Autotaxin interacts with lipoprotein(a) and oxidized phospholipids in predicting the risk of calcific aortic valve stenosis in patients with coronary artery disease.

BACKGROUND: Studies have shown that lipoprotein(a) [Lp(a)], an important carrier of oxidized phospholipids, is causally related to calcific aortic valve stenosis (CAVS). Recently, we found that Lp(a) mediates the development of CAVS through autotaxin (ATX). OBJECTIVE: To determine the predictive value of circulating ATX mass and activity for CAVS. METHODS: We performed a case-control study in 300 patients with coronary artery disease (CAD). Patients with CAVS plus CAD (cases, n = 150) were age- and gender-matched (1 : 1) to patients with CAD without aortic valve disease (controls, n = 150). ATX mass and enzymatic activity and levels of Lp(a) and oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) were determined in fasting plasma samples. RESULTS: Compared to patients with CAD alone, ATX mass (P < 0.0001), ATX activity (P = 0.05), Lp(a) (P = 0.003) and OxPL-apoB (P < 0.0001) levels were elevated in those with CAVS. After adjustment, we found that ATX mass (OR 1.06, 95% CI 1.03-1.10 per 10 ng mL-1 , P = 0.001) and ATX activity (OR 1.57, 95% CI 1.14-2.17 per 10 RFU min-1 , P = 0.005) were independently associated with CAVS. ATX activity interacted with Lp(a) (P = 0.004) and OxPL-apoB (P = 0.001) on CAVS risk. After adjustment, compared to patients with low ATX activity (dichotomized at the median value) and low Lp(a) (<50 mg dL-1 ) or OxPL-apoB (<2.02 nmol L-1 , median) levels (referent), patients with both higher ATX activity (≥84 RFU min-1 ) and Lp(a) (≥50 mg dL-1 ) (OR 3.46, 95% CI 1.40-8.58, P = 0.007) or OxPL-apoB (≥2.02 nmol L-1 , median) (OR 5.48, 95% CI 2.45-12.27, P < 0.0001) had an elevated risk of CAVS. CONCLUSION: Autotaxin is a novel and independent predictor of CAVS in patients with CAD.

Normalized left ventricular workload using phase-contrast magnetic resonance imaging in patients with aortic stenosis.

Aortic stenosis (AS) severity contributes to the left ventricle (LV) deterioration due to the aortic valve narrowing and the alteration of systemic hemodynamic load. This load increment may also increase the LV stroke work (SW) which represent the required energy to deliver the blood at ejection. In this study, SW was derived from in-vivo cardiovascular magnetic resonance (CMR) velocity measurements (n=57) using a lumped-parametric model. Furthermore, normalized SW (N-SW) was evaluated as AS severity parameter. SW differentiated from normal flow (>35 mL/m(2)) and low flow (<35 mL/m(2)) states (p<0.05). N-SW showed a good association with valve effective orifice area (EOA, r=-0.5, p<0.001) and valvulo-arterial impedance (ZVA, r=0.65, p<0.001). A severity threshold for N-SW (1.5 cJ/mL) was found using an EOA=1 cm(2) as AS severity marker. CMR-derived SW and N-SW may be useful to the assessment and grading of AS patients.

On the evaluation of vorticity using cardiovascular magnetic resonance velocity measurements.

Vorticity and vortical structures play a fundamental role affecting the evaluation of energetic aspects (mainly left ventricle work) of cardiovascular function. Vorticity can be derived from cardiovascular magnetic resonance (CMR) imaging velocity measurements. However, several numerical schemes can be used to evaluate the vorticity field. The main objective of this work is to assess different numerical schemes used to evaluate the vorticity field derived from CMR velocity measurements. We compared the vorticity field obtained using direct differentiation schemes (eight-point circulation and Chapra) and derivate differentiation schemes (Richardson 4* and compact Richardson 4*) from a theoretical velocity field and in vivo CMR velocity measurements. In all cases, the effect of artificial spatial resolution up-sampling and signal-to-noise ratio (SNR) on vorticity computation was evaluated. Theoretical and in vivo results showed that the eight-point circulation method underestimated vorticity. Up-sampling evaluation showed that the artificial improvement of spatial resolution had no effect on mean absolute vorticity estimation but it affected SNR for all methods. The Richardson 4* method and its compact version were the most accurate and stable methods for vorticity magnitude evaluation. Vorticity field determination using the eight-point circulation method, the most common method used in CMR, has reduced accuracy compared to other vorticity schemes. Richardson 4* and its compact version showed stable SNR using both theoretical and in vivo data.

Impact of global hemodynamic load on exercise capacity in aortic stenosis.

BACKGROUND: The determinants of maximal exercise capacity (MEC) in aortic stenosis (AS) are, in large part, unknown. We hypothesized that the left ventricular (LV) global hemodynamic load--as assessed by the valvulo-arterial impedance (Zva)--is one of the main determinants of MEC and we sought to evaluate the factors associated with reduced MEC in AS. METHOD AND RESULTS: Asymptomatic patients with moderate or severe AS (n=62, aortic valve area <1.5 cm(2), 65 ± 13 years, 68% men) and preserved LV systolic function (ejection fraction>50%) were prospectively referred for comprehensive resting echocardiography and cardiopulmonary exercise test. Absolute peak VO2 was 19.5 ± 5.7 mL/kg/min (median 19.6 mL/kg/min; range 7.2-33.1 mL/kg/min). There were significant correlations between peak VO2 and: age, body mass index, LV stroke volumes, cardiac output, mean flow rate, mitral annulus s' and e' wave velocities, E/e' ratio and left atrial diameter (all p<0.05). Indexed mean flow rate and Zva were the strongest univariable echocardiographic determinants of peak VO2 (r=0.44, p<0.001 and r=-0.39, p=0.002, respectively). In addition, patients with reduced MEC (peak VO2

Modeling the impact of concomitant aortic stenosis and coarctation of the aorta on left ventricular workload.

Coarctation of the aorta (COA) is an obstruction of the aorta and is usually associated with bicuspid and tricuspid aortic valve stenosis (AS). When COA coexists with AS, the left ventricle (LV) is facing a double hemodynamic load: a valvular load plus a vascular load. The objective of this study was to develop a lumped parameter model, solely based on non-invasive data, allowing the description of the interaction between LV, COA, AS and the arterial system. First, a formulation describing the instantaneous net pressure gradient through the COA was introduced and the predictions were compared to in vitro results. The model was then used to determine LV work induced by coexisting AS and COA with different severities. The results show that LV stroke work varies from 0.98J (no-AS; no-COA) up to 2.15J (AS: 0.61cm(2)+COA: 90%). Our results also show that the proportion of the total flow rate that will cross the COA is significantly reduced with the increasing COA severity (from 85% to 40%, for a variation of COA severity from 0% to 90%, respectively). Finally, we introduced simple formulations capable of, non-invasively, estimating both LV peak systolic pressure and workload. As a conclusion, this study allowed the development of a lumped parameter model, based on non-invasive measurements, capable of accurately investigating the impact of coexisting AS and COA on LV workload. This model can be used to optimize the management of patients with COA and AS in terms of the sequence of lesion repair.

Hypoadiponectinemia is associated with valvular inflammation and faster disease progression in patients with aortic stenosis.

OBJECTIVES: Adiponectin is a protein secreted by adipocytes which has anti-inflammatory properties. The objective of this study was to examine the relationship between adiponectinemia and the hemodynamic progression of aortic stenosis (AS) as well as the degree of inflammation in the valve explanted at the time of aortic valve replacement (AVR). METHODS: The plasma level of adiponectin was measured in 122 patients undergoing AVR. The explanted aortic valves were analyzed and the density of leukocytes (CD45+), T cells (CD3+) and blood vessels (von Willebrand factor positive; vWF+) was documented. Also, a subset of patients (n = 67) had ≥2 echocardiographic studies separated by at least 6 months, thereby allowing assessment of the rate of progression of stenosis during the preoperative period. RESULTS: Patients with lower plasma levels of adiponectin (<5.4 µg/ml) had a faster progression rate of the mean transvalvular gradient before surgery than those with higher levels (9 ± 1 vs. 4 ± 1 mm Hg/year; p = 0.008). Moreover, these patients with hypoadiponectinemia had significantly more leukocytes (CD45+), T cells and blood vessels (vWF+) in their explanted valves compared to those with higher adiponectin levels. CONCLUSION: These findings support the concept that adiponectin may play a protective role against the inflammatory process and progression of calcific AS.

A new index measured by cardiovascular magnetic resonance imaging to detect mechanical heart valve malfunction.

More than two thirds of valve replacement operations performed each year used mechanical heart valve. These valves are subject to complications such: pannus and/or thrombus formation. One other potential complication is a malfunction in one of the valve leaflets. It is then important to develop parameters that will allow a non-invasive diagnosis of such valve malfunction. In the present study, we evaluated under steady low flow (1-8 L/min) and pulsatile flow (3, 5 and 7 L/min) a bileafleat mechanical heart valve with normal function, 50% and 100% of one valve leaflet malfunction. Image analysis was performed using cardiovascular magnetic resonance imaging to evaluate transvalvular pressure gradients (TPG), effective orifice area and a new index given by central/lateral velocity ratio downstream of the valve. Our results showed that the flow upstream and downstream of the defective valve is highly influenced by malfunction severity. TPG did not allow differentiating valve malfunction at low flow under steady and pulsatile conditions. However the new index given by central/lateral ratio allowed differentiating the presence of valve malfunction using a single transverse velocity measurement.

Comparison between transcatheter and surgical prosthetic valve implantation in patients with severe aortic stenosis and reduced left ventricular ejection fraction.

BACKGROUND: Patients with severe aortic stenosis and reduced left ventricular ejection fraction (LVEF) have a poor prognosis with conservative therapy but a high operative mortality when treated surgically. Recently, transcatheter aortic valve implantation (TAVI) has emerged as an alternative to surgical aortic valve replacement (SAVR) for patients considered at high or prohibitive operative risk. The objective of this study was to compare TAVI and SAVR with respect to postoperative recovery of LVEF in patients with severe aortic stenosis and reduced LV systolic function. METHODS AND RESULTS: Echocardiographic data were prospectively collected before and after the procedure in 200 patients undergoing SAVR and 83 patients undergoing TAVI for severe aortic stenosis (aortic valve area ≤1 cm(2)) with reduced LV systolic function (LVEF ≤50%). TAVI patients were significantly older (81±8 versus 70±10 years; P<0.0001) and had more comorbidities compared with SAVR patients. Despite similar baseline LVEF (34±11% versus 34±10%), TAVI patients had better recovery of LVEF compared with SAVR patients (ΔLVEF, 14±15% versus 7±11%; P=0.005). At the 1-year follow-up, 58% of TAVI patients had a normalization of LVEF (>50%) as opposed to 20% in the SAVR group. On multivariable analysis, female gender (P=0.004), lower LVEF at baseline (P=0.005), absence of atrial fibrillation (P=0.01), TAVI (P=0.007), and larger increase in aortic valve area after the procedure (P=0.01) were independently associated with better recovery of LVEF. CONCLUSION: In patients with severe aortic stenosis and depressed LV systolic function, TAVI is associated with better LVEF recovery compared with SAVR. TAVI may provide an interesting alternative to SAVR in patients with depressed LV systolic function considered at high surgical risk.

In vitro investigation of the impact of aortic valve stenosis severity on left coronary artery flow.

Patients with aortic valve stenosis (AS) may experience angina pectoris even if they have angiographically normal coronary arteries. Angina is associated with a marked increase in the risk of sudden death in AS patients. Only a few in vitro models describing the interaction between the left ventricular and aortic pressures, and the coronary circulation have been reported. These models were designed for specific research studies and they need to be improved or modified when other specific studies are required. Consequently, we have developed an in vitro model that is able to mimic the coronary circulation in presence of aortic stenosis. First, we have validated the model under physiological conditions. Then, we have examined and quantified the hemodynamic effects of different degrees of AS (from normal to severe AS) on the coronary flow using a model of the normal left coronary artery. In the coronary in vitro model without AS (normal valve), the amplitude and shape of coronary flow were similar to those observed in in vivo measurements obtained under physiological conditions, as described by Hozumi et al. (1998, "Noninvasive Assessment of Significant Left Anterior Descending Coronary Artery Stenosis by Coronary Flow Velocity Reserve With Transthoracic Color Doppler Echocardiography," Circulation, 97, pp. 1557-1562). The presence of an AS induced an increase in the maximum and mean coronary flow rates (97% and 73%, respectively, for a very severe AS). Furthermore, when AS was very severe, a retrograde flow occurred during systole. This study allowed us to validate our coronary in vitro model under physiological conditions, both in the absence and presence of AS. These changes could explain the fact that even if patients have angiographically normal epicardial coronary arteries, we can observe the occurrence of angina pectoris in these patients in the presence of an AS.

Elevated left atrial pressure estimated by Doppler echocardiography is a key determinant of mitral valve tenting in functional mitral regurgitation.

BACKGROUND: Functional mitral regurgitation (FMR) may occur in patients with reduced or preserved left ventricular ejection fraction (LVEF) and has been associated with excess valvular tenting only in patients with reduced LVEF. This study aimed at identifying the predictors of FMR and to determine whether or not they are different in patients with reduced versus preserved LVEF. METHODS: 190 consecutive patients free of congenital or primary valvular disease had a comprehensive echocardiographic assessment of LV remodelling and function, diastolic function and FMR severity. RESULTS: 112 patients had depressed LVEF (<50%) and 78 had preserved LVEF. FMR was present in 30 patients with preserved LVEF and in 65 with reduced LVEF. Higher E/Ea, E/A and larger mitral tenting were independent predictors of FMR regardless of LVEF. The mitral tenting area was an independent predictor of FMR severity in patients with reduced or preserved LVEF (p = 0.04 and p = 0.0045) in addition to E/A (p = 0.0007), E/Ea (p = 0.004) in patients with reduced and preserved LVEF, respectively. Higher E/Ea was independently associated with larger mitral tenting in patients with reduced and preserved LVEF. Mitral tenting area was linearly related to E/Ea (r = 0.30, p<0.0001) and E/A (r = 0.43, p<0.0001) and LA enlargement (r = 0.54, p<0.0001) after having paired 96 patients with and without FMR on indices of LV remodelling. CONCLUSIONS: In both patients with preserved and reduced LVEF, mitral tenting that leads to FMR is mainly determined by both mitral tethering forces-that is, displacement of papillary muscles and by pushing forces-that is, increased left atrial pressure. This study underscores that LV preload is a key determinant of FMR.

Numerical and experimental investigations of pulsatile blood flow pattern through a dysfunctional mechanical heart valve.

Around 250,000 heart valve replacements are performed every year around the world. Due their higher durability, approximately 2/3 of these replacements use mechanical prosthetic heart valves (mainly bileaflet valves). Although very efficient, these valves can be subject to valve leaflet malfunctions. These malfunctions are usually the consequence of pannus ingrowth and/or thrombus formation and represent serious and potentially fatal complications. Hence, it is important to investigate the flow field downstream of a dysfunctional mechanical heart valve to better understand its impact on blood components (red blood cells, platelets and coagulation factors) and to improve the current diagnosis techniques. Therefore, the objective of this study will be to numerically and experimentally investigate the pulsatile turbulent flow downstream of a dysfunctional bileaflet mechanical heart valve in terms of velocity field, vortex formation and potential negative effect on blood components. The results show that the flow downstream of a dysfunctional valve was characterized by abnormally elevated velocities and shear stresses as well as large scale vortices. These characteristics can predispose to blood components damage. Furthermore, valve malfunction led to an underestimation of maximal transvalvular pressure gradient, using Doppler echocardiography, when compared to numerical results. This could be explained by the shifting of the maximal velocity towards the normally functioning leaflet. As a consequence, clinicians should try, when possible, to check the maximal velocity position not only at the central orifice but also through the lateral orifices. Finding the maximal velocity in the lateral orifice could be an indication of valve dysfunction.

Optimization of Doppler velocity echocardiographic measurements using an automatic contour detection method.

Intra- and inter-observer variability in Doppler velocity echocardiographic measurements (DVEM) is a significant issue. Indeed, imprecisions of DVEM can lead to diagnostic errors, particularly in the quantification of the severity of heart valve dysfunction. To minimize the variability and rapidity of DVEM, we have developed an automatic method of Doppler velocity wave contour detection, based on active contour models. To validate our new method, results obtained with this method were compared to those obtained manually by an experienced echocardiographer on Doppler echocardiographic images of left ventricular outflow tract and transvalvular flow velocity signals recorded in 30 patients, 15 with aortic stenosis and 15 with mitral stenosis. We focused on three essential variables that are measured routinely by Doppler echocardiography in the clinical setting: the maximum velocity, the mean velocity and the velocity-time integral. Comparison between the two methods has shown a very good agreement (linear correlation coefficient R(2) = 0.99 between the automatically and the manually extracted variables). Moreover, the computation time was really short, about 5s. This new method applied to DVEM could, therefore, provide a useful tool to eliminate the intra- and inter-observer variabilities associated with DVEM and thereby to improve the diagnosis of cardiovascular disease. This automatic method could also allow the echocardiographer to realize these measurements within a much shorter period of time compared to standard manual tracing method. From a practical point of view, the model developed can be easily implanted in a standard echocardiographic system.

Lipid-mediated inflammation and degeneration of bioprosthetic heart valves.

BACKGROUND: The durability of bioprosthetic valves is limited by structural valve degeneration (SVD) leading to bioprostheses (BPs) stenosis or regurgitation. We hypothesized that a lipid-mediated inflammatory mechanism is involved in the SVD of BPs. MATERIAL AND METHODS: Eighteen Freestyle stentless BP valves were explanted for SVD at a mean time of 5.9 +/- 3 years after implantation and were analysed by immunohistochemistry and transmission electron microscopy (TEM). RESULTS: The mean age of the patients was 65 +/- 8 years and there were 11 male and seven female patients. Two of the 18 BPs had macroscopic calcification, whereas the other valves had minimal or no macroscopic calcification. Tears at the commissures leading to regurgitation was present in 16 BPs. Immunohistochemistry showed the presence of oxidized low-density lipoprotein (ox-LDL) and glycosaminoglycans in the fibrosa layer of 13 BPs. Areas with ox-LDL were infiltrated by macrophages (CD68(+)) co-expressing the scavenger receptor CD36 and metalloproteinase-9 (MMP-9). Zymogram showed the active form of MMP-9 within explanted BPs. EM studies revealed the presence of lipid-laden cells featuring foam cells and fragmented collagen. Nonimplanted control BPs obtained from the manufacturer (n = 4) had no evidence of lipid accumulation, inflammatory cell infiltration or expression of MMP9 within the leaflets. CONCLUSIONS: These results support the concept that lipid-mediated inflammatory mechanisms may contribute to the SVD of BPs. These findings suggest that modification of atherosclerotic risk factors with the use of behavioural or pharmacological interventions could help to reduce the incidence of SVD.

Exercise testing and exercise stress echocardiography in asymptomatic aortic valve stenosis.

Management of asymptomatic patients with severe aortic valve stenosis (AVS) remains a source of debate. Exercise testing is no longer contraindicated and needs now to be considered when evaluating asymptomatic patients with AVS. Several studies have clearly demonstrated that exercise-elicited symptoms during conventional upright exercise portends clinical events. Semi-supine exercise with continuous Doppler echocardiography monitoring elicits cardiovascular abnormalities that are not detected at rest. Abnormal left ventricular response to exercise and/or major increase in mean transvalvular gradient add to the prognostic value of elicited symptoms in asymptomatic patients with severe AVS. However, preliminary experience needs to be confirmed to warrant routine use of exercise Doppler echocardiography in the evaluation of patients with asymptomatic AVS.

Myocardial blood flow in patients with low-flow, low-gradient aortic stenosis: differences between true and pseudo-severe aortic stenosis. Results from the multicentre TOPAS (Truly or Pseudo-Severe Aortic Stenosis) study.

BACKGROUND: Impairment of myocardial flow reserve (MFR) in aortic stenosis (AS) with normal left ventricular function relates to the haemodynamic severity. OBJECTIVES: To investigate whether myocardial blood flow (MBF) and MFR differ in low-flow, low-gradient AS depending on whether there is underlying true-severe AS (TSAS) or pseudo-severe AS (PSAS). METHODS: In 36 patients with low-flow, low-gradient AS, dynamic [13N]ammonia PET perfusion imaging was performed at rest (n = 36) and during dipyridamole stress (n = 20) to quantify MBF and MFR. Dobutamine echocardiography was used to classify patients as TSAS (n = 18) or PSAS (n = 18) based on the indexed projected effective orifice area (EOA) at a normal flow rate of 250 ml/s (EOAI(proj )0.55 cm(2)/m(2)). RESULTS: Compared with healthy controls (n = 14), patients with low-flow, low-gradient AS had higher resting mean (SD) MBF (0.83 (0.21) vs 0.69 (0.09) ml/min/g, p = 0.001), reduced hyperaemic MBF (1.16 (0.31) vs 2.71 (0.50) ml/min/g, p<0.001) and impaired MFR (1.44 (0.44) vs 4.00 (0.91), p<0.001). Resting MBF and MFR correlated with indices of AS severity in low-flow, low-gradient AS with the strongest relationship observed for EOAI(proj) (r(s) = -0.50, p = 0.002 and r(s) = 0.61, p = 0.004, respectively). Compared with PSAS, TSAS had a trend to a higher resting MBF (0.90 (0.19) vs 0.77 (0.21) ml/min/g, p = 0.06), similar hyperaemic MBF (1.16 (0.31) vs 1.17 (0.32) ml/min/g, p = NS), but a significantly smaller MFR (1.19 (0.26) vs 1.76 (0.41), p = 0.003). An MFR <1.8 had an accuracy of 85% for distinguishing TSAS from PSAS. CONCLUSIONS: Low-flow, low-gradient AS is characterised by higher resting MBF and reduced MFR that relates to the AS severity. The degree of MFR impairment differs between TSAS and PSAS and may be of value for distinguishing these entities.

Association between circulating oxidised low-density lipoprotein and fibrocalcific remodelling of the aortic valve in aortic stenosis.

INTRODUCTION: Aortic stenosis (AS) is the most common valvular heart disease in westernized societies. AS is a disease process akin to atherosclerosis in which calcification and tissue remodelling play a crucial role. In patients with moderate/severe AS, we sought to determine whether the remodelling process would be in relationship with transvalvular gradients and circulating oxidised low-density lipoprotein (ox-LDL) levels. METHODS: In 105 patients with AS, the aortic valve and blood plasma were collected at the time of valve replacement surgery. The degree of valve tissue remodelling was assessed using a scoring system (Score: 1-4) and the amount of calcium within the valve cusps was determined. The standard plasma lipid profile, the size of LDL particles and the plasma level of circulating ox-LDL (4E6 antibody) were determined. RESULTS: After adjustment for covariables, aortic remodelling score was significantly related to transvalvular gradients measured by Doppler echocardiography before surgery. Patients with higher valve remodelling score had higher circulating ox-LDL levels (score 2: 27.3 (SEM 2.6) U/l; score 3: 32.2 (SEM 2.3) U/l; score 4: 38.3 (SEM 2.3) U/l; p = 0.02). After correction for age, gender, hypertension and HDL-C, the plasma level of ox-LDL remained significantly associated with the aortic valve remodelling score (p<0.001). The plasma level of ox-LDL was significantly associated with LDL-C (r = 0.41; p<0.001), apoB (r = 0.59; p<0.001), triglyceride (r = 0.39; p<0.001), Apo A-I (r = 0.23; p = 0.01) and cholesterol in small (<255 A) LDL particles (r = 0.22; p = 0.02). After correction for covariables, circulating ox-LDL levels remained significantly associated with apoB (p<0.001) and triglyceride (p = 0.01) levels. CONCLUSION: Increased level of circulating ox-LDL is associated with worse fibrocalcific remodelling of valvular tissue in AS. It remains to be determined whether circulating ox-LDL is a risk marker for a highly atherogenic profile and/or a circulating molecule which is actively involved in the pathogenesis of calcific aortic valve disease.