Sex-differences in echocardiographic assessment of aortic valve in young adult LDLr−/−/ApoB100/100/IGF-II+/− mice

Annabi, Mohamed‐Salah; Clisson, Marine; Fleury, Marie-Ange; Voisine, Martine; Hervault, Maxime; Shen, Mylène; Boilard, Anne-Julie; Marette, André; Ong, Géraldine; Côté, Nancy; Clavel, Marie‐Annick

doi:10.1016/j.exger.2020.111075

Cited by 5 publications

(8 citation statements)

References 21 publications

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“…Male patients are reported to develop severe CAVD nearly 10 years earlier than female patients [ 22 ]. In an LDLr −/− /ApoB 100/100 /IGF-II CAVD mouse model, early initiation of CAVD in male mice is mediated by gonadal hormones to some degree, as validated through the attenuation effect of gonadectomy [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Changing epidemiology of calcific aortic valve disease: 30-year trends of incidence, prevalence, and deaths across 204 countries and territories

Zeng

et al. 2021

Aging

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Calcific aortic valve disease (CAVD) is associated with increased morbidity and mortality. We aimed to elucidate the 30-year epidemiology of CAVD globally. Global CAVD incidence, prevalence, and deaths increased 3.51-, 4.43-, and 1.38-fold from 1990 to 2019, respectively, without any decreasing trends, even after age standardization. In 2019, Slovenia had the highest age-standardized rate (ASR) of CAVD incidence (62.21/100,000 persons) and prevalence (1,080.06/100,000) whereas Cyprus had the highest ASR of deaths (8.20/100,000). Population aging was an important contributor to incidence. Compared with women, more men had CAVD and men had earlier peaks in disease prevalence. High systolic blood pressure, diet high in sodium, and lead exposure were the main risk factors for deaths owing to CAVD. The estimated annual percentage change, a measure to estimate the variation of ASR, was significantly associated with the ASR and sociodemographic index (SDI) in 2019 for incidence and prevalence across all 204 countries and territories (all p<0.0001). With increased lifespan and risk factors, the overall burden of CAVD is high and remains on the rise, with differences by sex, age, and SDI level. Our findings serve to sound the alarm for organizations, institutions, and resources whose primary purpose is to improve human health.

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Section: Discussionmentioning

confidence: 99%

Changing epidemiology of calcific aortic valve disease: 30-year trends of incidence, prevalence, and deaths across 204 countries and territories

Zeng

et al. 2021

Aging

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Section: Genetic Ablation Of Htr2b Rescues Hemodynamic Metrics Of Aormentioning

confidence: 75%

“…At 6 months, peak velocity is 15-20% higher than the average peak velocity found in the LDLr -/-/ApoB 100/100 /IGF-II +/mutant model of CAVD [35]. Using a previously reported threshold of 1320 mm/s [35], incidence of severe CAVD decreased with ablation of Htr2b gene (S1 Fig). Ablation of Htr2b from Notch1 +/mice decreases the average peak velocity during the cardiac cycle with a corresponding decrease in mean pressure gradient across the AV, relative to Notch1 +/-;Htr2b +/+ (Fig 2A and 2B).…”

Section: Genetic Ablation Of Htr2b Rescues Hemodynamic Metrics Of Aormentioning

confidence: 75%

Genetic ablation of serotonin receptor 2B improves aortic valve hemodynamics of Notch1 heterozygous mice in a high-cholesterol diet model

et al. 2020

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Calcific aortic valve disease (CAVD) is a deadly disease that is rising in prevalence due to population aging. While the disease is complex and poorly understood, one well-documented driver of valvulopathy is serotonin agonism. Both serotonin overexpression, as seen with carcinoid tumors and drug-related agonism, such as with Fenfluramine use, are linked with various diseases of the valves. Thus, the objective of this study was to determine if genetic ablation or pharmacological antagonism of the 5-HT2B serotonin receptor (gene: Htr2b) could improve the hemodynamic and histological progression of calcific aortic valve disease. Htr2b mutant mice were crossed with Notch1+/- mice, an established small animal model of CAVD, to determine if genetic ablation affects CAVD progression. To assess the effect of pharmacological inhibition on CAVD progression, Notch1+/- mice were treated with the 5-HT2B receptor antagonist SB204741. Mice were analyzed using echocardiography, histology, immunofluorescence, and real-time quantitative polymerase chain reaction. Htr2b mutant mice showed lower aortic valve peak velocity and mean pressure gradient–classical hemodynamic indicators of aortic valve stenosis–without concurrent left ventricle change. 5-HT2B receptor antagonism, however, did not affect hemodynamic progression. Leaflet thickness, collagen density, and CAVD-associated transcriptional markers were not significantly different in any group. This study reveals that genetic ablation of Htr2b attenuates hemodynamic development of CAVD in the Notch1+/- mice, but pharmacological antagonism may require high doses or long-term treatment to slow progression.

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“…Estrogen may protect against the development of valvular calcification, which could account for delayed accumulation in women as compared to men. Testosterone influenced the onset of AVC in an LDLr −/− /Apo B 100/100 /IGF-II mouse model, and sex-based differences in calcification were decreased with castration [ 18 ]. In relation to ABCA1, serum 17β-estradiol doses does not appear to influence efflux [ 45 , 46 ].…”

Section: Discussionmentioning

confidence: 99%

“…Women with severe AS are known to have a lesser burden of calcification than men as measured by computed tomography and lower valve weight on examination after surgical explant [ 4 , 12 – 15 ]. Some potential sex-specific mechanisms which might affect calcification involve the pro-calcific effect of testosterone, altered inflammatory responses, as well as differential expression of calcification inhibitor proteins [ 16 – 18 ]. Limited evidence suggests no link between HDL function and AS [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

Measures of high-density lipoprotein function in men and women with severe aortic stenosis

2022

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Background Calcification of the aortic valve is a common heart valve disorder, in some cases leading to clinically impactful severe aortic stenosis (AS). Sex-specific differences in aortic valve calcification (ACV) exist, with women having a lower burden of calcification than men as measured by computed tomography; however, the pathophysiological mechanism that leads to these differences remains unclear. Methods Using cultured human Tamm-Horsfall protein 1 (THP-1) macrophages and human aortic valve interstitial cells, the effects of high-density lipoprotein (HDL) particles isolated from the plasma of men and women with severe AS were studied for cholesterol efflux capacity (CEC). Results HDL-CEC was assessed in 46 patients with severe AS, n = 30 men, n = 16 women. ATP-Binding Cassette A1 (ABCA1)-mediated HDL-CEC was measured from human cultured THP-1 macrophages to plasma HDL samples. Women with severe AS had more ABCA1-mediated HDL-CEC, as compared to men (8.50 ± 3.90% cpm vs. 6.80 ± 1.50% cpm, P = 0.04). HDL pre-β1 and α-particles were higher in woman than in men by spectral density, (pre-β1 HDL, 20298.29 ± 1076.15 vs. 15,661.74 ± 789.00, P = 0.002, and α-HDL, 63006.35 ± 756.81 vs. 50,447.00 ± 546.52, P = 0.03). Lecithin-cholesterol acyltransferase conversion of free cholesterol into cholesteryl esters was higher in women than men (16.44 ± 9.11%/h vs. 12.00 ± 8.07%/h, P = 0.03). Conclusions Sex-specific changes in various parameters of HDL-CEC were found in patients with severe AS. Sex-based modifications in HDL functionality by HDL-CEC might account for the reduced burden of calcification in women vs. men with severe AS. Therefore, future studies should target sex-related pathways in AS to help to improve understanding and treatment of AS. Graphical abstract Sex specifc differences in AVC and differences associated with HDL function in men and women with severe AS. When compared to men, women had higher preβ-HDL and α-HDL migrating particles, higher cholesterol efflux to HDL, and higher lecithin cholesterol acyl transferase (LCAT) activity, possibly indicating that improved reverse cholesterol transport may be protective against worsened calcification.

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Sex-differences in echocardiographic assessment of aortic valve in young adult LDLr−/−/ApoB100/100/IGF-II+/− mice

Cited by 5 publications

References 21 publications

Changing epidemiology of calcific aortic valve disease: 30-year trends of incidence, prevalence, and deaths across 204 countries and territories

Changing epidemiology of calcific aortic valve disease: 30-year trends of incidence, prevalence, and deaths across 204 countries and territories

Genetic ablation of serotonin receptor 2B improves aortic valve hemodynamics of Notch1 heterozygous mice in a high-cholesterol diet model

Measures of high-density lipoprotein function in men and women with severe aortic stenosis

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