Impact of Vascular Hemodynamics on Aortic Stenosis Evaluation: New Insights Into the Pathophysiology of Normal Flow-Small Aortic Valve Area-Low Gradient Pattern.

BACKGROUND: About 50% of normal-flow/low-gradient patients (ie, low mean gradient [MG] or peak aortic jet velocity and small aortic valve area) have severe aortic valve calcification as measured by computed tomography. However, they are considered to have moderate aortic stenosis (AS) in current American College of Cardiology/American Heart Association guidelines. The objective was thus to evaluate the effect of hypertension and reduced arterial compliance (rAC) on MG and Vpeak measurements. METHODS AND RESULTS: Doppler-echocardiography was performed in 4 sheep with experimentally induced severe and critical AS at: (1) normal aortic pressure, (2) during hypertension, and (3) with rAC. Hypertension and rAC induced a substantial decrease in MG/Vpeak compared with normal stage (both P≤0.03) despite a stable transvalvular flow (P>0.16). Hypertension and rAC resulted in a greater reduction of MG in critical (-42%) compared with severe (-35%) AS (P˂0.0001). Comprehensive Doppler-echocardiography and computed tomography were performed in 220 AS patients (mean age: 69±13 years; MG 29±18 mm Hg) with normal flow. The population was divided in 3 groups according to the presence of hypertension and rAC. The slope of the linear association between MG/Vpeak and aortic valve calcification divided by the cross-sectional area of the aortic annulus was significantly reduced in patients with hypertension and/or rAC compared with normotensive/normal AC patients (P<0.01). Accordingly, patients with normal-flow/low-gradient and severe aortic valve calcification density were more frequent in hypertension and rAC groups compared with the normotensive/normal-AC group (16% and 12% compared with 2%; P=0.03). CONCLUSIONS: Hypertension and rAC are associated with a substantial reduction in MG/Vpeak for similar aortic valve calcification (ie, similar AS anatomic severity), which may lead to underestimation of AS hemodynamic severity.

Severe and Asymptomatic Aortic Stenosis Management Challenge: Knowing That We Do Not Really Know.

OPINION STATEMENT: The clinical management of asymptomatic patients with severe aortic valve stenosis (AS) may be challenging. Indeed, there is substantial controversy over the optimal timing of intervention for these patients, as some advocate early intervention while others urge for a conservative management until symptom onset. In the meantime of randomized clinical trials aiming to compare both strategies of management, an integrative approach including several imaging modalities as well as biomarkers of the myocardial damage may help to improve the risk stratification of patients with asymptomatic severe AS and individualize strategy of treatment. The extent of aortic valve calcification, semi-quantitatively assessed by echocardiography but better fully quantitatively measured by computed tomography (CT), provides incremental value to predict rapid disease progression and adverse event and thus could be a potential trigger for early referral to intervention or guide the timing of clinical follow-up. In addition, the assessment of disease activity using positron emission tomography, combined with CT calcium scoring, may also help to better predict the disease progression. The comprehensive assessment of left ventricular (LV) function using speckle-tracking echocardiography and/or cardiac magnetic resonance may provide useful information regarding the actual repercussion of AS on the myocardium. Besides imaging modalities, the measurement of several circulating biomarkers associated with the extent of the myocardial damage may also improve the risk stratification of asymptomatic patients with severe AS and help guiding management. Finally, it should be emphasized that a personalized medicine, including this comprehensive integrative approach in heart valve clinics, should be advocated for the management of these challenging patients.

Sex-Related Discordance Between Aortic Valve Calcification and Hemodynamic Severity of Aortic Stenosis: Is Valvular Fibrosis the Explanation?

RATIONALE: Calcific aortic stenosis (AS) is characterized by calcium deposition in valve leaflets. However, women present lower aortic valve calcification loads than men for the same AS hemodynamic severity. OBJECTIVE: We, thus, aimed to assess sex differences in aortic valve fibrocalcific remodeling. METHODS AND RESULTS: One hundred and twenty-five patients underwent Doppler echocardiography and multidetector computed tomography within 3 months before aortic valve replacement. Explanted stenotic tricuspid aortic valves were weighed, and fibrosis degree was determined. Sixty-four men and 39 women were frequency matched for age, body mass index, hypertension, renal disease, diabetes mellitus, and AS severity. Mean age (75±9 years), mean gradient (41±18 mm Hg), and indexed aortic valve area (0.41±0.12 cm2/m2) were similar between men and women (all P≥0.18). Median aortic valve calcification (1973 [1124-3490] Agatston units) and mean valve weight (2.36±0.99 g) were lower in women compared with men (both P<0.0001). Aortic valve calcification density correlated better with valve weight in men (r2=0.57; P<0.0001) than in women (r2=0.26; P=0.0008). After adjustment for age, body mass index, aortic valve calcification density, and aortic annulus diameter, female sex was an independent risk factor for higher fibrosis score in AS valves (P=0.003). Picrosirius red staining of explanted valves showed greater amount of collagen fibers (P=0.01), and Masson trichrome staining revealed a greater proportion of dense connective tissue (P=0.02) in women compared with men. CONCLUSIONS: In this series of patients with tricuspid aortic valve and similar AS severity, women have less valvular calcification but more fibrosis compared with men. These findings suggest that the pathophysiology of AS and thus potential targets for drug development may be different according to sex.

Biophysical characterization of the honeybee DSC1 orthologue reveals a novel voltage-dependent Ca2+ channel subfamily: CaV4.

Bilaterian voltage-gated Na(+) channels (NaV) evolved from voltage-gated Ca(2+) channels (CaV). The Drosophila melanogaster Na(+) channel 1 (DSC1), which features a D-E-E-A selectivity filter sequence that is intermediate between CaV and NaV channels, is evidence of this evolution. Phylogenetic analysis has classified DSC1 as a Ca(2+)-permeable Na(+) channel belonging to the NaV2 family because of its sequence similarity with NaV channels. This is despite insect NaV2 channels (DSC1 and its orthologue in Blatella germanica, BSC1) being more permeable to Ca(2+) than Na(+) In this study, we report the cloning and molecular characterization of the honeybee (Apis mellifera) DSC1 orthologue. We reveal several sequence variations caused by alternative splicing, RNA editing, and genomic variations. Using the Xenopus oocyte heterologous expression system and the two-microelectrode voltage-clamp technique, we find that the channel exhibits slow activation and inactivation kinetics, insensitivity to tetrodotoxin, and block by Cd(2+) and Zn(2+) These characteristics are reminiscent of CaV channels. We also show a strong selectivity for Ca(2+) and Ba(2+) ions, marginal permeability to Li(+), and impermeability to Mg(2+) and Na(+) ions. Based on current ion channel nomenclature, the D-E-E-A selectivity filter, and the properties we have uncovered, we propose that DSC1 homologues should be classified as CaV4 rather than NaV2. Indeed, channels that contain the D-E-E-A selectivity sequence are likely to feature the same properties as the honeybee's channel, namely slow activation and inactivation kinetics and strong selectivity for Ca(2+) ions.

Distribution, abundance, and seasonal ecology of Listronotus maculicollis (Coleoptera: Curculionidae) on golf courses in Québec, Canada.

The weevil Listronotus maculicollis Dietz (Coleoptera: Curculionidae) is a major pest of annual bluegrass, Poa annua L., on golf courses in northeastern North America. To determine the distribution, abundance, and seasonal ecology of L. maculicollis on golf courses in Québec, Canada, we sampled 19 golf courses (GC1-GC19) from different geographic and climatic conditions during 2001, 2002, and 2003. L. maculicollis was found on all golf courses except GC19, which was located in northeastern Québec. In most sites, L. maculicollis completed two generations per year. A linear regression model comparing L. maculicollis larval densities as a function of spatial coordinates revealed that L. maculicollis were more abundant in western Québec than in eastern Québec. Pearson correlations on the probability of both L. maculicollis larval and pupal presence with soil parameters indicated significant positive correlations for fine sand (larvae) and soil pH (pupae) and negative correlations for gravel.