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.     

Are the Current Doppler Echocardiography Criteria Able to Discriminate Mitral Bileaflet Mechanical Heart Valve Malfunction? An In Vitro Study

Malfunction of bileaflet mechanical heart valves in the mitral position could either be due to patient–prosthesis mismatch (PPM) or leaflet obstruction. The aim of this article is to investigate the validity of current echocardiographic criteria used for diagnosis of mitral prosthesis malfunction, namely maximum velocity, mean transvalvular pressure gradient, effective orifice area, and Doppler velocity index. In vitro testing was performed on a double activation left heart duplicator. Both PPM and leaflet obstruction were investigated on a St. Jude Medical Master. PPM was studied by varying the St. Jude prosthesis size (21, 25, and 29 mm) and stroke volume (70 and 90 mL). Prosthesis leaflet obstruction was studied by partially or totally blocking the movement of one valve leaflet. Mitral flow conditions were altered in terms of E/A ratios (0.5, 1.0, and 1.5) to simulate physiologic panel of diastolic function. Maximum velocity, effective orifice area, and Doppler velocity index are shown to be insufficient to distinguish normal from malfunctioning St. Jude prostheses. Doppler velocity index and effective orifice area were 1.3 ± 0.49 and 1.83 ± 0.43 cm² for testing conditions with no malfunction below the 2.2 and 2 cm² thresholds (1.19 cm² for severe PPM and 1.23 cm² for fully blocked leaflet). The mean pressure gradient reached 5 mm Hg thresholds for several conditions of severe PPM only (6.9 mm Hg and mean maximum velocity value: 183.4 cm/s) whereas such value was never attained in the case of leaflet obstruction. In the case of leaflet obstruction, the maximum velocity averaged over the nine pulsed‐wave Doppler locations increased by 38% for partial leaflet obstruction and 75% for a fully blocked leaflet when compared with normal conditions. Current echocardiographic criteria might be suboptimal for the detection of bileaflet mechanical heart valve malfunction. Further developments and investigations are required in order to further improve current guidelines.     

In vivo imaging of transplanted hepatocytes with a 1.5-T clinical MRI system—initial experience in mice

The feasibility of in vitro mature mouse hepatocyte labeling with a novel iron oxide particle was assessed and the ability of 1.5-T magnetic resonance imaging (MRI) to track labeled mouse hepatocytes in syngenic recipient livers following intraportal cell transplantation was tested. Mouse hepatocytes were incubated with anionic iron oxide nanoparticles at various iron concentrations. Cell viability was assessed and iron oxide particle uptake quantified. Labeled hepatocytes were intraportally injected into 20 mice, while unlabeled hepatocytes were injected into two mice. Liver T2 values, spleen-to-muscle relative signal intensity (RI _{spleen/muscle} ), and liver-to-muscle relative signal intensity (RI _liver/muscle ) on gradient-echo T2-weighted imaging after injection of either labeled or unlabeled hepatocytes were compared with an ANOVA test followed by Fisher’s a posteriori PLSD test. Livers, spleens and lungs were collected for histological analysis. Iron oxide particle uptake was saturable with a maximum iron content of 20 pg per cell and without viability alteration after 3 days of culture. Following labeled-cell transplantation, recipient livers showed well-defined nodular foci of low signal intensity on MRI—consistent with clusters of labeled hepatocytes on pathological analysis—combined with a significant decrease in both liver T2 values and liver-to-muscle RI _liver/muscle (P = 0.01) with minimal T2 values demonstrated 8 days after transplantation. Conventional MRI can demonstrate the presence of transplanted iron-labeled mature hepatocytes in mouse liver.     

An uncertainty-based approach to drive product preliminary design

In order to reduce time to market and to master the costs, the design process of industrial companies is more and more structured. It enables collaborative design for experts integration and for improving the decision-making process. Decision making under uncertainties remains an important issue, especially at the beginning of this design process. The product performances are a common reference in collaborative design, and their management involves interactive design. In this paper, a functional analysis under uncertainties approach is proposed, as a means to improve interactive design. It enables to manage the risk of not fulfilling the required performances throughout the design process. This methodology makes it easy to link the data usually handled in engineering design (especially the technical requirements) with those handled for risk assessment (especially failure analysis). Using logical trees, the product functions and the associated chosen technologies are analyzed in terms of risk, taking account of the uncertainties that lead to risk and the potential failure that can arise.     

Comparison between cardiovascular magnetic resonance and transthoracic doppler echocardiography for the estimation of effective orifice area in aortic stenosis

Background

The effective orifice area (EOA) estimated by transthoracic Doppler echocardiography (TTE) via the continuity equation is commonly used to determine the severity of aortic stenosis (AS). However, there are often discrepancies between TTE-derived EOA and invasive indices of stenosis, thus raising uncertainty about actual definite severity. Cardiovascular magnetic resonance (CMR) has emerged as an alternative method for non-invasive estimation of valve EOA. The objective of this study was to assess the concordance between TTE and CMR for the estimation of valve EOA.

Methods and results

31 patients with mild to severe AS (EOA range: 0.72 to 1.73 cm²) and seven (7) healthy control subjects with normal transvalvular flow rate underwent TTE and velocity-encoded CMR. Valve EOA was calculated by the continuity equation. CMR revealed that the left ventricular outflow tract (LVOT) cross-section is typically oval and not circular. As a consequence, TTE underestimated the LVOT cross-sectional area (A_LVOT, 3.84 ± 0.80 cm²) compared to CMR (4.78 ± 1.05 cm²). On the other hand, TTE overestimated the LVOT velocity-time integral (VTI_LVOT: 21 ± 4 vs. 15 ± 4 cm). Good concordance was observed between TTE and CMR for estimation of aortic jet VTI (61 ± 22 vs. 57 ± 20 cm). Overall, there was a good correlation and concordance between TTE-derived and CMR-derived EOAs (1.53 ± 0.67 vs. 1.59 ± 0.73 cm², r = 0.92, bias = 0.06 ± 0.29 cm²). The intra- and inter- observer variability of TTE-derived EOA was 5 ± 5% and 9 ± 5%, respectively, compared to 2 ± 1% and 7 ± 5% for CMR-derived EOA.

Conclusion

Underestimation of A_LVOT by TTE is compensated by overestimation of VTI_LVOT, thereby resulting in a good concordance between TTE and CMR for estimation of aortic valve EOA. CMR was associated with less intra- and inter- observer measurement variability compared to TTE. CMR provides a non-invasive and reliable alternative to Doppler-echocardiography for the quantification of AS severity.     

Flow-dependent changes in Doppler-derived aortic valve effective orifice area are real and not due to artifact.

OBJECTIVES: We sought to determine whether the flow-dependent changes in Doppler-derived valve effective orifice area (EOA) are real or due to artifact. BACKGROUND: It has frequently been reported that the EOA may vary with transvalvular flow in patients with aortic stenosis. However, the explanation of the flow dependence of EOA remains controversial and some studies have suggested that the EOA estimated by Doppler-echocardiography (EOA(Dop)) may underestimate the actual EOA at low flow rates. METHODS: One bioprosthetic valve and three rigid orifices were tested in a mock flow circulation model over a wide range of flow rates. The EOA(Dop) was compared with reference values obtained using particle image velocimetry (EOA(PIV)). RESULTS: There was excellent agreement between EOA(Dop) and EOA(PIV) (r2 = 0.94). For rigid orifices of 0.5 and 1.0 cm2, no significant change in the EOA was observed with increasing flow rate. However, substantial increases of both EOA(Dop) and EOA(PIV) were observed when stroke volume increased from 20 to 70 ml both in the 1.5 cm2 rigid orifice (+52% for EOA(Dop) and +54% for EOA(PIV)) and the bioprosthetic valve (+62% for EOA(Dop) and +63% for EOA(PIV)); such changes are explained either by the presence of unsteady effects at low flow rates and/or by an increase in valve leaflet opening. CONCLUSIONS: The flow-dependent changes in EOA(Dop) are not artifacts but represent real changes in EOA attributable either to unsteady effects at low flow rates and/or to changes in valve leaflet opening. Such changes in EOA(Dop) can be relied on for clinical judgment making.     

Everolimus for patients with mantle cell lymphoma refractory to or intolerant of bortezomib: multicentre,single‐arm,phase 2 study

The multicentre, open‐label, two‐stage, single‐arm, phase 2, PILLAR (PIvotaL Lymphoma triAls of RAD001)‐1 study (NCT00702052) assessed the efficacy and safety of everolimus 10 mg/d in adults with confirmed mantle cell lymphoma (MCL) refractory to or intolerant of bortezomib who received ≥1 other antineoplastic agent, either separately or in combination with bortezomib. Primary endpoint was overall response rate (ORR) per investigator review according to the response criteria for malignant lymphoma. Secondary endpoints included progression‐free survival (PFS), overall survival (OS) and safety. Fifty‐eight patients were enrolled from August 2008–January 2011. Five partial responses were observed (ORR 8·6%; 90% confidence interval [CI] 3·5–17·3%); the study did not meet the prespecified objective of ≥8 objective responses among 57 patients. Median PFS and OS were 4·4 months (95% CI 3·5–6·1) and 16·9 months (95% CI 14·4–29·9), respectively. Grade 3/4 non‐haematological toxicities occurred in 70·7% of patients. Based on laboratory values, grade 3/4 thrombocytopenia, neutropenia and anaemia occurred in 13·8%, 13·8% and 8·6% of patients, respectively. Everolimus demonstrated modest activity and acceptable tolerability in heavily pretreated patients with MCL refractory to or intolerant of bortezomib. Future studies evaluating everolimus in a less refractory population or in combination with other targeted therapies in refractory MCL are warranted.