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BACKGROUND - Valvular disease is characterized in part by lipid deposition, but systematic analysis of the patterns of global lipid expression in healthy and diseased valve tissues are unknown. This is due in part to tissue limitations for lipidomic preparations and technologies for evaluating lipid distribution in tissues. The study aim was to examine the application of matrixassisted laser desorption ionization imaging mass spectrometry (MALDI IMS) to the aortic valve during development and disease, as an approach to detect and map lipids and ultimately better understand valve structure and function.
METHODS - Established MALDI IMS strategies were applied to thin tissue sections of heart valves to map lipids to corresponding morphological features. Healthy prenatal and adult ovine aortic valve tissues were evaluated using the developed techniques. Lipid expression levels were compared between prenatal and adult valves using Wilcoxon rank sum testing and area under the receiver operating curves. A classification algorithm was used to determine distinct lipid signatures in adult extracellular matrix (ECM) substructures, including fibrosa and spongiosa layers. Lipid patterns were examined in heart valve tissue from pediatric patients with congenital aortic valve stenosis (CAVS).
RESULTS - Lipid levels were decreased in adult ovine aortic valves when compared with prenatal valves. Classification algorithms applied to lipid signatures reported distinct lipid signatures mapping to ECM substructures in the adult aortic valve, but could not distinguish amorphous structures at pre-natal day 5. In CAVS, the in-situ lipid aggregation of distinct lipid species showed unique patterning both concurrent and divergent with ECM disarray. Fatty acid content varied between normal and diseased human aortic valves.
CONCLUSIONS - MALDI IMS provides a new and useful approach to evaluate lipid biology in heart valve tissue. These findings define a role for lipid regulation in aortic valve development and demonstrate patterns of lipid deregulation in congenital disease.
Calcific aortic valve disease (CAVD) is a significant cardiovascular disorder characterized by the formation of calcific nodules (CN) on the valve. In vitro assays studying the formation of these nodules were developed and have led to many significant mechanistic findings; however, the biophysical properties of CNs have not been clearly defined. A thorough analysis of dystrophic and osteogenic nodules utilizing scanning electron microscopy (SEM), energy dispersive spectrometry (EDS), and atomic force microscopy (AFM) was conducted to describe calcific nodule properties and provide a link between calcific nodule morphogenesis in vitro and in vivo. Unique nodule properties were observed for dystrophic and osteogenic nodules, highlighting the distinct mechanisms occurring in valvular calcification.
Calcific aortic valve disease (CAVD) affects 25% of people over 65, and the late-stage stenotic state can only be treated with total valve replacement, requiring 85,000 surgeries annually in the US alone (University of Maryland Medical Center, 2013, http://umm.edu/programs/services/heart-center-programs/cardiothoracic-surgery/valve-surgery/facts). As CAVD is an age-related disease, many of the affected patients are unable to undergo the open-chest surgery that is its only current cure. This challenge motivates the elucidation of the mechanisms involved in calcification, with the eventual goal of alternative preventative and therapeutic strategies. There is no sufficient animal model of CAVD, so we turn to potential in vitro models. In general, in vitro models have the advantages of shortened experiment time and better control over multiple variables compared to in vivo models. As with all models, the hypothesis being tested dictates the most important characteristics of the in vivo physiology to recapitulate. Here, we collate the relevant pieces of designing and evaluating aortic valve calcification so that investigators can more effectively draw significant conclusions from their results.
Copyright © 2014 Elsevier Inc. All rights reserved.
Calcific aortic valve disease (CAVD) is increasingly prevalent worldwide with significant morbidity and mortality. Therapeutic options beyond surgical valve replacement are currently limited. In 2011, the National Heart Lung and Blood Institute assembled a working group on aortic stenosis. This group identified CAVD as an actively regulated disease process in need of further study. As a result, the Alliance of Investigators on CAVD was formed to coordinate and promote CAVD research, with the goals of identifying individuals at risk, developing new therapeutic approaches, and improving diagnostic methods. The group is composed of cardiologists, geneticists, imaging specialists, and basic science researchers. This report reviews the current status of CAVD research and treatment strategies with identification of areas in need of additional investigation for optimal management of this patient population.
© 2014 American Heart Association, Inc.
Calcific aortic valve disease (CAVD) results in impaired function through the inability of valves to fully open and close, but the causes of this pathology are unknown. Stiffening of the aorta is associated with CAVD and results in exposing the aortic valves to greater mechanical strain. Transforming growth factor β1 (TGF-β1) is enriched in diseased valves and has been shown to combine with strain to synergistically alter aortic valve interstitial cell (AVIC) phenotypes. Therefore, we investigated the role of strain and TGF-β1 on the calcification of AVICs. Following TGF-β1 pretreatment, strain induced intact monolayers to aggregate and calcify. Using a wound assay, we confirmed that TGF-β1 increases tension in the monolayer in parallel with α-smooth muscle actin (αSMA) expression. Continual exposure to strain accelerates aggregates to calcify into mature nodules that contain a necrotic core surrounded by an apoptotic ring. This phenotype appears to be mediated by strain inhibition of AVIC migration after the initial formation of aggregates. To better interpret the extent to which externally applied strain physically impacts this process, we modified the classical Lamé solution, derived using principles from linear elasticity, to reveal strain magnification as a novel feature occurring in a mechanical environment that supports nodule formation. These results indicate that strain can impact multiple points of nodule formation: by modifying tension in the monolayer, remodeling cell contacts, migration, apoptosis, and mineralization. Therefore, strain-induced nodule formation provides new directions for developing strategies to address CAVD.
Aortic valvular stenosis remains the most common debilitating valvular heart lesion. Despite the benefit of aortic valve (AV) replacement, many high-risk patients cannot tolerate surgery. AV implantation treats aortic stenosis without subjecting patients to sternotomy, cardiopulmonary bypass (CPB), and aorta cross-clamping. This transcatheter procedure is performed via puncture of the left ventricular (LV) apex or percutaneously, via the femoral artery or vein. Patients undergo general anesthesia, intense hemodynamic manipulation, and transesophageal echocardiography (TEE). To elucidate the role of the anesthesiologist in the management of transcatheter AV implantation, we review the literature and provide our experience, focusing on anesthetic care, intraoperative events, TEE, and perioperative complications. Two approaches to the aortic annulus are performed today: transfemoral retrograde and transapical antegrade. Iliac artery size and tortuosity, aortic arch atheroma, and pathology in the area of the (LV) apex help determine the preferred approach in each patient. A general anesthetic is tailored to achieve extubation after procedure completion, whereas IV access and pharmacological support allow for emergent sternotomy and initiation of CPB. Rapid ventricular pacing and cessation of mechanical ventilation interrupts cardiac ejection and minimizes heart translocation during valvuloplasty and prosthesis implantation. Although these maneuvers facilitate exact prosthesis positioning within the native annulus, they promote hypotension and arrhythmia. Vasopressor administration before pacing and cardioversion may restore adequate hemodynamics. TEE determines annulus size, aortic pathology, ventricular function, and mitral regurgitation. TEE and fluoroscopy are used for positioning the introducer catheter within the aortic annulus. The prosthesis, crimped on a valvuloplasty balloon catheter, is implanted by inflation. TEE immediately measures aortic regurgitation and assesses for aortic dissection. After repair of femoral vessels or LV apex, patients are allowed to emerge and assessed for extubation. Observed and published complications include aortic regurgitation, prosthesis embolization, mitral valve disruption, hemorrhage, aortic dissection, CPB, stroke, and death. Transcatheter AV implantation relies on intraoperative hemodynamic manipulation for success. Transfemoral and transapical approaches pose unique management challenges, but both require rapid ventricular pacing, the management of hypotension and arrhythmias during beating-heart valve implantation, and TEE. Anesthesiologists will care for debilitated patients with aortic stenosis receiving transcatheter AV implantation.
BACKGROUND - Previous epidemiologic studies have shown that low-density lipoprotein is an independent risk factor for prevalent aortic valve calcification (AVC); however, to our knowledge, the interactions between plasma lipoprotein concentrations and age on the relative risks (RRs) for AVC prevalence and severity have not been examined in a large, racially and ethnically diverse cohort.
METHODS - Using stepwise RR regression, the relationships of baseline fasting lipid levels and lipoprotein levels to baseline prevalence and severity of AVC were determined in 5801 non-statin-using participants in the Multi-Ethnic Study of Atherosclerosis (MESA).
RESULTS - In age-stratified, adjusted analyses, the low-density lipoprotein-associated RRs (95% confidence intervals) for prevalent AVC were higher for younger compared with older participants (age 45-54 years, 1.69 [1.19-2.39]; age 55-64 years, 1.48 [1.24-1.76]; age 65-74 years, 1.09 [0.95-1.25]; and age 75-84 years, 1.16 [0.99-1.36]; P interaction = .04]. There was a similar, significant interaction of age with total cholesterol-associated RR for prevalent AVC (P interaction = .04). In contrast, total- to high-density lipoprotein cholesterol ratio RRs were similar across all age strata (P interaction = .68). At multivariate analyses, no lipoprotein parameter was associated with AVC severity.
CONCLUSIONS - In this racially and ethnically diverse, preclinical cohort, low-density lipoprotein was a risk factor for AVC only in participants younger than 65 years, whereas the total cholesterol/high-density lipoprotein cholesterol ratio was associated with a modest increased risk of AVC across all ages. These findings may have important implications for the efficacy of and targets for dyslipidemia therapies in calcific aortic valve disease.
RATIONALE AND OBJECTIVES - Extracoronary calcifications may have clinical significance. The error in extracoronary calcification measurements is still unknown. Accurate quantification of calcifications of the aortic valve (AVC), mitral annulus (MAC), and aortic wall (AWC) may be possible by using cardiac computed tomography (CT). We sought to establish the interscan, interobserver, and intraobserver reproducibility of these measures in all cardiac CT scans in the Multi-Ethnic Study of Atherosclerosis.
MATERIALS AND METHODS - We measured extracoronary calcifications in 100 randomly selected participants to assess interobserver, interscan, and intraobserver variability. Two scans were available for analysis in 99 of these participants, and we quantified thoracic aorta and valvular calcifications.
RESULTS - Mean interscan variability of AVC was 9.7% +/- 11.4% and 8% +/- 10.3% for Agatston and volume scores, with variability of the median at 6.4% and 5.5%, respectively (P > .05). MAC inter-reader variability was 8.2% and 8.9%, with interscan variability of 28% and 33% and intrareader variability of 4% and 4.1%, respectively. For AWC, inter-reader variability was 3%-7.1%, interscan variability was 17%-18%, and intrareader variability was 0.4%-1.4%.
CONCLUSION - AVC, MAC, and AWC measurements are sufficiently reproducible to allow serial investigations over a time suitable for clinical studies.
Autonomic dysfunction and aortic stenosis share several clinical characteristics, including, in severe cases, syncope. Both illnesses tend to manifest later in life, and most cases are idiopathic in origin. In a short period of 4 weeks, the authors noted that three patients out of 36 referrals for autonomic dysfunction also had histories of aortic valve replacement due to stenosis. In each case, similar presenting symptoms of fatigue, light-headedness, and syncope were attributed to aortic stenosis without mention of autonomic failure as a possible contributor. The authors propose that patients for whom symptoms of aortic valve stenosis are not relieved by surgical intervention may have concomitant autonomic dysfunction contributing significantly to their symptoms. Furthermore, the two conditions may comprise a dangerous combination, aortic stenosis causing physical obstruction of ventricular outflow, and autonomic dysfunction causing decreased venous return and insufficient cardiac filling. It may be beneficial for patients with aortic stenosis who present with syncope to be considered for possible autonomic dysfunction to address both potential pathophysiologies contributing to the syncope.