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Aortic Valve Stenosis↗
Biomedical subjects
Damien Garcia
Publications and source records attributed to Damien Garcia.
Characterization of circulatory disorders in beta-thalassemic mice by noninvasive ultrasound biomicroscopy.
Beta-thalassemia is an inherited hematological disease caused by a decrease or absence of production of beta-globin that requires chronic therapeutic interventions. This condition leads to important arterial and venous thromboembolic events, transitory ischemic attacks, and microcirculatory obstructions, indicative of circulatory disturbances. To investigate the presence of microcirculatory disorders without the confounding effect of treatments, we used beta-thalassemic mice with typical clinical characteristics of human beta-thalassemia major. One impediment to the understanding of microcirculatory physiology, in particular for beta-thalassemic mice, has been the lack of an appropriate noninvasive imaging approach. We thus developed a novel noninvasive high-frequency ultrasound imaging method to evaluate murine vascular hemodynamic properties. In our beta-thalassemic mice, total peripheral vascular resistance was significantly increased (P < 0.01) compared with wildtype littermates, whereas mean blood pressure, heart rate, and cardiac output were similar (P = nonsignificant). Importantly, the vascular hemodynamics in beta-thalassemic mice were significantly affected according to the Pourcelot indexes measured in the common carotid artery and abdominal aorta (P < 0.01 and P < 0.05, respectively). Hence, our beta-thalassemia characterization of vascular hemodynamics by noninvasive ultrasonic approaches proves the existence and provides unique quantitative assessment of microcirculatory flow disturbances in those mice.
Animals↗
Respective impacts of aortic stenosis and systemic hypertension on left ventricular hypertrophy.
It has been reported that 30-40% of patients with aortic stenosis are hypertensive. In such patients, the left ventricle faces a double (i.e. valvular and vascular) pressure overload, which results in subsequent wall volume hypertrophy. From a clinical standpoint, it is difficult to separate the respective contributions of aortic stenosis and systemic hypertension to left ventricular burden and patient's symptoms and thus to predict whether valve replacement would be beneficial. The objective of this theoretical study was therefore to investigate the relative effects of valvular and vascular afterloads on left ventricular hypertrophy. We used a ventricular-valvular-vascular mathematical model in combination with the Arts' model describing the myofiber stress. Left ventricular wall volume was computed for different aortic blood pressure levels and different degrees of aortic stenosis severity. Our simulations show that the presence of concomitant systemic hypertension has a major influence on the development of left ventricular hypertrophy in patients with aortic stenosis. These results also suggest that mild-to-moderate aortic stenosis has a minor impact on left ventricular wall volume when compared with hypertension. On the other hand, when aortic stenosis is severe, wall volume increases exponentially with increasing aortic stenosis severity and the impact of aortic stenosis on left ventricular hypertrophy becomes highly significant.
Aortic Valve Stenosis↗
Specification of leaf polarity in Arabidopsis via the trans-acting siRNA pathway.
Plants leaves develop proximodistal, dorsoventral (adaxial-abaxial), and mediolateral patterns following initiation. The Myb domain gene PHANTASTICA (PHAN) is required for adaxial fate in many plants , but the Arabidopsis ortholog ASYMMETRIC LEAVES1 (AS1) has milder effects, suggesting that alternate or redundant pathways exist . We describe enhancers of as1 with more elongate and dissected leaves. As well as RDR6, an RNA-dependent RNA polymerase previously proposed to influence as1 through microRNA , these enhancers disrupt ARGONAUTE7 (AGO7)/ZIPPY, SUPPRESSOR OF GENE SILENCING3 (SGS3), and DICER-LIKE4 (DCL4), which instead regulate trans-acting small interfering RNA (ta-siRNA) . Microarray analysis revealed that the AUXIN RESPONSE FACTOR genes ETTIN (ETT)/ARF3 and ARF4 were upregulated in ago7, whereas FILAMENTOUS FLOWER (FIL) was upregulated only in as1 ago7 double mutants. RDR6 and SGS3 likewise repress these genes, which specify abaxial fate . We show that the trans-acting siRNA gene TAS3, which targets ETT and ARF4, is expressed in the adaxial domain, and ett as1 ago7 triple mutants resemble as1. Thus FIL is downregulated redundantly by AS1 and by TAS3, acting through ETT, revealing a role for ta-siRNA in leaf polarity. RDR6 and DCL4 are required for systemic silencing, perhaps implicating ta-siRNA as a mobile signal.
Arabidopsis↗
Projected valve area at normal flow rate improves the assessment of stenosis severity in patients with low-flow, low-gradient aortic stenosis: the multicenter TOPAS (Truly or Pseudo-Severe Aortic Stenosis) study.
BACKGROUND: We sought to investigate the use of a new parameter, the projected effective orifice area (EOAproj) at normal transvalvular flow rate (250 mL/s), to better differentiate between truly severe (TS) and pseudo-severe (PS) aortic stenosis (AS) during dobutamine stress echocardiography (DSE). Changes in various parameters of stenosis severity have been used to differentiate between TS and PS AS during DSE. However, the magnitude of these changes lacks standardization because they are dependent on the variable magnitude of the transvalvular flow change occurring during DSE. METHODS AND RESULTS: The use of EOAproj to differentiate TS from PS AS was investigated in an in vitro model and in 23 patients with low-flow AS (indexed EOA <0.6 cm2/m2, left ventricular ejection fraction < or =40%) undergoing DSE and subsequent aortic valve replacement. For an individual valve, EOA was plotted against transvalvular flow (Q) at each dobutamine stage, and valve compliance (VC) was derived as the slope of the regression line fitted to the EOA versus Q plot; EOAproj was calculated as EOAproj=EOArest+VCx(250-Q(rest)), where EOArest and Q(rest) are the EOA and Q at rest. Classification between TS and PS was based on either response to flow increase (in vitro) or visual inspection at surgery (in vivo). EOAproj was the most accurate parameter in differentiating between TS and PS both in vitro and in vivo. In vivo, 15 of 23 patients (65%) had TS and 8 of 23 (35%) had PS. The percentage of correct classification was 83% for EOAproj and 91% for indexed EOAproj compared with percentages of 61% to 74% for the other echocardiographic parameters usually used for this purpose. CONCLUSIONS: EOAproj provides a standardized evaluation of AS severity with DSE and improves the diagnostic accuracy for distinguishing TS and PS AS in patients with low-flow, low-gradient AS.
Aged↗
What do you mean by aortic valve area: geometric orifice area, effective orifice area, or gorlin area?
Aortic valve area can be measured by cardiac catheterization, Doppler echocardiography, or imaging planimetry to assess aortic stenosis severity. These diagnostic techniques provide the Gorlin area, the effective orifice area (EOA) and the geometric orifice area (GOA), respectively. The differences between these three parameters depend mainly on the valve inflow shape and cross-sectional area of the ascending aorta. Because the values obtained may differ noticeably in the same patient, they may lead to different estimations of stenosis severity depending on the measurement method used. It is therefore essential to be aware of the underlying fundamentals on which these parameters are based. The aim of this state-of-the-art report was to clarify these hemodynamic concepts and to underline their clinical implications. Because planimetry only provides GOA and does not characterize the flow property, this method should preferably not be used to assess stenosis severity. The most appropriate parameters for this purpose are the Gorlin area and the energy loss coefficient (E(L)Co), which corresponds to the EOA adjusted for aortic cross-sectional area. From a hemodynamic viewpoint, Doppler E(L)Co and Gorlin area both reflect the fluid energy loss induced by aortic stenosis, and describe better the increased overload imposed on the left ventricle. Although the Gorlin area and Doppler E(L)Co are equivalent, the latter parameter has the advantage of being measurable non-invasively using Doppler echocardiography.
Aortic Valve↗
Value and limitations of peak-to-peak gradient for evaluation of aortic stenosis.
BACKGROUND AND AIM OF THE STUDY: In patients with aortic stenosis (AS), it has been reported that the transvalvular pressure gradients (APs) may be reduced or even abolished in the presence of concomitant arterial hypertension, but the mechanisms underlying this phenomenon remain unclear. The study aim was to: (i) examine the relationship between systemic arterial hemodynamics and the peak-to-peak (deltaP(PtoP)), peak deltaP and mean deltaP; and (ii) propose and validate a new formula for the non-invasive estimation of the deltaP(PtoP) and of the peak left ventricular systolic pressure (LVSP) using Doppler echocardiography. METHODS: Two fixed stenoses (geometric orifice area 1.0 and 1.35 cm2) and one bioprosthesis (effective orifice area (EOA) 1.2 cm2) were tested in a mock flow circulation model. Systemic vascular resistance (R) was increased from 1,500 to 3,300 dyne.s/cm5, and systemic arterial compliance (C) was decreased from 2.9 to 0.9 ml/mmHg, while transvalvular flow was held constant. RESULTS: Neither C nor R had any significant impact on EOA, peak deltaP and mean deltaP. deltaP(PtoP) was decreased markedly, however, when C was reduced (bioprosthesis: -15 mmHg (-69%); orifice 1.35 cm2: -24 mmHg (-30%); cm2: (-13%)). Subsequently, an equation was proposed to predict deltaP(PtoP) from EOA, mean deltaP, and C measured by Doppler echocardiography. LVSP calculated by adding the predicted deltaP(Ptop) to systolic arterial pressure (SAP) was compared with LVSP measured directly in a dataset of 24 pigs with experimentally induced AS. There was a strong agreement between the estimated and measured LVSP (r = 0.97; mean absolute error 5 +/- 5 mmHg). CONCLUSION: deltaP(Ptop) should not be used to evaluate AS severity because, as opposed to peak and mean deltaPs, it is highly influenced by C. The new non-invasive method proposed in this study to estimate the LVSP may be useful for obtaining a more accurate estimate of global LV afterload in patients with AS.
Animals↗
Analytical modeling of the instantaneous maximal transvalvular pressure gradient in aortic stenosis.
In presence of aortic stenosis, a jet is produced downstream of the aortic valve annulus during systole. The vena contracta corresponds to the location where the cross-sectional area of the flow jet is minimal. The maximal transvalvular pressure gradient (TPG(max)) is the difference between the static pressure in the left ventricle and that in the vena contracta. TPG(max) is highly time-dependent over systole and is known to depend upon the transvalvular flow rate, the effective orifice area (EOA) of the aortic valve and the cross-sectional area of the left ventricular outflow tract. However, it is still unclear how these parameters modify the TPG(max) waveform. We thus derived an explicit analytical model to describe the instantaneous TPG(max) across the aortic valve during systole. This theoretical model was validated with in vivo experiments obtained in 19 pigs with supravalvular aortic stenosis. Instantaneous TPG(max) was measured by catheter and its waveform was compared with the one determined from the derived equation. Our results showed a very good concordance between the measured and predicted instantaneous TPG(max). Total relative error and mean absolute error were on average 9.4+/-4.9% and 2.1+/-1.1 mmHg, respectively. The analytical model proposed and validated in this study provides new insight into the behaviour of the TPG(max) and thus of the aortic pressure at the level of vena contracta. Because the static pressure at the coronary inlet is similar to that at the vena contracta, the proposed equation will permit to further examine the impact of aortic stenosis on coronary blood flow.
Aortic Valve↗
Reduced systemic arterial compliance impacts significantly on left ventricular afterload and function in aortic stenosis: implications for diagnosis and treatment.
OBJECTIVES: We sought to determine to what extent systemic arterial compliance (SAC) might impact on afterload and left ventricular (LV) function in patients with aortic stenosis (AS). BACKGROUND: Although AS and reduced SAC may often coexist in the same patient, their relative impact on LV function is not well understood. METHODS: Systemic arterial compliance was calculated as the ratio of stroke volume index to arterial pulse pressure in 208 patients with at least moderate AS. As a measure of global afterload, we calculated the valvulo-arterial impedance (Zva), which theoretically accounts for the effects of both AS and SAC. RESULTS: Patients were divided into four groups: group 1, moderate AS and normal SAC (n = 77; 37%); group 2, moderate AS and low SAC (n = 50; 24%); group 3, severe AS and normal SAC (n = 45; 22%); and group 4, severe AS and low SAC (n = 36; 17%). The prevalences of LV diastolic and systolic dysfunction were 60% and 6% in group 1, 86% and 12% in group 2, 82% and 16% in group 3, and 94% and 31% in group 4. In multivariate analysis excluding Zva, energy loss index and SAC were both independent predictors of LV dysfunction, but when Zva was entered into the analyses, it became the only hemodynamic variable to be independently associated with LV dysfunction. CONCLUSIONS: Reduced SAC is a frequent occurrence in elderly patients with AS, where it independently contributes to increased afterload and decreased LV function. Systemic arterial compliance should be taken into consideration when evaluating these patients with regard to diagnosis and treatment.
Aged↗
Analytical modeling of the instantaneous pressure gradient across the aortic valve.
Aortic stenosis is the most frequent valvular heart disease. The mean systolic value of the transvalvular pressure gradient (TPG) is commonly utilized during clinical examination to evaluate its severity and it can be determined either by cardiac catheterization or by Doppler echocardiography. TPG is highly time-dependent over systole and is known to depend upon the transvalvular flow rate, the effective orifice area (EOA) of the aortic valve and the cross-sectional area of the ascending aorta. However it is still unclear how these parameters modify the TPG waveform. We thus derived a simple analytical model from the energy loss concept to describe the instantaneous TPG across the aortic valve during systole. This theoretical model was validated with orifice plates and bioprosthetic heart valves in an in vitro aortic flow model. Instantaneous TPG was measured by catheter and its waveform was compared with the one determined from the transvalvular flow rate, the valvular EOA and the aortic cross-sectional area, using the derived equation. Our results showed a very good concordance between the measured and predicted instantaneous TPG. The analytical model proposed and validated in this study provides a comprehensive description of the aortic valve hemodynamics that can be used to accurately predict the instantaneous transvalvular pressure gradient in native and bioprosthetic aortic valves. The consideration of this model suggests that: (1) TPG waveform is exclusively dependent upon transvalvular flow rate and flow geometry, (2) the frequently applied simplified Bernoulli equation may overestimate mean TPG by more than 30% and (3) the measurement of ejection time by cardiac catheterization may underestimate the actual ejection time, especially in patients with mild/moderate aortic stenosis and low cardiac output.
Animals↗
A ventricular-vascular coupling model in presence of aortic stenosis.
In patients with aortic stenosis, the left ventricular afterload is determined by the degree of valvular obstruction and the systemic arterial system. We developed an explicit mathematical model formulated with a limited number of independent parameters that describes the interaction among the left ventricle, an aortic stenosis, and the arterial system. This ventricular-valvular-vascular (V(3)) model consists of the combination of the time-varying elastance model for the left ventricle, the instantaneous transvalvular pressure-flow relationship for the aortic valve, and the three-element windkessel representation of the vascular system. The objective of this study was to validate the V(3) model by using pressure-volume loop data obtained in six patients with severe aortic stenosis before and after aortic valve replacement. There was very good agreement between the estimated and the measured left ventricular and aortic pressure waveforms. The total relative error between estimated and measured pressures was on average (standard deviation) 7.5% (SD 2.3) and the equation of the corresponding regression line was y = 0.99x - 2.36 with a coefficient of determination r(2) = 0.98. There was also very good agreement between estimated and measured stroke volumes (y = 1.03x + 2.2, r(2) = 0.96, SEE = 2.8 ml). Hence, this mathematical V(3) model can be used to describe the hemodynamic interaction among the left ventricle, the aortic valve, and the systemic arterial system.
Aortic Valve Stenosis↗
Maternal control of integument cell elongation and zygotic control of endosperm growth are coordinated to determine seed size in Arabidopsis.
We use Arabidopsis thaliana as a model to investigate coordination of cell proliferation and cell elongation in the three components that develop side by side in the seed. Two of these, the embryo and its nurturing annex, the endosperm, are placed under zygotic control and develop within the seed integument placed under maternal control. We show that integument cell proliferation and endosperm growth are largely independent from each other. By contrast, prevention of cell elongation in the integument by the mutation transparent testa glabra2 (ttg2) restricts endosperm and seed growth. Conversely, endosperm growth controlled by the HAIKU (IKU) genetic pathway modulates integument cell elongation. Combinations of TTG2 defective seed integument with reduction of endosperm size by iku mutations identify integument cell elongation and endosperm growth as the primary regulators of seed size. Our results strongly suggest that a cross talk between maternal and zygotic controls represents the primary regulator of the coordinated control of seed size in Arabidopsis.
Arabidopsis↗
Estimation of aortic valve effective orifice area by Doppler echocardiography: effects of valve inflow shape and flow rate.
BACKGROUND: The effective orifice area (EOA) is the standard parameter for the clinical assessment of aortic stenosis severity. It has been reported that EOA measured by Doppler echocardiography does not necessarily provide an accurate estimate of the cross-sectional area of the flow jet at the vena contracta, especially at low flow rates. The objective of this study was to test the validity of the Doppler-derived EOA. METHODS: Triangular and circular orifice plates, funnels, and bioprosthetic valves were inserted into an in vitro aortic flow model and were studied under different physiologic flow rates corresponding to cardiac outputs varying from 1.5 to 7 L/min. For each experiment, the EOA was measured by Doppler and compared with the catheter-derived EOA and with the EOA derived from a theoretic formula. In bioprostheses, the geometric orifice area (GOA) was estimated from images acquired by high-speed video recording. RESULTS: There was no significant difference between the EOA derived from the 3 methods with the rigid orifices (Doppler vs catheter: y = 0.97x +0.18 mm(2), r(2) = 0.98; Doppler vs theory: y = 1.00x -3.60 mm(2), r(2) = 0.99). Doppler EOA was not significantly influenced by the flow rate in rigid orifices. As predicted by theory, the average contraction coefficient (EOA/GOA) was around 0.6 in the orifice plates and around 1.0 in the funnels. In the bioprosthetic valves, both EOA and GOA increased with increasing flow rate whereas contraction coefficient was almost constant with an average value of 0.99. There was also a very good concordance between EOA and GOA (y = 0.94x +0.05 mm(2), r(2) = 0.88). CONCLUSIONS: In rigid aortic stenosis, the Doppler EOA is much less flow dependent than generally assumed. Indeed, it depends mainly on the GOA and the inflow shape (flat vs funnel-shaped) of the stenosis. The flow dependence of Doppler EOA observed in clinical studies is likely a result of a variation of the valve GOA or of the valve inflow shape and not an inherent flow dependence of the EOA derived by the continuity equation.
Aortic Valve↗
Non-Gaussian statistics and temporal variations of the ultrasound signal backscattered by blood at frequencies between 10 and 58 MHz.
Very little is known about the blood backscattering behavior and signal statistics following flow stoppage at frequencies higher than 10 MHz. Measurements of the radio frequency (rf) signals backscattered by normal human blood (hematocrit = 40%, temperature = 37 degrees C) were performed in a tube flow model at mean frequencies varying between 10 and 58 MHz. The range of increase of the backscattered power during red blood cell (RBC) rouleau formation was close to 15 dB at 10 and 36 MHz, and dropped, for the same blood samples, below 8 dB at 58 MHz. Increasing the frequency from 10 to 58 MHz raised the slope of the power changes at the beginning of the kinetics of aggregation, and could emphasize the non-Gaussian behavior of the rf signals interpreted in terms of the K and Nakagami statistical models. At 36 and 58 MHz, significant increases of the kurtosis coefficient, and significant reductions of the Nakagami parameter were noted during the first 30 s of flow stoppage. In conclusion, increasing the transducer frequency reduced the magnitude of the backscattered power changes attributed to the phenomenon of RBC aggregation, but improved the detection of rapid growth in aggregate sizes and non-Gaussian statistical behavior.
Acoustics↗
Discrepancies between catheter and Doppler estimates of valve effective orifice area can be predicted from the pressure recovery phenomenon: practical implications with regard to quantification of aortic stenosis severity.
OBJECTIVES: We sought to obtain more coherent evaluations of aortic stenosis severity. BACKGROUND: The valve effective orifice area (EOA) is routinely used to assess aortic stenosis severity. However, there are often discrepancies between measurements of EOA by Doppler echocardiography (EOA(Dop)) and those by a catheter (EOA(cath)). We hypothesized that these discrepancies might be due to the influence of pressure recovery. METHODS: The relationship between EOA(cath) and EOA(Dop) was studied as follows: 1) in an in vitro model measuring the effects of different flow rates and aortic diameters on two fixed stenoses and seven bioprostheses; 2) in an animal model of supravalvular aortic stenosis (14 pigs); and 3) based on catheterization data from 37 patients studied by Schöbel et al. RESULTS: Pooling of in vitro, animal, and patient data showed a good correlation (r = 0.97) between EOA(cath) (range 0.3 to 2.3 cm(2)) and EOA(Dop) (range 0.2 to 1.7 cm(2)), but EOA(cath) systematically overestimated EOA(Dop) (24 +/- 17% [mean +/- SD]). However, when the energy loss coefficient (ELCo) was calculated from EOA(Dop) and aortic cross-sectional area (A(A)) to account for pressure recovery, a similar correlation (r = 0.97) with EOA(cath) was observed, but the previously noted overestimation was no longer present. CONCLUSIONS: Discrepancies between EOA(cath) and EOA(Dop) are largely due to the pressure recovery phenomenon and can be reconciled by calculating ELCo from the echocardiogram. Thus, ELCo and EOA(cath) are equivalent indexes representing the net energy loss due to stenosis and probably are the most appropriate for quantifying aortic stenosis severity.
Animals↗
Arabidopsis haiku mutants reveal new controls of seed size by endosperm.
In flowering plants, maternal seed integument encloses the embryo and the endosperm, which are both derived from double fertilization. Although the development of these three components must be coordinated, we have limited knowledge of mechanisms involved in such coordination. The endosperm may play a central role in these mechanisms as epigenetic modifications of endosperm development, via imbalance of dosage between maternal and paternal genomes, affecting both the embryo and the integument. To identify targets of such epigenetic controls, we designed a genetic screen in Arabidopsis for mutants that phenocopy the effects of dosage imbalance in the endosperm. The two mutants haiku 1 and haiku 2 produce seed of reduced size that resemble seed with maternal excess in the maternal/paternal dosage. Homozygous haiku seed develop into plants indistinguishable from wild type. Each mutation is sporophytic recessive, and double-mutant analysis suggests that both mutations affect the same genetic pathway. The endosperm of haiku mutants shows a premature arrest of increase in size that causes precocious cellularization of the syncytial endosperm. Reduction of seed size in haiku results from coordinated reduction of endosperm size, embryo proliferation, and cell elongation of the maternally derived integument. We present further evidence for a control of integument development mediated by endosperm-derived signals.
Arabidopsis↗