Calcific Aortic Valve Stenosis Research Articles

A-210 Comparison of Two Lipoprotein(a) Methods: Validation, Sample Stability, and Patient Characteristics

Abstract Background Lipoprotein(a) [Lp(a)] is now thought of as an independent risk factor for coronary heart disease, stroke, and calcific aortic valve stenosis, and drugs specifically targeting Lp(a) are showing promise in clinical trials. Our laboratory recently validated two commercially available methods and used them to characterize a randomly selected group of samples from an outpatient clinic in the United States. Since the assays have different stated sample stabilities, this was also compared. Methods Both the Roche Lp(a) and the Randox Lp(a) immunoturbidimetric methods were run on a Roche cobas c501 platform across several months. In the U.S., the Roche assay is calibrated in mg/dL, while Randox provides both mg/dL and nmol/L units. Assays were tested for reproducibility, intermediate precision and accuracy. Stability of samples and AMR were established. Additionally, 78 residual samples were randomly selected to assess the percentage with high Lp(a) in our patient population. Results Method validation showed acceptable within-run and between-run precision as both assays met or exceeded manufacturer’s specifications. The stated AMR for the Roche assay is 6.0 – 80.0 mg/dL; linearity was verified through 90.0 mg/dL using the Randox calibrators. For the Randox assay, linearity was verified for the manufacturer’s AMR of 5.2–206.0 nmol/L using estimated values assigned to the Roche calibrators. Both assays allow for x3 dilutions to extend the range. Method comparison of the Randox results (nmol/L) was performed with samples sent to Quest. Deming regression results were acceptable (r = 0.995, slope 1.2, y-intercept—2.3). The stated sample stability from Roche is 8 h at room temperature and 48 h at 2–8oC; however, our results suggest 7 h at room temperature and up to 10 days at 2–8oC. Our study also extended the number of freeze-thaws to two. The Randox package insert gives no information on freeze-thaws or room temperature stability, but states stability at 4oC for 14 days. In our assessment, some samples were not stable past 10 days at 2–8oC. We found samples stable for 2 days at room temperature and up to one month at −20oC. Three freeze-thaws was acceptable. Our patient population included 49 Caucasians, 19 Blacks, 2 Asians, 3 Hispanics, and 5 with race unknown. The median Lp(a) for Blacks was 151.1 nmol/L (65.1 mg/dL) while for Caucasians it was 17.9 nmol/L (14.5 mg/dL) for samples within range. The extended range with dilutions allowed all high values to be quantified; however, 12 were below the AMR for the Roche method and 8 below the AMR for Randox method. Based on the Roche assay, 20 (25.6%) subjects had Lp(a) > 50 mg/dL and would be considered to have increased cardiovascular risk. By the Randox assay, the same 20 had an Lp(a) > 100 nmol/L, while 19 had Lp(a) > 125 nmol/L. Conclusions Both assays met performance goals and showed no significant difference in % subjects with elevated risk for cardiovascular events using typical cut-offs. Our data suggests greater stability of samples at room temperature and additional stability to freeze-thaws when using the Randox assay.

Abstract P3070: Aortic Valve Calcification Is Accelerated By DNMT3A And TET2 Gene Driver Mutations Associated With Clonal Hematopoiesis

Background: Clonal hematopoiesis (CH) due to DNMT3A or TET2-driver mutations associates with heightened inflammation and a worse prognosis among patients with severe calcific aortic valve stenosis (AS). However, it is unknown what role CH plays in the pathogenesis of AS. AS is the most common age-related heart valve disease, with no medical therapy to halt progression. Methods and Results: Single-cell RNA-sequencing of immune cells of CAVD patients (n=13) with and without the most prevalent CH-mutations (DNMT3A and TET2), having a mean CH-driver gene variant allele frequency was 6.5% for DNMT3A and 17.9% for TET2. Monocytes of patients harboring DNMT3A and TET2 mutations shared 836 upregulated genes, which were associated with glycolytic, pro-inflammatory activation (CXCL10, IL38) along with paracrine pro-calcific factors (Oncostatin M (OSM), S100A9), signifying that CH might be causally involved in AS. Indeed, silencing of TET2 or DNMT3A in macrophages promotes M1-like polarization and increases release of pro-calcific mediators, particularly S100A9 and OSM. To assess whether CH-gene silenced macrophages may stimulate mesenchymal cells to secrete calcium, secreted factors from TET2 or DNMT3A-silenced macrophages were applied mesenchymal cells. Indeed, CH-gene silenced supernatants induced osteoblastic differentiation of mesenchymal cells, evidenced by increased Alizarin red calcium staining and elevated levels of ALP and RUNX2. This CH-mediated enhancement in osteoblastic transformation could be ablated by silencing of OSM. Finally, valves from atheroprone Ldlr-/- mice receiving Tet2-/- bone marrow transplants demonstrated increased total calcified area (p<0.05, 1.49-fold) along with increased numbers of calcification deposits (p<0.05, 2.33-fold) as shown by von Kossa staining, along with enhanced OSM and S100A9 levels. Conclusion: This is the first study to show that somatic CH-driver mutations in monocytes may accelerate AS. Moreover, calcification was ablated via silencing of OSM in CH-gene silenced macrophages. These data suggest Oncostatin M may be a therapeutically promising target in halting the development of AS in patients harboring CH mutations.

Degenerative calcific aortic valve stenosis: why not neglect vitamin D?

Degenerative calcific aortic valve stenosis: why not neglect vitamin D?

The Complex Relationship between Hypoxia Signaling, Mitochondrial Dysfunction and Inflammation in Calcific Aortic Valve Disease: Insights from the Molecular Mechanisms to Therapeutic Approaches

Calcific aortic valve stenosis (CAVS) is among the most common causes of cardiovascular mortality in an aging population worldwide. The pathomechanisms of CAVS are such a complex and multifactorial process that researchers are still making progress to understand its physiopathology as well as the complex players involved in CAVS pathogenesis. Currently, there is no successful and effective treatment to prevent or slow down the disease. Surgical and transcatheter valve replacement represents the only option available for treating CAVS. Insufficient oxygen availability (hypoxia) has a critical role in the pathogenesis of almost all CVDs. This process is orchestrated by the hallmark transcription factor, hypoxia-inducible factor 1 alpha subunit (HIF-1α), which plays a pivotal role in regulating various target hypoxic genes and metabolic adaptations. Recent studies have shown a great deal of interest in understanding the contribution of HIF-1α in the pathogenesis of CAVS. However, it is deeply intertwined with other major contributors, including sustained inflammation and mitochondrial impairments, which are attributed primarily to CAVS. The present review aims to cover the latest understanding of the complex interplay effect of hypoxia signaling pathways, mitochondrial dysfunction, and inflammation in CAVS. We propose further hypotheses and interconnections on the complexity of these impacts in a perspective of better understanding the pathophysiology. These interplays will be examined considering recent studies that shall help us better dissect the molecular mechanism to enable the design and development of potential future therapeutic approaches that can prevent or slow down CAVS processes.

Risk factors for depresion and anxiety in the patient with aortic valve stenosis

Anxiety disorders and depression are common along with negative effects in different areas of the patient such as lower quality of life, lower adherence to treatment, negative perception of oneself along with underlying comorbidities and mortality, which is why these disorders are usually considered as symptoms and not as an independent factor that require greater detection, care and early treatment. Cardiovascular diseases are among the leading causes of mortality and morbidity in the world. Among them there is a subgroup of valvopathies which can occur in young patients (congenital alterations) and in elderly patients (called calcific or degenerative aortic valve stenosis) consisting of calcium crystal formation and lipid accumulation. These processes damage the valve generating aortic sclerosis characterized by thickening of the leaflets. Valvopathies are usually asymptomatic during the first years after their onset, and several modifiable and non-modifiable factors have been related to the progression of the disease. Psychological alterations can occur in these patients before, during and/or after discharge, generating mood disorders such as anxiety and depression, the frequency of which is unknown, which is why the general objective of the article is the importance of recognizing the symptomatology to favour prognosis through timely diagnosis to generate future interdisciplinary interventions and improve the quality of patients.

Niclosamide Inhibits Aortic Valve Interstitial Cell Calcification by Interfering with the GSK-3β/β-Catenin Signaling Pathway.

The most common heart valve disorder is calcific aortic valve stenosis (CAVS), which is characterized by a narrowing of the aortic valve. Treatment with the drug molecule, in addition to surgical and transcatheter valve replacement, is the primary focus of researchers in this field. The purpose of this study is to determine whether niclosamide can reduce calcification in aortic valve interstitial cells (VICs). To induce calcification, cells were treated with a pro-calcifying medium (PCM). Different concentrations of niclosamide were added to the PCM-treated cells, and the level of calcification, mRNA, and protein expression of calcification markers was measured. Niclosamide inhibited aortic valve calcification as observed from reduced alizarin red s staining in niclosamide treated VICs and also decreased the mRNA and protein expressions of calcification-specific markers: runt-related transcription factor 2 and osteopontin. Niclosamide also reduced the formation of reactive oxygen species, NADPH oxidase activity and the expression of Nox2 and p22phox. Furthermore, in calcified VICs, niclosamide inhibited the expression of β-catenin and phosphorylated glycogen synthase kinase (GSK-3β), as well as the phosphorylation of AKT and ERK. Taken together, our findings suggest that niclosamide may alleviate PCM-induced calcification, at least in part, by targeting oxidative stress mediated GSK-3β/β-catenin signaling pathway via inhibiting activation of AKT and ERK, and may be a potential treatment for CAVS.

Human and porcine aortic valve endothelial and interstitial cell isolation and characterization.

Calcific aortic valve stenosis (AVS) is defined by pathological changes in the aortic valve (AV) and their predominant cell types: valvular interstitial (VICs) and endothelial cells (VECs). Understanding the cellular and molecular mechanisms of this disease is a prerequisite to identify potential pharmacological treatment strategies. In this study, we present a unique aortic valve cell isolation technique to acquire specific human and porcine cell populations and compared VICs and VECs of these species with each other for the first time. AV cells were isolated from tissue obtained from human patients undergoing surgical aortic valve replacement (SAVR) or from porcine hearts. Functional analysis and in vitro experiments revealed that endothelial-to-mesenchymal transition (EndMT) can be induced in hVECs, leading to a significant increase in mesenchymal markers. In vitro calcification experiments of VICs demonstrated pronounced expression of calcification markers and visible calcific deposits in Alizarin Red staining in both species after incubation with pro-calcific media. Cells isolated from patient-derived AVs showed mesenchymal and endothelial-specific gene signatures (VIC and VEC, respectively). For instance, von Willebrand factor (vWF) and platelet endothelial adhesion molecule-1 (PECAM1) were upregulated in VECs, while the myofibroblastic markers alpha-smooth muscle actin (α-SMA) and vimentin (VIM) were downregulated in VECs compared to VICs. Analysis of cell function by migration revealed that VECs are more migratory than VICs. Induction of EndMT in vitro in VECs displayed increased expression of EndMT markers and decreased expression of endothelial markers, confirming their mesenchymal transdifferentiation ability. In vitro calcification of VICs revealed upregulation of alkaline phosphatase (ALPL), a hallmark of calcification. In addition, other calcification-related genes such as osteocalcin (BGLAP) and runt-related factor 2 (RUNX2) were upregulated. Alizarin red staining of calcified cells provided a further layer of confirmation that the isolated cells were VICs with osteoblastic differentiation capacity. This study aims to take a first step towards standardizing a reproducible isolation technique for specific human and porcine VEC and VIC populations. A comparison of human and porcine aortic valve cells demonstrated that porcine cells may serve as an alternative cellular model system in settings where human tissue is difficult to obtain.

Evidence and Uncertainties on Lipoprotein(a) as a Marker of Cardiovascular Health Risk in Children and Adolescents.

Lipoprotein(a) (Lp(a)) is made up of apoprotein(a) (apo(a)) and an LDL-like particle. The LPA gene encodes apo(a) and thus determines the characteristics and amount of apo(a) and Lp(a). The proportion of Lp(a) in each individual is genetically determined and is only minimally modifiable by the environment or diet. Lp(a) has important pro-atherosclerotic and pro-inflammatory effects. It has been hypothesized that Lp(a) also has pro-coagulant and antifibrinolytic actions. For these reasons, high Lp(a) values are an important independent risk factor for cardiovascular disease and calcific aortic valve stenosis. Numerous studies have been performed in adults about the pathophysiology and epidemiology of Lp(a) and research is under way for the development of drugs capable of reducing Lp(a) plasma values. Much less information is available regarding Lp(a) in children and adolescents. The present article reviews the evidence on this topic. The review addresses the issues of Lp(a) changes during growth, the correlation between Lp(a) values in children and those in their parents, and between Lp(a) levels in children, and the presence of cardiovascular disease in the family. Gaining information on these points is particularly important for deciding whether Lp(a) assay may be useful for defining the cardiovascular risk in children, in order to plan a prevention program early.

P481 PREDICTIVE FACTORS OF CLINICAL OUTCOME IN PATIENTS WITH AORTIC STENOSIS: DATA FROM THE VENETO REGISTER

Abstract Background Aortic valve stenosis represents the most relevant valve disease in the Western world, with a mortality rate exceeding 50%. Calcific aortic valve stenosis was once considered a passive process of the valve deposition of calcium salts, but is now considered a cell–mediated disease. The aim of the present study is to search for predictors of mortality, cardiovascular events and valve replacement in patients with aortic stenosis. Materials and Methods A subgroup of 140 patients affected by moderate–severe aortic valve stenosis from the Cardiology departments of the Treviso Hospital and the High Specialization Hospital of Motta di Livenza included in the Veneto Register. For each patient, information relating to deaths, cardiovascular events and valve staging was therefore collected over time. Results The deceased were 36% of which 22.9% without having replaced the valve. The mean follow–up was 24.99±21.72 months. In the follow–up, the deceased were characterized by an older age, a greater frequency of ischemic heart disease, atrial fibrillation and chronic kidney disease (CKD), a worse eGFR, a higher phosphate level. Among the Cox regression biohumoral data, serum phosphate was significantly associated with mortality in the univariate survey, and eGFR values were also always independently significantly associated with mortality. Kaplan Meyer curves also showed significant differences in the risk of CV events over time between groups with eGFR values greater than equal and less than 60 mL/min. Conclusions The results of the study suggest that the pathology appears to be linked to senescence processes and shares a common basis with atherosclerotic pathology, but also appears to be influenced in its evolution by further determinants such as CKD and blood phosphorus values. These considerations prompt us to reflect on the need for studies aimed at understanding the pathogenetic mechanisms of the proven relationship between cardiovascular MACE and phosphorus values, and that between worse renal function and cardiovascular mortality/morbidity. On the other hand, it seems urgent to be able to propose in the near future an internationally shared prognostic score that considers these predictive variables and can help us to better stratify the clinical evolution of aortic stenosis and influencing the surgical timing.

Role of hypercholesterolemia and PSCK9 in bioprosthetic aortic valve degeneration

Calcific aortic valve stenosis (CAVS) is one of the most frequent cardiovascular diseases affecting more than 10% of the population over 70 years old. There is currently no pharmacological treatment to stop this process, and the only solution remains to replace the diseased valve with a prosthesis. A shift toward the use of biological prosthesis occurred in the last 10 years, as these protheses presented better hemodynamic profile without lifelong anticoagulation treatment. However, the main disadvantage of the bioprostheses is their limited durability overtime, with the development of a gradual structural bioprosthetic degeneration (SVD) in the following years post intervention. Our objective is to test the role of hypercholesterolemia and/or PCSK9, a well-know modulator of the cholesterol metabolism, on the early process leading to SVD. As the currently gold standard technic to test calcification potential of biological tissue from bioprosthetic valve, we implanted subcutaneously 5 mm punches of biological matrix from bovine pericardium, in 3 groups of mice: PCSK9 KO, WT and overexpressing hepatic PCSK9 (with AAV injection). After 28 days, punches werehandled and analyzed. Histology and molecular screening were performed. As compared to WT, KO PCSK9 mice presented a 25% to 50% reduction in cholesterol, and mice overexpressing hepatic PCSK9 a 2-time higher circulating cholesterol over the course of the protocol (all P < 0.003). PCSK9 circulating level was not detectable in KO and was significantly increased in mice overexpressing hepatic PCSK9 (fold change > 10 vs. WT; all P < 0.001). Preliminary histological analysis of explanted punches after 28 days revealed an important infiltration of mononuclear cells into the pericardial matrix, consistent over the 3 groups of mice. However, the quantity and degree of infiltration of these cells appeared to be exacerbated in mice overexpressing hepatic PCSK9. Further molecular screening is ongoing. We successfully developed an animal model allowing us the investigation of PCSK9 and hypercholesterolemia roles in SVD. Preliminary analyses suggest that high PCSK9 and/or cholesterol can potentiate cell infiltration post-implantation of bovine pericardial matrix. Further molecular analyses will provide key elements to decipher the mechanisms related to PCSK9 and cholesterol in the development of SVD.

Lipoprotein(a) As a Risk Factor in a Cohort of Hospitalised Cardiovascular Patients: A Retrospective Clinical Routine Data Analysis.

Lipoprotein(a) (Lp(a)) is a well-recognised risk factor for ischemic heart disease (IHD) and calcific aortic valve stenosis (AVS). A retrospective observational study of Lp(a) levels (mg/dL) in patients hospitalised for cardiovascular diseases (CVD) in our clinical routine was performed. The Lp(a)-associated risk of hospitalisation for IHD, AVS, and concomitant IHD/AVS versus other non-ischemic CVDs (oCVD group) was assessed by means of logistic regression. In total of 11,767 adult patients, the association with Lp(a) was strongest in the IHD/AVS group (eβ = 1.010, p < 0.001), followed by the IHD (eβ = 1.008, p < 0.001) and AVS group (eβ = 1.004, p < 0.001). With increasing Lp(a) levels, the risk of IHD hospitalisation was higher compared with oCVD in women across all ages and in men aged ≤75 years. The risk of AVS hospitalisation was higher only in women aged ≤75 years (eβ = 1.010 in age < 60 years, eβ = 1.005 in age 60-75 years, p < 0.05). The Lp(a)-associated risk was highest for concomitant IHD/AVS hospitalisations. The differential impact of sex and age was most pronounced in the AVS group with an increased risk only in women aged ≤75 years.

Molecular Mechanisms Underlying the Progression of Aortic Valve Stenosis: Bioinformatic Analysis of Signal Pathways and Hub Genes.

The calcification of the aortic valve causes increased leaflet stiffness and leads to the development and progression of stenotic aortic valve disease. However, the molecular and cellular mechanisms underlying stenotic calcification remain poorly understood. Herein, we examined the gene expression associated with valve calcification and the progression of calcific aortic valve stenosis. We downloaded two publicly available gene expression profiles (GSE83453 and GSE51472) from NCBI-Gene Expression Omnibus database for the combined analysis of samples from human aortic stenosis and normal aortic valve tissue. After identifying the differentially expressed genes (DEGs) using the GEO2R online tool, we performed Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. We also analyzed the protein-protein interactions (PPIs) of the DEGs using the NetworkAnalyst online tool. We identified 4603 upregulated and 6272 downregulated DEGs, which were enriched in the positive regulation of cell adhesion, leukocyte-mediated immunity, response to hormones, cytokine signaling in the immune system, lymphocyte activation, and growth hormone receptor signaling. PPI network analysis identified 10 hub genes: VCAM1, FHL2, RUNX1, TNFSF10, PLAU, SPOCK1, CD74, SIPA1L2, TRIB1, and CXCL12. Through bioinformatic analysis, we identified potential biomarkers and therapeutic targets for aortic stenosis, providing a theoretical basis for future studies.

Capsaicin inhibits aortic valvular interstitial cell calcification via the redox-sensitive NFκB/AKT/ERK1/2 pathway

Calcific aortic valve stenosis (CAVS), the third most prevalent cardiovascular disorder is known to impose a huge social and economic burden on patients. However, no pharmacotherapy has yet been established. Aortic valve replacement is the only treatment option, although its lifelong efficacy is not guaranteed and involves inevitable complications. So, there is a crucial need to find novel pharmacological targets to delay or prevent CAVS progression. Capsaicin is well known for its anti-inflammatory and antioxidant properties and has recently been revealed to inhibit arterial calcification. We thus investigated the effect of capsaicin in attenuating aortic valve interstitial cells (VICs) calcification induced by pro-calcifying medium (PCM). Capsaicin reduced the level of calcium deposition in calcified VICs, along with reductions in gene and protein expression of the calcification markers Runx2, osteopontin, and BMP2. Based on Gene Ontology biological process and Kyoto Encyclopedia of Genes and Genomes pathway analysis oxidative stress, AKT and AGE–RAGE signaling pathways were selected. The AGE–RAGE signaling pathway activates oxidative stress and inflammation-mediated pathways including ERK and NFκB signaling pathways. Capsaicin successfully inhibited oxidative stress- and reactive oxygen species-related markers NOX2 and p22phox. The markers of the AKT, ERK1/2, and NFκB signaling pathways, namely, phosphorylated AKT, ERK1/2, NFκB, and IκBα were upregulated in calcified cells, while being significantly downregulated upon capsaicin treatment. Capsaicin attenuates VICs calcification in vitro by inhibition of redox-sensitive NFκB/AKT/ERK1/2 signaling pathway, indicating its potential as a candidate to alleviate CAVS.

Lipoprotein(a) and Its Autoantibodies in Association with Calcific Aortic Valve Stenosis.

Aortic valve stenosis is the most common valvular heart disease in the Western world. Lipoprotein(a) (Lp(a)) is an independent risk factor of coronary heart disease (CHD) and calcific aortic valve stenosis (CAVS). The aim of this study was to assess the role of Lp(a) and its autoantibodies [autoAbs] in CAVS in patients with and without CHD. We included 250 patients (mean age 69 ± 3 years, males 42%) and divided them into three groups. There were two groups of patients with CAVS depending on the presence (group 1) or absence of CHD (group 2). The control group included the patients without CHD or CAVS. According to logistic regression analysis, levels of Lp(a), IgM autoAbs to oxidized Lp(a) (oxLp(a)), and age were independent predictors of CAVS. A concomitant increase in Lp(a) level (≥30 mg/dL) and a decrease in IgM autoAbs concentration (<9.9 lab. Units) are associated with CAVS with an odds ratio (OR) of 6.4, p < 0.01, and with CAVS and CHD with an OR of 17.3, p < 0.001. IgM autoantibodies to oxLp(a) are associated with calcific aortic valve stenosis regardless of Lp(a) concentration and other risk factors. Higher Lp(a) and lower IgM autoantibodies to oxLp(a) levels are associated with a much higher risk of calcific aortic valve stenosis.

Impact of C-reactive protein levels on lipoprotein(a)-associated aortic stenosis incidence and progression.

Elevated lipoprotein(a) [Lp(a)] levels are associated with the risk of coronary artery disease (CAD) and calcific aortic valve stenosis (CAVS). Observational studies revealed that Lp(a) and C-reactive protein (CRP) levels, a biomarker of systemic inflammation, may jointly predict CAD risk. Whether Lp(a) and CRP levels also jointly predict CAVS incidence and progression is unknown. We investigated the association of Lp(a) with CAVS according to CRP levels in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk study (n = 18 226, 406 incident cases) and the UK Biobank (n = 438 260, 4582 incident cases), as well as in the ASTRONOMER study (n = 220), which assessed the haemodynamic progression rate of pre-existing mild-to-moderate aortic stenosis. In EPIC-Norfolk, in comparison to individuals with low Lp(a) levels (<50 mg/dL) and low CRP levels (<2.0 mg/L), those with elevated Lp(a) (>50 mg/dL) and low CRP levels (<2.0 mg/L) and those with elevated Lp(a) (>50 mg/dL) and elevated CRP levels (>2.0 mg/L) had a higher CAVS risk [hazard ratio (HR) = 1.86 (95% confidence intervals, 1.30-2.67) and 2.08 (1.44-2.99), respectively]. A comparable predictive value of Lp(a) in patients with vs. without elevated CRP levels was also noted in the UK Biobank. In ASTRONOMER, CAVS progression was comparable in patients with elevated Lp(a) levels with or without elevated CRP levels. Lp(a) predicts the incidence and possibly progression of CAVS regardless of plasma CRP levels. Lowering Lp(a) levels may warrant further investigation in the prevention and treatment of CAVS, regardless of systemic inflammation.

Lipoprotein(a): Its Association with Calcific Aortic Valve Stenosis, the Emerging RNA-Related Treatments and the Hope for a New Era in "Treating" Aortic Valve Calcification.

The treatment of patients with aortic valve calcification (AVC) and calcific aortic valve stenosis (CAVS) remains challenging as, until today, all non-invasive interventions have proven fruitless in preventing the disease's onset and progression. Despite the similarities in the pathogenesis of AVC and atherosclerosis, statins failed to show a favorable effect in preventing AVC progression. The recognition of lipoprotein(a) [Lp(a)] as a strong and potentially modifiable risk factor for the development and, perhaps, the progression of AVC and CAVS and the evolution of novel agents leading in a robust Lp(a) reduction, have rekindled hope for a promising future in the treatment of those patients. Lp(a) seems to promote AVC via a 'three hit' mechanism including lipid deposition, inflammation and autotaxin transportation. All of these lead to valve interstitial cells transition into osteoblast-like cells and, thus, to parenchymal calcification. Currently available lipid-lowering therapies have shown a neutral or mild effect on Lp(a), which was proven insufficient to contribute to clinical benefits. The short-term safety and the efficacy of the emerging agents in reducing Lp(a) have been proven; nevertheless, their effect on cardiovascular risk is currently under investigation in phase 3 clinical trials. A positive result of these trials will probably be the spark to test the hypothesis of the modification of AVC's natural history with the novel Lp(a)-lowering agents.

Metals and Trace Elements in Calcified Valves in Patients with Acquired Severe Aortic Valve Stenosis: Is There a Connection with the Degeneration Process?

Acquired calcified aortic valve stenosis is the most common valve disease in adulthood. In the etiopathogenesis of this complex pathology, the importance of inflammation is mentioned, in which non-infectious influences represented by the biological effects of metal pollutants may participate. The main goal of the study was to determine the concentration of 21 metals and trace elements-aluminium (Al), barium (Ba), cadmium (Cd), calcium (Ca), chrome (Cr), cobalt (Co), copper (Cu), gold (Au), lead (Pb), magnesium (Mg), mercury (Hg), molybdenum (Mo), nickel (Ni), phosphorus (P), selenium (Se), strontium (Sr), sulfur (S), tin (Sn), titanium (Ti), vanadium (V) and zinc (Zn)-in the tissue of calcified aortic valves and to compare them with the concentrations of the same elements in the tissue of healthy aortic valves in the control group. The study group consisted of 49 patients (25 men, mean age: 74) with acquired, severe, calcified aortic valve stenosis with indicated heart surgery. The control group included 34 deceased (20 men, median age: 53) with no evidence of heart disease. Calcified valves were explanted during cardiac surgery and deep frozen. Similarly, the valves of the control group were removed. All valves were lyophilized and analyzed by inductively coupled plasma mass spectrometry. The concentrations of selected elements were compared by means of standard statistical methods. Calcified aortic valves contained significantly higher (p < 0.05) concentrations of Ba, Ca, Co, Cr, Mg, P, Pb, Se, Sn, Sr and Zn and-in contrast-lower concentrations of Cd, Cu, Mo, S and V than valves of the control group. Significant positive correlations of concentrations between the pairs Ca-P, Cu-S and Se-S and strong negative correlations between the elements Mg-Se, P-S and Ca-S were found in the affected valves. Aortic valve calcification is associated with increased tissue accumulation of the majority of the analyzed elements, including metal pollutants. Some exposure factors may increase their accumulation in the valve tissue. A relationship between exposure to environmental burden and the aortic valve calcification process cannot be ruled out. Advances in histochemical and imaging techniques allowing imaging of metal pollutants directly in valve tissue may represent an important future perspective.

Left Ventricular Filling Pressure in Chronic Thromboembolic Pulmonary Hypertension

BackgroundChronic thromboembolic pulmonary hypertension (CTEPH) is characterized by obstruction of major pulmonary arteries with organized thrombi. Clinical risk factors for pulmonary hypertension due to left heart disease including metabolic syndrome, left-sided valvular heart disease, and ischemic heart disease are common in CTEPH patients. ObjectivesThe authors sought to investigate prevalence and prognostic implications of elevated left ventricular filling pressures (LVFP) in CTEPH. MethodsA total of 593 consecutive CTEPH patients undergoing a first diagnostic right and left heart catheterization were included in this study. Mean pulmonary arterial wedge pressure (mPAWP) and left ventricular end-diastolic pressure (LVEDP) were utilized for assessment of LVFP. Two cutoffs were applied to identify patients with elevated LVFP: 1) for the primary analysis mPAWP and/or LVEDP >15 mm Hg, as recommended by the current pulmonary hypertension guidelines; and 2) for the secondary analysis mPAWP and/or LVEDP >11 mm Hg, representing the upper limit of normal. Clinical and echocardiographic features, and long-term mortality were assessed. ResultsLVFP was >15 mm Hg in 63 (10.6%) and >11 mm Hg in 222 patients (37.4%). Univariable logistic regression analysis identified age, systemic hypertension, diabetes, atrial fibrillation, calcific aortic valve stenosis, mitral regurgitation, and left atrial volume as significant predictors of elevated LVFP. Atrial fibrillation, calcific aortic valve stenosis, mitral regurgitation, and left atrial volume remained independent determinants of LVFP in adjusted analysis. At follow-up, higher LVFPs were measured in patients who had meanwhile undergone pulmonary endarterectomy (P = 0.002). LVFP >15 mm Hg (P = 0.021) and >11 mm Hg (P = 0.006) were both associated with worse long-term survival. ConclusionsElevated LVFP is common, appears to be due to comorbid left heart disease, and predicts prognosis in CTEPH.

The contribution of amyloid deposition in the aortic valve to calcification and aortic stenosis.

Calcific aortic valve disease (CAVD) and stenosis have a complex pathogenesis, and no therapies are available that can halt or slow their progression. Several studies have shown the presence of apolipoprotein-related amyloid deposits in close proximity to calcified areas in diseased aortic valves. In this Perspective, we explore a possible relationship between amyloid deposits, calcification and the development of aortic valve stenosis. These amyloid deposits might contribute to the amplification of the inflammatory cycle in the aortic valve, including extracellular matrix remodelling and myofibroblast and osteoblast-like cell proliferation. Further investigation in this area is needed to characterize the amyloid deposits associated with CAVD, which could allow the use of antisense oligonucleotides and/or isotype gene therapies for the prevention and/or treatment of CAVD.

Orengedokuto inhibits TNF-α-induced HAVIC calcification obtained from calcific aortic valve stenosis patients

Orengedokuto inhibits TNF-α-induced HAVIC calcification obtained from calcific aortic valve stenosis patients