencing. Conclusions: We showed the first case of genetically confirmed Renpenning syndrome in Serbia. Our patient had classical clinical manifestations for Renpenning syndrome as a consequence of frameshift mutation in the PRD of the PQBP1 gene. To the best of our knowledge, according to the literature, this is the first patient with Renpenning syndrome with asymmetric cerebellar hemispheres (mild right cerebellar hemisphere hypoplasia).

Collagen Fibrillogenesis in the Mitral Valve: It’s a Matter of Compliance

Collagen fibers are essential structural components of mitral valve leaflets, their tension apparatus (chordae tendineae), and the associated papillary muscles. Excess or lack of collagen fibers in the extracellular matrix (ECM) in any of these structures can adversely affect mitral valve function. The organization of collagen fibers provides a sophisticated framework that allows for unidirectional blood flow during the precise opening and closing of this vital heart valve. Although numerous ECM molecules are essential for the differentiation, growth, and homeostasis of the mitral valve (e.g., elastic fibers, glycoproteins, and glycans), collagen fibers are key to mitral valve integrity. Besides the inert structural components of the tissues, collagen fibers are dynamic structures that drive outside-to-inside cell signaling, which informs valvular interstitial cells (VICs) present within the tissue environment. Diversity of collagen family members and the closely related collagen-like triple helix-containing proteins found in the mitral valve, will be discussed in addition to how defects in these proteins may lead to valve disease.