Airway smooth muscle adapting in dynamic conditions is refractory to the bronchodilator effect of a deep inspiration.

Airway smooth muscle (ASM) is continuously strained during breathing at tidal volume. Whether this tidal strain influences the magnitude of the bronchodilator response to a deep inspiration (DI) is not clearly defined. The present in vitro study examines the effect of tidal strain on the bronchodilator effect of DIs. ASM strips from sheep tracheas were mounted in organ baths and then subjected to stretches (30% strain), simulating DIs at varying time intervals. In between simulated DIs, the strips were either held at a fixed length (isometric) or oscillated continuously by 6% (length oscillations) to simulate tidal strain. The contractile state of the strips was also controlled by adding either methacholine or isoproterenol to activate or relax ASM, respectively. Although the time-dependent gain in force caused by methacholine was attenuated by length oscillations, part of the acquired force in the oscillating condition was preserved postsimulated DIs, which was not the case in the isometric condition. Consequently, the bronchodilator effect of simulated DIs (i.e., the decline in force postsimulated versus presimulated DIs) was attenuated in oscillating versus isometric conditions. These findings suggest that an ASM operating in a dynamic environment acquired adaptations that make it refractory to the decline in contractility inflicted by a larger strain simulating a DI.

Progression of aortic stenosis after an acute myocardial infarction.

BACKGROUND: Myocardial infarction (MI) has been shown to induce fibrotic remodelling of the mitral and tricuspid valves. It is unknown whether MI also induces pathological remodelling of the aortic valve and alters aortic stenosis (AS) progression. We thus compared AS progression after an acute MI and in patients with/without history of MI, and assessed post-MI pathobiological changes within the aortic valve leaflets in a sheep model. METHODS: Serial echocardiograms in human patients with AS were retrospectively analysed and compared between 3 groups: (1) acute MI at baseline (n=68), (2) prior history of MI (n=45) and (3) controls without MI (n=101). Annualised progression rates of AS severity were compared between these 3 groups. In addition, aortic valves were harvested from 15 sheep: (1) induced inferior MI (n=10) and (2) controls without MI (n=5), for biological and histological analyses. RESULTS: In humans, the acute MI, previous MI and control groups had comparable baseline AS severity. Indexed aortic valve area (AVAi) declined faster in the acute MI group compared with controls (-0.07±0.06 vs -0.04±0.04 cm2/m2/year; p=0.004). After adjustment, acute MI status was significantly associated with faster AVAi progression (mean difference: -0.013 (95% CI -0.023 to -0.003) cm2/m2/year, p=0.008). In the post-MI experimental animal model, aortic valve thickness and qualitative/quantitative expression of collagen were significantly increased compared with controls. CONCLUSIONS: The results of this study suggest that AS progression is accelerated following acute MI, which could be caused by increased collagen production and thickening of the aortic valve after the ischaemic event.

Flexibility of microstructural adaptations in airway smooth muscle.

The airway smooth muscle undergoes an elastic transition during a sustained contraction, characterized by a gradual decrease in hysteresivity caused by a relatively greater rate of increase in elastance than resistance. We recently demonstrated that these mechanical changes are more likely to persist after a large strain when they are acquired in dynamic versus static conditions; as if the microstructural adaptations liable for the elastic transition are more flexible when they evolve in dynamic conditions. The extent of this flexibility is undefined. Herein, contracted ovine tracheal smooth muscle strips were kept in dynamic conditions simulating tidal breathing (sinusoidal length oscillations at 5% amplitude) and then subjected to simulated deep inspirations (DI). Each DI was straining the muscle by either 10%, 20%, or 30% and was imposed at either 2, 5, 10, or 30 min after the preceding DI. The goal was to assess whether and the extent by which the time-dependent decrease in hysteresivity is preserved following the DI. The results show that the time-dependent decrease in hysteresivity seen pre-DI was preserved after a strain of 10%, but not after a strain of 20% or 30%. This suggests that the microstructural adaptations liable for the elastic transition withstood a strain at least twofold greater than the oscillating strain that pertained during their evolution (10% vs. 5%). We propose that a muscle adapting in dynamic conditions forges microstructures exhibiting a substantial degree of flexibility.NEW & NOTEWORTHY This study confirms that airway smooth muscle undergoes an elastic transition during a sustained contraction even when it operates in dynamic conditions simulating breathing at tidal volume. It also demonstrates that the microstructural adaptations liable for this elastic transition withstand a strain that is at least twice as large as the oscillating strain that pertains during their evolution. This degree of flexibility might be an asset with major significant impact for a tissue such as the airway smooth muscle that displays an everchanging shape due to breathing.

Correlates of Coronary Artery Calcification Prevalence and Severity in Patients With Heterozygous Familial Hypercholesterolemia.

BACKGROUND: Determinants of coronary artery calcification (CAC) prevalence and severity in heterozygous familial hypercholesterolemia (HeFH) remain understudied. The objective of this cross-sectional study was to investigate correlates of CAC in patients with HeFH. METHODS: A CAC score was calculated by a noncontrast computed tomography scan in women (n = 68) and men (n = 78) with genetically defined HeFH. We classified CAC prevalence and severity using 3 categories: CAC score = 0 Agatston Unit (AU), CAC score = 1-100 AU, and CAC score > 100 AU. Information on potential correlates of CAC including familial and personal health history, cardiovascular risk factors, lipid-lowering medication, and lifestyle habits was collected. RESULTS: A total of 95 patients had prevalent CAC. Independent correlates of CAC prevalence and severity included age (odds ratio [OR] per 10 years: 5.06, 95% confidence interval [CI]: 3.19, 7.93, P < 0.0001), family history of premature cardiovascular disease (OR: 3.88, 95% CI: 1.71, 8.81, P = 0.001), male sex (OR: 3.40, 95% CI: 1.49, 7.78, P = 0.004), statin use (OR: 15.5, 95% CI: 1.89, 126, P = 0.01), diet quality assessed with the Alternative Healthy Eating Index score (OR per 1 standard deviation: 0.59, 95% CI: 0.39, 0.90, P = 0.01), ever smoking (OR: 3.06, 95% CI: 1.20, 7.81, P = 0.02), receptor-negative genotype (OR: 3.17, 95% CI: 1.16, 8.66, P = 0.02), lipoprotein(a) year-score (OR per 1 standard deviation of log-transformed year-score: 1.53, 95% CI: 0.99, 2.36, P = 0.05). CONCLUSIONS: In individuals with HeFH, age, family history of premature cardiovascular disease, sex, statin use, diet quality, smoking status, the LDLR genotype, and lipoprotein(a) concentrations were independently associated with CAC prevalence and severity.

CONTEXTE: Les déterminants de la prévalence et de la sévérité de la calcification des artères coronaires (CAC) dans l'hypercholestérolémie familiale hétérozygote (HFHe) demeurent peu étudiés. L'objectif de cette étude transversale était d'identifier les corrélats de la CAC chez des patients atteints d'HFHe. MÉTHODOLOGIE: Un score calcique coronarien (SCC) a été calculé par un examen de tomodensitométrie sans contraste chez des femmes (n = 68) et des hommes (n = 78) avec HFHe génétiquement définie. Nous avons classé la prévalence et la gravité de la CAC en trois catégories : SCC = 0 unité d'Agatston (UA), SCC = 1 à 100 UA et SCC > 100 UA. Des renseignements ont été recueillis sur des corrélats potentiels de la CAC, dont les antécédents médicaux familiaux et personnels, les facteurs de risque cardiovasculaire, les médicaments hypolipidémiants et les habitudes de vie. RÉSULTATS: Au total, 95 patients présentaient une CAC. Les corrélats indépendants de la prévalence et de la gravité de la CAC comprenaient l'âge (rapport de cotes [RC] par tranche de 10 ans : 5,06; intervalle de confiance [IC] à 95 % : 3,19 à 7,93; p < 0,0001), des antécédents familiaux de maladie cardiovasculaire précoce (RC : 3,88; IC à 95 % : 1,71 à 8,81; p = 0,001), le sexe masculin (RC : 3,40; IC à 95 % : 1,49 à 7,78; p = 0,004), l'emploi de statines (RC : 15,5; IC à 95 % : 1,89 à 126; p = 0,01), la qualité du régime alimentaire évaluée selon le score AHEI (Alternative Healthy Eating Index) (RC par écart-type : 0,59; IC à 95 % : 0,39 à 0,90; p = 0,01), le tabagisme (RC : 3,06; IC à 95 % : 1,20 à 7,81; p = 0,02), le génotype récepteur-négatif (RC : 3,17; IC à 95 % : 1,16 à 8,66; p = 0,02) et le score lipoprotéine(a)-année (RC par écart-type du score-année transformé en logarithme : 1,53; IC à 95 % : 0,99 à 2,36; p = 0,05). CONCLUSIONS: Chez les personnes atteintes d'HFHe, l'âge, les antécédents familiaux de maladie cardiovasculaire précoce, le sexe, l'emploi de statines, la qualité du régime alimentaire, le statut de tabagisme, le génotype du LDLR et les concentrations de lipoprotéine(a) ont été associés de façon indépendante à la prévalence et à la gravité de la CAC.

Left ventricular asymmetric remodeling and subclinical left ventricular dysfunction in patients with calcific aortic valve stenosis - Results from a subanalysis of the PROGRESSA study.

BACKGROUND: LV asymmetric remodeling (LVAR) is a feature commonly found in AS patients and it is presumed to be mainly related to the severity of valve stenosis. The aim of this study was to determine the associated factors and impact on left ventricular (LV) systolic function of LVAR in patients with mild and moderate aortic valve stenosis (AS). METHODS: Clinical, Doppler-echocardiographic and computed-tomographic data of 155 AS patients with preserved LV ejection fraction (≥50%) prospectively recruited in the PROGRESSA study (NCT01679431) were analyzed. LVAR was defined as a septal wall thickness ≥ 13 mm and a ratio of septal/posterior wall thickness > 1.5. LV global longitudinal strain (LV-GLS) was available in 129 patients. Plasma levels of N-terminal natriuretic B-type peptides (Nt-proBNP) were also measured. RESULTS: Mean age was 63 ± 15 years (70% men). LVAR was present in 21% (n = 33) of patients. A series of nested multivariate analysis revealed that age was the only factor associated with LVAR (all p ≤ 0.03). Additionally, these patients had higher baseline Nt-proBNP ratio (median [25-75 percentiles]: 1.04 [0.66-2.41] vs. 0.65 [0.33-1.19], p = 0.02), and significantly reduced LV-GLS (17.9[16.6-19.5] vs. 19.3[17.4-20.7] |%|, p = 0.04). A 1:1 matched analysis showed a significant association of LVAR with reduced LV-GLS (17.9[16.6-19.5] vs. 19.8[18.1-20.7] |%|, p = 0.02) and elevated Nt-proBNP (134[86-348] vs. 83[50-179]pg/ml, p = 0.03). Multivariable analysis also revealed that LVAR remains significantly associated with reduced LV-GLS (p = 0.03) and elevated Nt-proBNP (p = 0.001). LVAR was significantly associated with increased risk of major adverse cardiac events and death (Hazard ratio [95% confidence interval]: 2.32[1.28-4.22], p = 0.006). CONCLUSIONS: LVAR was found in ~20% of patients with mild or moderate AS and was not related to the degree of AS severity or concomitant comorbidities, but rather to older age. LVAR was significantly associated with reduced LV longitudinal systolic function, increased Nt-proBNP levels, and higher risk of major adverse events and death. These findings provide support for closer clinical and echocardiographic surveillance of patients harboring this adverse LV remodeling feature.

Association of Bioprosthetic Aortic Valve Leaflet Calcification on Hemodynamic and Clinical Outcomes.

BACKGROUND: The prognostic value of aortic valve calcification (AVC) measured by using multidetector computed tomography imaging has been well validated in native aortic stenosis, and sex-specific thresholds have been proposed. However, few data are available regarding the impact of leaflet calcification on outcomes after biological aortic valve replacement (AVR). OBJECTIVES: The goal of this study was to analyze the association of quantitative bioprosthetic leaflet AVC with hemodynamic and clinical outcomes, as well as its possible interaction with sex. METHODS: From 2008 to 2010, a total of 204 patients were prospectively enrolled with a median of 7.0 years (interquartile range: 5.1 to 9.2 years) after biological surgical AVR. AVC measured by using the Agatston method was indexed to the cross-sectional area of aortic annulus measured by echocardiography to calculate the AVC density (AVCd). Presence of hemodynamic valve deterioration (HVD; increase in mean gradient [MG] ≥10 mm Hg and/or increase in transprosthetic regurgitation ≥1) was assessed by echocardiography in 137 patients at the 3-year follow-up. The primary clinical endpoint was mortality or aortic valve re-intervention. RESULTS: There was no significant sex-related difference in the relationship between bioprosthetic AVCd and the progression of MG. Baseline AVCd showed an independent association with HVD at 3 years. During follow-up, there were 134 (65.7%) deaths (n = 100) or valve re-interventions (n = 47). AVCd ≥58 AU/cm2 was independently associated with an increased risk of mortality or aortic valve re-intervention (adjusted hazard ratio: 2.23; 95% confidence interval: 1.44 to 3.35; p < 0.001). The AVCd threshold combined with an MG progression threshold of 10 mm Hg amplified the stratification of patients at risk (log-rank, p < 0.001). The addition of AVCd threshold into the prediction model including traditional risk factors improved outcome prediction (net classification improvement: 0.25, p = 0.04; likelihood ratio test, p < 0.001). CONCLUSIONS: Aortic bioprosthetic leaflet calcification is strongly and independently associated with HVD and the risk of death or aortic valve re-intervention. As opposed to native aortic stenosis, there is no sex-related differences in the relationship between AVCd and hemodynamic or clinical outcomes.

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

BACKGROUND: LDLr-/-/ApoB100/100/IGF-II+/- mice are used as a calcific aortic valve disease (CAVD) model. However, normal aortic valve hemodynamics i.e. remotely from CAVD onset and the sex-related differences are poorly known. METHODS AND RESULTS: Four groups of mice, intact males (IM, n = 49) and females (IF, n = 50), castrated males (CxM, n = 79) and ovariectomized females (OxF: 73), underwent a Doppler-echocardiography at 12 weeks of age. Gonadectomy was performed at 8 weeks. Aortic valve assessment using effective orifice area (EOA, using the continuity equation) and peak aortic transvalvular velocity (VPeak) was feasible in 89% of the mice with good to excellent reliability (intraclass correlation coefficients ranging from 0.90 to 0.98, p < 0.001). Mean VPeak was 104 ± 17 cm/s and mean EOA was 1.18*10-2 ± 0.22*10-2 cm2. EOA indexed to body surface area was 1.5 ± 0.3 cm2/m2. The 95th percentile of Vpeak was 132 cm/s and the 5th percentile of indexed EOA was 1.0 cm2/m2. Interestingly, IM had the highest VPeak (114 ± 14 cm/s) vs each of the other groups (CxM: 106 ± 19 cm/s, OxF: 97 ± 13 cm/s and IF: 96 ± 12 cm/s, ANOVA and corrected p < 0.001). This was mostly explained by a higher stroke volume (ANOVA and corrected p < 0.001) in IM compared to other groups. There were no major sex-differences in ventricular systolic function parameters. CONCLUSION: In LDLr-/-/ApoB100/100/IGF-II CAVD mice model, an aortic EOA <0.8*10-2 cm2 (or indexed EOA <1.0cm2/m2), and a peak aortic valve velocity > 132 cm/s may be proposed as thresholds to define CAVD. Intact male mice appear to have higher velocities.

Attenuated Mitral Leaflet Enlargement Contributes to Functional Mitral Regurgitation After Myocardial Infarction.

BACKGROUND: Mitral leaflet enlargement has been identified as an adaptive mechanism to prevent mitral regurgitation in dilated left ventricles (LVs) caused by chronic aortic regurgitation (AR). This enlargement is deficient in patients with functional mitral regurgitation, which remains frequent in the population with ischemic cardiomyopathy. Maladaptive fibrotic changes have been identified in post-myocardial infarction (MI) mitral valves. It is unknown if these changes can interfere with valve growth and whether they are present in other valves. OBJECTIVES: This study sought to test the hypothesis that MI impairs leaflet growth, seen in AR, and induces fibrotic changes in mitral and tricuspid valves. METHODS: Sheep models of AR, AR + MI, and controls were followed for 90 days. Cardiac magnetic resonance, echocardiography, and computed tomography were performed at baseline and 90 days to assess LV volume, LV function, mitral regurgitation and mitral leaflet size. Histopathology and molecular analyses were performed in excised valves. RESULTS: Both experimental groups developed similar LV dilatation and dysfunction. At 90 days, mitral valve leaflet size was smaller in the AR + MI group (12.8 ± 1.3 cm2 vs. 15.1 ± 1.6 cm2, p = 0.03). Mitral regurgitant fraction was 4% ± 7% in the AR group versus 19% ± 10% in the AR + MI group (p = 0.02). AR + MI leaflets were thicker compared with AR and control valves. Increased expression of extracellular matrix remodeling genes was found in both the mitral and tricuspid leaflets in the AR + MI group. CONCLUSIONS: In these animal models of AR, the presence of MI was associated with impaired adaptive valve growth and more functional mitral regurgitation, despite similar LV size and function. More pronounced extracellular remodeling was observed in mitral and tricuspid leaflets, suggesting systemic valvular remodeling after MI.

Shortening of airway smooth muscle is modulated by prolonging the time without simulated deep inspirations in ovine tracheal strips.

The shortening of airway smooth muscle (ASM) is greatly affected by time. This is because stimuli affecting ASM shortening, such as bronchoactive molecules or the strain inflicted by breathing maneuvers, not only alter quick biochemical processes regulating contraction but also slower processes that allow ASM to adapt to an ever-changing length. Little attention has been given to the effect of time on ASM shortening. The present study investigates the effect of changing the time interval between simulated deep inspirations (DIs) on ASM shortening and its responsiveness to simulated DIs. Excised tracheal strips from sheep were mounted in organ baths and either activated with methacholine or relaxed with isoproterenol. They were then subjected to simulated DIs by imposing swings in distending stress, emulating a transmural pressure from 5 to 30 cmH2O. The simulated DIs were intercalated by 2, 5, 10, or 30 min. In between simulated DIs, the distending stress was either fixed or oscillating to simulate tidal breathing. The results show that although shortening was increased by prolonging the interval between simulated DIs, the bronchodilator effect of simulated DIs (i.e., the elongation of the strip post- vs. pre-DI) was not affected, and the rate of re-shortening post-simulated DIs was decreased. As the frequency with which DIs are taken increases upon bronchoconstriction, our results may be relevant to typical alterations observed in asthma, such as an increased rate of re-narrowing post-DI.NEW & NOTEWORTHY The frequency with which patients with asthma take deep inspirations (DIs) increases during bronchoconstriction. This in vitro study investigated the effect of changing the time interval between simulated DIs on airway smooth muscle shortening. The results demonstrated that decreasing the interval between simulated DIs not only decreases shortening, which may be protective against excessive airway narrowing, but also increases the rate of re-shortening post-simulated DIs, which may contribute to the increased rate of re-narrowing post-DI observed in asthma.

Workup and Management of Patients With Paradoxical Low-Flow, Low-Gradient Aortic Stenosis.

About 60% of patients with paradoxical low-flow, low-gradient (PLF-LG) aortic stenosis (AS) have a severe disease that justifies aortic valve replacement (AVR). The first step in patients with symptomatic PLF AS should be to rule out measurement errors and treat hypertension. The second step is to distinguish pseudo-severe from true severe AS (TSAS). The third step is to select the optimal treatment modality at the right time. Regarding the second step, projected aortic valve area calculated using stress echocardiography is superior to traditional severity criteria (AVA < 1.0 cm2 and mean gradient ≥ 40 mmHg) to unmask TSAS and predict outcomes. Aortic valve calcification score quantitated by computed tomography is helpful to identify TSAS by applying thresholds of 2000 and 1200 AU, respectively, for men and women. This modality should be considered, particularly if stress echocardiography is either not feasible or inconclusive. Once AS severity is confirmed, a risk stratification based on symptomatic status and the importance of left ventricular (LV) systolic impairment will guide therapeutic decision. Symptomatic assessment should not solely rely on patient-reported symptom status, but rather include an objective exercise test. The presence of symptomatic PLF-LG TSAS is a class IIa indication for AVR in the guidelines. In asymptomatic patients, a markedly reduced stroke volume, the presence of myocardial fibrosis by cardiac magnetic resonance imaging, a poor longitudinal LV function as assessed by speckle tracking echocardiography, and/or a moderate to severe LV diastolic dysfunction are predictors of poor outcome in PLF-LG patients and may indicate the need of early AVR. The type of AVR should be discussed within a multidisciplinary team, bearing in mind that transcatheter AVR (TAVR) is superior to medical treatment in inoperable patients. Furthermore, TAVR may be a useful alternative to surgical AVR (SAVR) in high-risk patients. Nevertheless, the potential benefits of TAVR, including the lower risk of severe patient-prosthesis mismatch, should be weighed against the risk of paravalvular regurgitation, which is likely poorly tolerated by patients with PLF-LG who often harbor a small and non-compliant LV cavity.

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.