Evaluating left atrial strain and left ventricular diastolic strain rate as markers for diastolic dysfunction in patients with mitral annular calcification.

BACKGROUND: Mitral annular calcification (MAC) poses many challenges to the evaluation of diastolic function using standard echocardiography. Left atrial (LA) strain and left ventricular early diastolic strain rate (DSr) measured by speckle-tracking echocardiography (STE) are emerging techniques in the noninvasive evaluation of diastolic function. We aim to evaluate the utility of LA strain and early DSr in predicting elevated left ventricular filling pressures (LVFP) in patients with MAC and compare their effectiveness to ratio of mitral inflow velocity in early and late diastole (E/A). METHODS: We included adult patients with MAC who presented between January 1 and December 31, 2014 and received a transthoracic echocardiogram (TTE) and cardiac catheterization with measurement of LVFP within a 24-h period. We used Spearman's rank correlation coefficient to assess associations of LA reservoir strain and average early DSr with LVFP. Receiver operating characteristic (ROC) curves were computed to assess the effectiveness of LA strain and DSr in discriminating elevated LVFP as a dichotomized variable and to compare their effectiveness with E/A ratio categorized according to grade of diastolic dysfunction. RESULTS: Fifty-five patients were included. LA reservoir strain demonstrated poor correlation with LVFP (Spearman's rho = 0.03, p = 0.81) and poor discriminatory ability for detecting elevated LVFP (AUC = 0.54, 95% CI 0.38-0.69). Categorical E/A ratio alone also demonstrated poor discriminatory ability (AUC = 0.53, 95% CI 0.39-0.67), and addition of LA reservoir strain did not significantly improve effectiveness (AUC = 0.58, 95% CI 0.42-0.74, p = 0.56). Average early DSr also demonstrated poor correlation with LVFP (Spearman's rho = -0.19, p = 0.16) and poor discriminatory ability for detecting elevated LVFP (AUC = 0.59, 95% CI 0.44-0.75). Addition of average early DSr to categorical E/A ratio failed to improve effectiveness (AUC = 0.62, 95% CI 0.46-0.77 vs. AUC = 0.54, 95% CI 0.39-0.69, p = 0.38). CONCLUSIONS: In our sample, LA reservoir strain and DSr do not accurately predict diastolic filling pressure. Further research is required before LA strain and early DSr can be routinely used in clinical practice to assess filling pressure in patients with MAC.

Presentation, Diagnosis, and Management of Subglottic and Tracheal Stenosis During Systemic Inflammatory Diseases.

BACKGROUND: Subglottic stenosis (SGS) and tracheal stenosis (TS) are characterized by a narrowing of the airways. The goal of this study was to describe the characteristics and prognosis of nontraumatic and nontumoral SGS or TS. RESEARCH QUESTION: What are the inflammatory etiologies of SGS and TS, and what are their characteristics and prognosis? STUDY DESIGN AND METHODS: This multicenter, observational retrospective study was performed in patients with SGS or TS that was neither traumatic nor tumoral. RESULTS: Eighty-one patients were included, 33 (41%) with granulomatosis with polyangiitis (GPA) and 21 (26%) with relapsing polychondritis (RP). GPA-related stenoses exhibited circumferential subglottic narrowing in 85% of cases, without calcifications. In contrast, RP-related stenoses displayed anterior involvement in 76%, in a longer distance from vocal cords (4 cm), with calcifications in 62%, and extension to bronchi in 86%. Other diagnoses included bullous dermatoses (n = 3), amyloidosis (n = 3), sarcoidosis (n = 2), and Crohn's disease (n = 2); the remaining stenoses (n = 15) were idiopathic. SGS/TS was the initial manifestation of the disease in 66% of cases, with a median interval from stenosis to disease diagnosis of 12 months (interquartile range, 0-48 months). Despite the use of glucocorticoids in 80%, combined with methotrexate in 49%, endoscopic procedures were required in 68% of patients. Relapses of stenoses occurred in 76% without any difference between causes (82% in GPA, 67% in RP, and 75% in idiopathic SGS/TS). Three patients died due to the stenosis, two of RP and one of GPA. INTERPRETATION: These data show that GPA and RP are the two main inflammatory diseases presenting with SGS/TS. GPA-related stenoses are mostly subglottic and circumferential, whereas RP-related stenoses are mostly tracheal, anterior, and calcified with a frequent extension to bronchi. Relapses of stenoses are common, and relapse rates do not differ between causes. Diagnosis and management of SGS/TS require a multidisciplinary approach.

Calcinose distrófica cutânea na doença venosa crônica de membros inferiores / Dystrophic calcinosis cutis in chronic venous disease of the lower limbs

Resumo As úlceras de membros inferiores, secundárias à doença venosa crônica (DVC), constituem um problema significativo de saúde pública no Brasil e representam cerca de 70% do total dessas úlceras. Apesar dos recentes avanços tecnológicos e das diversas opções terapêuticas utilizadas para essas lesões crônicas, existem diversos fatores que podem estar implicados na resistência ao tratamento. A calcificação distrófica cutânea (CDC) é uma condição rara e frequentemente subdiagnosticada, que, quando associada à DVC, pode estar associada à refratariedade no processo cicatricial. Neste artigo, relatamos um caso de CDC em paciente portador de DVC e discutimos a sua etiologia, fisiopatologia e possíveis opções de tratamento.

Abstract Lower limb ulcers secondary to chronic venous disease (CVD) are a significant public health problem in Brazil and account for about 70% of these ulcers. Despite recent technological advances and the various therapeutic options for treatment of these chronic injuries, several factors may be involved in resistance to treatment. Dystrophic calcinosis cutis (DCC) is a rare and often underdiagnosed condition that, when in conjunction with CVD, may be associated with a refractory healing process. In this article, we report a case of DCC in a patient with CVD and discuss its etiology, pathophysiology and possible treatment options.

Circulatory microRNA expression profile for coronary artery calcification in chronic kidney disease patients.

BACKGROUND & AIM: Coronary artery disease (CAD) is the primary cause of mortality in patients with end stage renal disease (ESRD). MicroRNA profiling is proven as a powerful tool in the diagnosis of any disease at the molecular level. Hence, the present study aimed to profile the microRNA expression for CAD especially coronary artery calcification in CKD patients. MATERIALS AND METHODS: Two hundread patients with CKD stages 3 to 5 without dialysis and healthy controls were included in this study. All two hundred patients underwent 1024 multi sliceardiac computed tomography (CT) scan for calcium scoring. The calcium scoring more than 100 have been included in the study. We performed miRNA microarray analysis from serum samples of seven high calcium scored with CKD patients and one control patients. RESULTS: Seven patients have observed circulating miRNAs has significantly upregulated and downregulated when compared with control patients. mir21, mir 67, mir 390, mir 56, mir 250, mir 65 and mir 13 were up regulated and mir235, mir256, mir226, mir207, mir255, mir193 were downregulated. There was no significant difference in left ventricle function. CONCLUSION: 13 microRNAs play a potential role in coronary artery calcification in CKD patients.

Restoration of 5-methoxytryptophan protects against atherosclerotic chondrogenesis and calcification in ApoE-/- mice fed high fat diet.

BACKGROUND: Toll-like receptor-2 (TLR2) promotes vascular smooth muscle cell (VSMC) transdifferentiation to chondrocytes and calcification in a p38 MAPK-dependent manner. Vascular 5-methoxytryptophan (5-MTP) is a newly identified factor with anti-inflammatory actions. As 5-MTP targets p38 MAPK for its actions, we postulated that 5-MTP protects against vascular chondrogenesis and calcification. METHODS: High-fat diet-induced advanced atherosclerosis in mice were performed to investigate the effect of 5-MTP on atherosclerotic lesions and calcification. VSMCs were used to determine the role of 5-MTP in VSMC chondrogenic differentiation and calcification. Alizarin red S and Alcian blue staining were used to measure VSMC calcification and chondrogenic differentiation, respectively. RESULTS: 5-MTP was detected in aortic tissues of ApoE-/- mice fed control chow. It was reduced in ApoE-/- mice fed high-fat diet (HFD), but was restored in ApoE-/-Tlr2-/- mice, suggesting that HFD reduces vascular 5-MTP production via TLR2. Intraperitoneal injection of 5-MTP or its analog into ApoE-/- mice fed HFD reduced aortic atherosclerotic lesions and calcification which was accompanied by reduction of chondrogenesis and calcium deposition. Pam3CSK4 (Pam3), ligand of TLR2, induced SMC phenotypic switch to chondrocytes. Pretreatment with 5-MTP preserved SMC contractile proteins and blocked Pam3-induced chondrocyte differentiation and calcification. 5-MTP inhibited HFD-induced p38 MAPK activation in vivo and Pam3-induced p38 MAPK activation in SMCs. 5-MTP suppressed HFD-induced CREB activation in aortic tissues and Pam3-induced CREB and NF-κB activation in SMCs. CONCLUSIONS: These findings suggest that 5-MTP is a vascular arsenal against atherosclerosis and calcification by inhibiting TLR2-mediated SMC phenotypic switch to chondrocytes and the consequent calcification. 5-MTP exerts these effects by blocking p38 MAPK activation and inhibiting CREB and NF-κB transactivation activity.

Progressive Calcification in Bicuspid Valves: A Coupled Hemodynamics and Multiscale Structural Computations.

Bicuspid aortic valve (BAV) is the most common congenital heart disease. Calcific aortic valve disease (CAVD) accounts for the majority of aortic stenosis (AS) cases. Half of the patients diagnosed with AS have a BAV, which has an accelerated progression rate. This study aims to develop a computational modeling approach of both the calcification progression in BAV, and its biomechanical response incorporating fluid-structure interaction (FSI) simulations during the disease progression. The calcification is patient-specifically reconstructed from Micro-CT images of excised calcified BAV leaflets, and processed with a novel reverse calcification technique that predicts prior states of CAVD using a density-based criterion, resulting in a multilayered calcified structure. Four progressive multilayered calcified BAV models were generated: healthy, mild, moderate, and severe, and were modeled by FSI simulations during the full cardiac cycle. A valve apparatus model, composed of the excised calcified BAV leaflets, was tested in an in-vitro pulse duplicator, to validate the severe model. The healthy model was validated against echocardiography scans. Progressive AS was characterized by higher systolic jet flow velocities (2.08, 2.3, 3.37, and 3.85 m s-1), which induced intense vortices surrounding the jet, coupled with irregular recirculation backflow patterns that elevated viscous shear stresses on the leaflets. This study shed light on the fluid-structure mechanism that drives CAVD progression in BAV patients.

Association between Periodontitis and Carotid Artery Calcification: A Systematic Review and Meta-Analysis.

Recent studies have supported the relationship between periodontitis and carotid artery calcification (CAC), but still uncertain. This systematic review is aimed at evaluating the association between periodontitis and CAC. The search was conducted in four electronic databases: PubMed, EMBASE, Web of Science, and The Cochrane Library, supplemented by checking references of included articles and related review articles. Eligibility assessment and data extraction were conducted independently. The quality assessment and publication bias analysis were performed. The association between periodontitis and CAC was presented in odd ratio (OR) with 95% confidence interval (CI). Additional outcomes included the percentage of alveolar bone loss in CAC versus non-CAC. Twelve studies were included, and 10 were performed quantity analysis. Periodontitis with secure definition (OR = 2.02, 95%CI = 1.18 - 3.45) and insecure definition (OR = 10.78, 95%CI = 4.41 - 26.34) was associated with CAC. And a higher average percentage of alveolar bone loss (weighted mean difference = 10.84%; 95%CI = 6.40 - 15.48) was also observed in CAC patients compared to non-CAC patients. No significant publication bias was found. The results of this systematic review and meta-analysis revealed a significant relationship between periodontitis and CAC.

Innate and adaptive immunity: the understudied driving force of heart valve disease.

Calcific aortic valve disease (CAVD), and its clinical manifestation that is calcific aortic valve stenosis, is the leading cause for valve disease within the developed world, with no current pharmacological treatment available to delay or halt its progression. Characterized by progressive fibrotic remodelling and subsequent pathogenic mineralization of the valve leaflets, valve disease affects 2.5% of the western population, thus highlighting the need for urgent intervention. Whilst the pathobiology of valve disease is complex, involving genetic factors, lipid infiltration, and oxidative damage, the immune system is now being accepted to play a crucial role in pathogenesis and disease continuation. No longer considered a passive degenerative disease, CAVD is understood to be an active inflammatory process, involving a multitude of pro-inflammatory mechanisms, with both the adaptive and the innate immune system underpinning these complex mechanisms. Within the valve, 15% of cells evolve from haemopoietic origin, and this number greatly expands following inflammation, as macrophages, T lymphocytes, B lymphocytes, and innate immune cells infiltrate the valve, promoting further inflammation. Whether chronic immune infiltration or pathogenic clonal expansion of immune cells within the valve or a combination of the two is responsible for disease progression, it is clear that greater understanding of the immune systems role in valve disease is required to inform future treatment strategies for control of CAVD development.

A Novel Two-Dimensional Echocardiography Method to Objectively Quantify Aortic Valve Calcium and Predict Aortic Stenosis Severity.

Aortic valve calcium (AVC) is a strong predictor of aortic stenosis (AS) severity and is typically calculated by multidetector computed tomography (MDCT). We propose a novel method using pixel density quantification software to objectively quantify AVC by two-dimensional (2D) transthoracic echocardiography (TTE) and distinguish severe from non-severe AS. A total of 90 patients (mean age 76 ± 10 years, 75% male, mean AV gradient 32 ± 11 mmHg, peak AV velocity 3.6 ± 0.6 m/s, AV area (AVA) 1.0 ± 0.3 cm2, dimensionless index (DI) 0.27 ± 0.08) with suspected severe aortic stenosis undergoing 2D echocardiography were retrospectively evaluated. Parasternal short axis aortic valve views were used to calculate a gain-independent ratio between the average pixel density of the entire aortic valve in short axis at end diastole and the average pixel density of the aortic annulus in short axis (2D-AVC ratio). The 2D-AVC ratio was compared to echocardiographic hemodynamic parameters associated with AS, MDCT AVC quantification, and expert reader interpretation of AS severity based on echocardiographic AVC interpretation. The 2D-AVC ratio exhibited strong correlations with mean AV gradient (r = 0.72, p < 0.001), peak AV velocity (r = 0.74, p < 0.001), AVC quantified by MDCT (r = 0.71, p <0.001) and excellent accuracy in distinguishing severe from non-severe AS (area under the curve = 0.93). Conversely, expert reader interpretation of AS severity based on echocardiographic AVC was not significantly related to AV mean gradient (t = 0.23, p = 0.64), AVA (t = 2.94, p = 0.11), peak velocity (t = 0.59, p = 0.46), or DI (t = 0.02, p = 0.89). In conclusion, these data suggest that the 2D-AVC ratio may be a complementary method for AS severity adjudication that is readily quantifiable at time of TTE.

Heterotopic ossification in mice overexpressing Bmp2 in Tie2+ lineages.

Bone morphogenetic protein (Bmp) signaling is critical for organismal development and homeostasis. To elucidate Bmp2 function in the vascular/hematopoietic lineages we generated a new transgenic mouse line in which ectopic Bmp2 expression is controlled by the Tie2 promoter. Tie2CRE/+;Bmp2tg/tg mice develop aortic valve dysfunction postnatally, accompanied by pre-calcific lesion formation in valve leaflets. Remarkably, Tie2CRE/+;Bmp2tg/tg mice develop extensive soft tissue bone formation typical of acquired forms of heterotopic ossification (HO) and genetic bone disorders, such as Fibrodysplasia Ossificans Progressiva (FOP). Ectopic ossification in Tie2CRE/+;Bmp2tg/tg transgenic animals is accompanied by increased bone marrow hematopoietic, fibroblast and osteoblast precursors and circulating pro-inflammatory cells. Transplanting wild-type bone marrow hematopoietic stem cells into lethally irradiated Tie2CRE/+;Bmp2tg/tg mice significantly delays HO onset but does not prevent it. Moreover, transplanting Bmp2-transgenic bone marrow into wild-type recipients does not result in HO, but hematopoietic progenitors contribute to inflammation and ectopic bone marrow colonization rather than to endochondral ossification. Conversely, aberrant Bmp2 signaling activity is associated with fibroblast accumulation, skeletal muscle fiber damage, and expansion of a Tie2+ fibro-adipogenic precursor cell population, suggesting that ectopic bone derives from a skeletal muscle resident osteoprogenitor cell origin. Thus, Tie2CRE/+;Bmp2tg/tg mice recapitulate HO pathophysiology, and might represent a useful model to investigate therapies seeking to mitigate disorders associated with aberrant extra-skeletal bone formation.

Application of three-dimensional transesophageal echocardiography in preoperative evaluation of transcatheter aortic valve replacement.

BACKGROUND: Our goal was to determine the accuracy of 3-dimensional transesophageal echocardiography (3D-TEE) compared with that of computed tomography (CT) in the preoperative evaluation for transcatheter aortic valve replacement (TAVR) when the errors caused by inconsistent software and method have been eliminated and the representativeness of the sample has been improved. We also investigated the influence of aortic root calcification on the accuracy of 3D-TEE in aortic annulus evaluations. METHODS: Part I: 45 of 233 patients who underwent TAVR in the department of cardiovascular surgery at the Xijing hospital from January 2016 to August 2019 were studied retrospectively. Materialise Mimics software and the multiplanar reconstruction method were used for evaluation, based on 3D-TEE and CT. The annulus area-derived diameter, the annulus perimeter-derived diameter (Dp), the annulus mean diameter, the left ventricular outflow tract Dp diameter, the sinotubular junction (STJ) diameter-Dp, and the aortic sinus diameter were compared and analyzed. Part II: 31 of 233 patients whose 3D-TEE and CT data were well preserved and in the required format were included. HU450 and HU850 were used as indicators to measure the severity of calcification. The Spearman rank correlation and Linear regression were used to analyze the correlation between aortic root calcification and the accuracy of 3D-TEE in aortic annulus measurement. RESULTS: The measurement results based on 3D-TEE were significantly lower than those obtained using CT (P < 0.05), except for the STJ diameter-Dp in diastole (P = 0.11). The correlation coefficient of the two groups was 0.699-0.954 (P < 0.01), which also indicated a significant correlation between the two groups. A Bland-Altman plot showed that the ordinate values were mostly within the 95% consistency limit; the consistency of the two groups was good. By establishing the linear regression equation, the two groups can be inferred from each other. The Spearman rank correlation analysis and the Linear regression analysis showed that the influence of aortic calcification on the accuracy of the 3D-TEE annulus evaluation was limited. CONCLUSIONS: Although an evaluation based on 3D-TEE underestimated the results, we can deduce CT results from 3D-TEE because the two methods exhibit considerable correlation and consistency. TRIAL REGISTRATION: Name: Surgery and Transcatheter Intervention for Structural Heart Diseases. Number: NCT02917980. URL: https://clinicaltrials.gov/ct2/results?term=NCT02917980 .

AGEs promote calcification of HASMCs by mediating Pi3k/AKT-GSK3ß signaling.

This study aimed to investigate the effects of advanced glycation end products (AGEs) on the calcification of human arterial smooth muscle cells (HASMCs) and to explore whether AGEs can promote the calcification of HASMCs by activating the phosphoinositide 3-kinase (PI3K)/AKT-glycogen synthase kinase 3 beta (GSK3-ß) axis. Cultured HASMCs were divided into five groups: blank control group, dimethyl sulfoxide (vehicle) group, AGEs group, LY294002 (AKT inhibitor) group, and TWS119 (GSK3-ß inhibitor) group. Cells were pretreated with either vehicle, LY294002, or TWS119 for 2 hours followed by incubation with AGEs (25 µg/mL) for 5 days, and the expression levels of proteins in each group were analyzed by western blotting. AGE treatment promoted HASMC calcification, which coincided with increased expression of p-AKT and p-GSK3-ß (serine 9). Also, AGEs upregulated the expression of osteoprotegerin and bone morphogenetic protein, and these effects were suppressed by LY294002 but enhanced by TWS119. In conclusion, AGEs promote calcification of HASMCs, and this effect is ameliorated by inhibition of AKT activity but potentiated by inhibition of GSK3-ß activity. Hence, AGEs trigger HASMC calcification by regulating PI3K/AKT-GSK3-ß signaling.

Bilateral brachial artery infiltration by tumoral calcinosis: A case report.

We, herein, presented a rare case of bilateral brachial artery infiltration by tumoral calcinosis located on both elbows. A 58-yearold man presented with a history of painless, palpable solid mass restricting the range of motion of both elbows. These masses were located on the anterior aspect of the elbows and gradually enlarged. After clinical, laboratory and radiological examinations, tumoral calcinosis was suspected, and excisional biopsy was planned for a definite diagnosis. Surgery was first performed on the left elbow. The median nerve was found to be compressed but not infiltrated by the mass. Interestingly, the brachial artery was totally infiltrated throughout the entire mass. Occlusion was observed in the brachial artery located within the mass. The tumor on the left elbow, 8.5 × 5.5 × 2.5 cm in size, was totally excised with approximately 12-cm brachial artery segment. The artery was resected until the healthy tissue was reached. The defect was reconstructed with saphenous vein graft obtained from the ipsilateral lower extremity. The same surgical procedure was performed on the right elbow after 3 months. The tumor size on the right elbow was 7 × 3.5 × 1.7 cm. Approximately 15-cm brachial artery segment was excised, and the defect was reconstructed with saphenous vein graft. Tumoral calcinosis is a rare benign condition that can be located in close relationship with neurovascular structures. In such cases, detailed neurologic and vascular examination, including imaging modalities, for arterial flow is essential to establish a more accurate surgical plan and avoid any unexpected situation during surgery.

Isolation of Human Primary Valve Cells for In vitro Disease Modeling.

Calcific aortic valve disease (CAVD) is present in nearly a third of the elderly population. Thickening, stiffening, and calcification of the aortic valve causes aortic stenosis and contributes to heart failure and stroke. Disease pathogenesis is multifactorial, and stresses such as inflammation, extracellular matrix remodeling, turbulent flow, and mechanical stress and strain contribute to the osteogenic differentiation of valve endothelial and valve interstitial cells. However, the precise initiating factors that drive the osteogenic transition of a healthy cell into a calcifying cell are not fully defined. Further, the only current therapy for CAVD-induced aortic stenosis is aortic valve replacement, whereby the native valve is removed (surgical aortic valve replacement, SAVR) or a fully collapsible replacement valve is inserted via a catheter (transcatheter aortic valve replacement, TAVR). These surgical procedures come at a high cost and with serious risks; thus, identifying novel therapeutic targets for drug discovery is imperative. To that end, the present study develops a workflow where surgically removed tissues from patients and donor cadaver tissues are used to create patient-specific primary lines of valvular cells for in vitro disease modeling. This protocol introduces the utilization of a cold storage solution, commonly utilized in organ transplant, to reduce the damage caused by the often-lengthy procurement time between tissue excision and laboratory processing with the benefit of greatly stabilizing cells of the excised tissue. The results of the present study demonstrate that isolated valve cells retain their proliferative capacity and endothelial and interstitial phenotypes in culture upwards of several days after valve removal from the donor. Using these materials allows for the collection of control and CAVD cells, from which both control and disease cell lines are established.

Comparison of Tympanic Membrane Perforation With and Without Calcification of Anterior Mallear Ligament Under Transcanal Endoscopic Type I Tympanoplasty.

OBJECTIVES: Chronic suppurative otitis media (CSOM) induced tympanic membrane perforation (TMP) can be accompanied by anterior mallear ligament (AML) calcification. So far, comparative evaluations of TMP with and without AML calcification have rarely been reported. The aim of the current study is to compare the hearing outcomes of TMP with and without calcification of AML under transcanal endoscopic type I tympanoplasty. METHODS: Records of 67 patients diagnosed with CSOM and receiving transcanal endoscopic type I tympanoplasty were divided into the AML calcification group (Cal group, n = 31) and the non-AML calcification group (non-Cal group, n = 36). The 31 patients in the Cal group were divided into subgroup A and B according to the severity of calcification. The operation time, closure rate, and pre- and postoperative audiometric results were retrospectively collected and analyzed. RESULTS: Preoperatively, the Cal group had higher mean air-bone gap (ABG; P = .022), and ABGs at 250 Hz (P = .017) and 500 Hz (P = .008) compared with the non-Cal groups. The Cal group showed higher improvements of ABGs at 250 Hz (P = .039) and 500 Hz (P = .021) compared with the non-Cal groups postoperatively. CONCLUSIONS: The TMP with AML calcification leads to higher ABGs at low frequencies. The hearing outcomes are similar for TMP both with and without AML calcification after surgery. Our results suggest that transcanal endoscopic type I tympanoplasty is an appropriate surgical method for TMP with AML calcification, if the lesion can be detected and completely eliminated.

First pediatric case with primary familial brain calcification due to a novel variant on the MYORG gene and review of the literature.

Variants in the myogenesis-regulating glycosidase (MYORG) gene which is known as the first autosomal recessive gene that has been associated with primary familial brain calcification (AR-PFBC). Although adult patients have been reported, no pediatric case has been reported until now. Herein, we review the clinical and radiological features of all AR- PFBC patients with biallelic variants in the MYORG gene who were reported until now, and we report the youngest patient who has a novel homozygous variant. Since the first identification of the MYORG gene in 2018, 74cases of MYORG variants related to AR-PFBC were evaluated. The ages of symptom onset of the patients ranged between 7.5 and 87 years. The most frequent clinical courses were speech impairment, movement disorder and cerebellar signs. All patients showed basal ganglia calcification usually bilaterally with different severities. Conclusion; herein, we reported the first pediatric patient in the literature who had a novel homozygous variant in the MYORG gene with mild clinic findings.

Histopathological study of JNK in venous wall of patients with chronic venous insufficiency related to osteogenesis process.

Chronic venous insufficiency (CVI) is one of the most common vascular pathologies worldwide. One of the risk factors for the development of CVI is aging, which is why it is related to senile changes. The main trigger of the changes that occur in the venous walls in CVI is blood flow reflux, which produces increased hydrostatic pressure, leading to valve incompetence. The cellular response is one of the fundamental processes in vascular diseases, causing the activation of cell signalling pathways such as c-Jun N-terminal kinase (JNK). Metabolic changes and calcifications occur in vascular pathology as a result of pathophysiological processes. The aim of this study was to determine the expression of JNK in venous disease and its relationship with the role played by the molecules involved in the osteogenic processes in venous tissue calcification. This was a cross-sectional study that analyzed the greater saphenous vein wall in 110 patients with (R) and without venous reflux (NR), classified according to age. Histopathological techniques were used and protein expression was analysed using immunohistochemistry techniques for JNK and markers of osteogenesis (RUNX2, osteocalcin (OCN), osteopontin (OPN)). Significantly increased JNK, RUNX2, OCN, OPN and pigment epithelium-derived factor (PEDF) protein expression and the presence of osseous metaplasia and amorphous calcification were observed in younger patients (<50 years) with venous reflux. This study shows for the first time the existence of an osteogenesis process related to the expression of JNK in the venous wall.

Multi-Omics Approaches to Define Calcific Aortic Valve Disease Pathogenesis.

Calcific aortic valve disease sits at the confluence of multiple world-wide epidemics of aging, obesity, diabetes, and renal dysfunction, and its prevalence is expected to nearly triple over the next 3 decades. This is of particularly dire clinical relevance, as calcific aortic valve disease can progress rapidly to aortic stenosis, heart failure, and eventually premature death. Unlike in atherosclerosis, and despite the heavy clinical toll, to date, no pharmacotherapy has proven effective to halt calcific aortic valve disease progression, with invasive and costly aortic valve replacement representing the only treatment option currently available. This substantial gap in care is largely because of our still-limited understanding of both normal aortic valve biology and the key regulatory mechanisms that drive disease initiation and progression. Drug discovery is further hampered by the inherent intricacy of the valvular microenvironment: a unique anatomic structure, a complex mixture of dynamic biomechanical forces, and diverse and multipotent cell populations collectively contributing to this currently intractable problem. One promising and rapidly evolving tactic is the application of multiomics approaches to fully define disease pathogenesis. Herein, we summarize the application of (epi)genomics, transcriptomics, proteomics, and metabolomics to the study of valvular heart disease. We also discuss recent forays toward the omics-based characterization of valvular (patho)biology at single-cell resolution; these efforts promise to shed new light on cellular heterogeneity in healthy and diseased valvular tissues and represent the potential to efficaciously target and treat key cell subpopulations. Last, we discuss systems biology- and network medicine-based strategies to extract meaning, mechanisms, and prioritized drug targets from multiomics datasets.

Wave Reflection at the Origin of a First-Generation Branch Artery and Target Organ Protection: The AGES-Reykjavik Study.

[Figure: see text].

Surgical and Transcatheter Mitral Valve Replacement in Mitral Annular Calcification: A Systematic Review.

Mitral annular calcification with mitral valve disease is a challenging problem that could necessitate surgical mitral valve replacement (SMVR). Transcatheter mitral valve replacement (TMVR) is emerging as a feasible alternative in high-risk patients with appropriate anatomy. PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched from inception to December 25, 2019 for studies discussing SMVR or TMVR in patients with mitral annular calcification; 27 of 1539 articles were selected for final review. TMVR was used in 15 studies. Relevant data were available on 82 patients who underwent hybrid transatrial TMVR, and 354 patients who underwent transapical or transseptal TMVR. Outcomes on SMVR were generally reported as small case series (447 patients from 11 studies); however, 1 large study recently reported outcomes in 9551 patients. Patients who underwent TMVR had a shorter median follow-up of 9 to 12 months (range, in-hospital‒19 months) compared with patients with SMVR (54 months; range, in-hospital‒120 months). Overall, those undergoing TMVR were older and had higher Society of Thoracic Surgeons risk scores. SMVR showed a wide range of early (0%-27%; median 6.3%) and long-term mortality (0%-65%; median at 1 year, 15.8%; 5 years, 38.8%, 10 years, 62.4%). The median in-hospital, 30-day, and 1-year mortality rates were 16.7%, 22.7%, and 43%, respectively, for transseptal/transapical TMVR, and 9.5%, 20.0%, and 40%, respectively, for transatrial TMVR. Mitral annular calcification is a complex disease and TMVR, with a versatile option of transatrial approach in patients with challenging anatomy, offers a promising alternative to SMVR in high-risk patients. However, further studies are needed to improve technology, patient selection, operative expertise, and long-term outcomes.