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      The Association between Aortic Valve Weight, Echocardiographic Indices, and All-Cause Death in 1,046 Patients Undergoing Surgical Aortic Valve Replacement for Aortic Stenosis

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          Background: Aortic valve weight (AVW), a flow independent measure of aortic stenosis (AS) severity, is reported to have heterogeneous associations with the echocardiographic variables used for AS evaluation. Controversy exists regarding its impact on survival after aortic valve replacement (AVR). Objective: We sought to determine the association between AVW with echocardiographic measures of AS severity and all-cause mortality after surgical AVR. Methods: One thousand and forty-sixconsecutive patients underwent surgical AVR for AS, the excised valves were weighed, and an echocardiogram was done before surgery. Results: Males had heavier valves than females, for both absolute and body surface are (BSA)-indexed values (2.78 ± 1.23 vs. 2.08 ± 0.68 g, p < 0.001; and 1.38 ± 0.61 vs. 1.19 ± 0.41 g/m<sup>2</sup>, p < 0.001, respectively). In a restricted cohort of 634 patients with isolated severe AS and normal ejection fraction, the correlations of AVW with echocardiographic variables of AS were modest, the strongest being with the dimensionless index ( r = 0.27 and 0.26 for male and female, both p < 0.01). Stratified by stroke volume index and mean gradient (MG), no associations were found in the low-gradient groups (i.e., MG <40 mmHg). At a median follow-up of 3.5 years, there were only 244 deaths in the entire cohort. Mortality was not related to AVW, except in females who displayed an inverse relationship (HR = 0.67; 95% CI 0.47 0.95) only when it was analyzed as a continuous variable. Conclusions: The weak correlation between AVW with the echocardiographic indices of AS may reflect its complex pathophysiology, heterogeneous hemodynamics, and possible pitfalls in the current echocardiographic methods used in clinical practice. The prognostic value of AVW after AVR warrants further evaluation.

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          Genetic associations with valvular calcification and aortic stenosis.

          Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease. We determined genomewide associations with the presence of aortic-valve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis. One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aortic-valve calcification (odds ratio per allele, 2.05; P=9.0×10(-10)), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aortic-valve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P=1.5×10(-8) and P=1.8×10(-8), respectively), but the findings were not replicated consistently. Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aortic-valve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.).
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            Characterization of the early lesion of 'degenerative' valvular aortic stenosis. Histological and immunohistochemical studies.

            Nonrheumatic stenosis of trileaflet aortic valves, often termed senile or calcific valvular aortic stenosis, is considered a "degenerative" process, but little is known about the cellular or molecular factors that mediate its development. To characterize the developing aortic valvular lesion, we performed histological and immunohistochemical studies on Formalin-fixed and methanol-Carnoy's-fixed paraffin-embedded aortic valve leaflets or on frozen sections obtained at autopsy from 27 adults (age, 46 to 82 years) with normal leaflets (n = 6), mild macroscopic leaflet thickening (n = 15), or clinical aortic stenosis (n = 6). Focal areas of thickening ("early lesions") were characterized by (1) subendothelial thickening on the aortic side of the leaflet, between the basement membrane (PAS-positive) and elastic lamina (Verhoeff-van Gieson), (2) the presence of large amounts of intracellular and extracellular neutral lipids (oil red O) and fine, stippled mineralization (von Kossa), and (3) disruption of the basement membrane overlying the lesion. Regions of the fibrosa adjacent to these lesions were characterized by thickening and by protein, lipid, and calcium accumulation. Control valves showed none of these abnormalities. Immunohistochemical studies were performed using monoclonal antibodies directed against macrophages (anti-CD68 or HAM-56), and contractile proteins of smooth muscle cells or myofibroblasts (anti-alpha-actin and HHF-35) or rabbit polyclonal antiserum against T lymphocytes (anti-CD3). In normal valves, scattered macrophages were present in the fibrosa and ventricularis, and occasional muscle actin-positive cells were detected in the proximal portion of the ventricularis near the leaflet base, but no T lymphocytes were found. In contrast, early lesions were characterized by the presence of an inflammatory infiltrate composed of non-foam cell and foam cell macrophages, occasional T cells, and rare alpha-actin-positive cells. In stenotic aortic valves, a similar but more advanced lesion was seen. The early lesion of "degenerative" aortic stenosis is an active inflammatory process with some similarities (lipid deposition, macrophage and T-cell infiltration, and basement membrane disruption) and some dissimilarities (presence of prominent mineralization and small numbers of smooth muscle cells) to atherosclerosis.
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              A classification system for the bicuspid aortic valve from 304 surgical specimens.

              In general, classification of a disease has proven to be advantageous for disease management. This may also be valid for the bicuspid aortic valve, because the term "bicuspid aortic valve" stands for a common congenital aortic valve malformation with heterogeneous morphologic phenotypes and function resulting in different treatment strategies. We attempted to establish a classification system based on a 5-year data collection of surgical specimens. Between 1999 and 2003 a precise description of valve pathology was obtained from operative reports of 304 patients with a diseased bicuspid aortic valve. Several different characteristics of bicuspid aortic valves were tested to generate a pithy and easily applicable classification system. Three characteristics for a systematic classification were found appropriate: (1) number of raphes, (2) spatial position of cusps or raphes, and (3) functional status of the valve. The first characteristic was found to be the most significant and therefore termed "type." Three major types were identified: type 0 (no raphe), type 1 (one raphe), and type 2 (two raphes), followed by two supplementary characteristics, spatial position and function. These characteristics served to classify and codify the bicuspid aortic valves into three categories. Most frequently, a bicuspid aortic valve with one raphe was identified (type 1, n = 269). This raphe was positioned between the left (L) and right (R) coronary sinuses in 216 (type 1, L/R) with a hemodynamic predominant stenosis (S) in 119 (type 1, L/R, S). Only 21 patients had a "purely" bicuspid aortic valve with no raphe (type 0). A classification system for the bicuspid aortic valve with one major category ("type") and two supplementary categories is presented. This classification, even if used in the major category (type) alone, might be advantageous to better define bicuspid aortic valve disease, facilitate scientific communication, and improve treatment.

                Author and article information

                S. Karger AG
                April 2020
                11 March 2020
                : 145
                : 4
                : 251-261
                aSt. Francis Hospital, The Heart Center, Roslyn, New York, USA
                bStony Brook University (SUNY), Stony Brook, New York, USA
                Author notes
                *Dr. Eddy Barasch, MD, St. Francis Hospital, The Heart Center/SUNY at Stony Brook, 100 Port Washington Blvd, Roslyn, NY 11576 (USA),
                505870 Cardiology 2020;145:251–261
                © 2020 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 6, Pages: 11
                Valvular Heart Disease: Research Article


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