Search

Objectives In this study, we sought to determine the metabolic markers associated with structural valve degeneration (SVD). Background Structural valve degeneration (SVD) is the major cause of bioprosthetic valve failure leading to bioprostheses (BPs) stenosis or regurgitation. We hypothesized that lipoprotein-associated phospholipase A2 (Lp-PLA2) is involved in the SVD of BPs. Methods We included 197 patients who underwent aortic valve replacement with a bioprosthetic valve and had echocardiographic follow-up to evaluate valve function. Moreover, explanted BPs (n = 39) were analysed by immunohistochemistry for the expression of Lp-PLA2. Results After a mean follow-up of 7·9 ±0·2 years, forty-one patients (21%) were identified as developing SVD. Patients with SVD had significantly higher plasma level of Lp-PLA2 mass (151·8 ± 9·2 ng/mL vs. 133·2 ± 3·4 ng/mL, P = 0·03) and activity (27·6 ± 0·9 nmol/min/mL vs. 25·0 ± 0·4 nmol/min/mL, P = 0·005). Multivariate analysis revealed that Lp-PLA2 activity (OR: 1·09, 95% CI: 1·01–1·18; P = 0·03) was the strongest independent predictor of SVD. Immunohistochemistry studies of explanted BP showed that 77% of explanted BPs had the expression of Lp-PLA2, which correlated with the density of macrophages (CD68), and ox-LDL levels in bioprosthetic tissues. Conclusions Increased blood plasma activity of Lp-PLA2 is associated with higher prevalence of SVD. These findings open new avenues for the identification of patients at risk for SVD and for the development of pharmacotherapy aiming at the prevention of SVD.

Eur J Clin Invest 2011; 41 (11): 1172–1179 Abstract Background Experimental and clinical studies have suggested that inhibitors of the renin angiotensin system (RAS) might be useful to slow the progression of valvular calcification in patients with aortic stenosis (AS). Objectives The aim of this study was to evaluate the relationships between the weight and tissue remodelling score of stenotic aortic valves explanted at the time of valve replacement surgery and to determine the effect of medications including angiotensin II receptor type I blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors on these variables. Methods Aortic valve and blood plasma were collected in 208 patients with AS (mean age: 69 ± 9) who underwent aortic valve replacement. Valves were weighed and the degree of valve tissue remodelling was assessed using a modified scoring system from Warren (Score: 1–4). Also, the 0-cresolphtalein complexone method was used to measure the amount of calcium within the valve cusps. Results The mean weight of aortic valves was higher in men than in women (2·83 ± 0·09 vs. 1·91 ± 0·09 g, P

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.

Background Experimental studies revealed that renin–angiotensin system (RAS) could play a crucial role in the pathophysiology of aortic stenosis (AS). The objectives of this study were to examine (i) the impact of hypertension on AS progression and clinical events and (ii) the effect of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs). Materials and methods In this observational study, we retrospectively analysed clinical and Doppler echocardiographic data prospectively collected in 338 patients with AS. Patients were separated into four groups: patients without hypertension and not treated by RAS medication (Ctrl group), patients with hypertension but not treated by RAS medication (HTN group), patients treated with ACEIs, and patients treated with ARBs. AS progression rate was assessed by the annualized increase in peak aortic jet velocity. Results Compared with Ctrl group, patients in HTN group had faster stenosis progression (P = 0·01). Patients on ARBs had slower AS progression compared with Ctrl (trend P = 0·10) and HTN (P = 0·002) groups, whereas patients on ACEIs had similar progression rate compared with Ctrl group (P = NS) but lower compared with HTN group (P = 0·02). On multivariable analysis, compared with Ctrl group, HTN group was associated with faster AS progression rate (P = 0·002), whereas ARBs with slower progression (P = 0·0008). During a mean follow-up of 6·2 ± 2·4 years, HTN (hazard ratio [HR] = 2·45; P = 0·006) and ACEI (HR = 2·30; P = 0·01) groups were associated with a significant increase in all-cause mortality compared with Ctrl group, whereas ARB group (HR: 0·89; P = 0·80) not. In multivariable analysis, HTN and ACEI groups remained associated with increased mortality. Conclusions Hypertension is associated with significantly faster stenosis progression and higher incidence of clinical events in patients with AS. ARBs but not ACEs were found to abolish the increased risk of mortality associated with hypertension.

Background Calcific aortic valve disease (CAVD) is a chronic disorder characterized by a fibrocalcific remodelling. It is suspected that lipid retention within the aortic valve may be one important mechanism participating to aortic valve remodelling. Lipoprotein lipase (LPL) is implicated in lipid metabolism and may play a role in lipid retention within the aortic valve. Methods In 57 patients, CAVD were analysed for the expression of LPL by q-PCR and immunohistochemistry. Expression of oxidized-LDL (ox-LDL) and decorin was also documented. In addition, a complete blood profile, including the size of LDL and high-density lipoprotein (HDL) particles, were performed to find associations between the blood lipid profile and expression of ox-LDL and LPL within CAVD. Results Immunohistochemistry studies revealed that LPL was expressed in stenotic aortic valves as a diffuse staining and also in dense cellular areas where macrophages were abundant. Expression of LPL co-localized with decorin and ox-LDL. In turn, valves with higher amount of ox-LDL had elevated number of LPL transcripts. In addition, we documented that the small, dense HDL phenotype was associated with an elevated amount of ox-LDL and LPL transcripts within CAVD. Furthermore, expression of LPL was associated with several indices of fibrocalcific remodelling of the aortic valve. Conclusion Expression of LPL within CAVD is related to the amount of ox-LDL, which is, in turn, associated with the small, dense HDL phenotype. Lipid retention associated with smaller HDL particles may participate in the expression of LPL, whereby a fibrocalcific remodelling of the aortic valve is promoted.

Experimental and clinical studies have suggested that inhibitors of the renin angiotensin system (RAS) might be useful to slow the progression of valvular calcification in patients with aortic stenosis (AS).The aim of this study was to evaluate the relationships between the weight and tissue remodelling score of stenotic aortic valves explanted at the time of valve replacement surgery and to determine the effect of medications including angiotensin II receptor type I blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors on these variables.Aortic valve and blood plasma were collected in 208 patients with AS (mean age: 69 ± 9) who underwent aortic valve replacement. Valves were weighed and the degree of valve tissue remodelling was assessed using a modified scoring system from Warren (Score: 1-4). Also, the 0-cresolphtalein complexone method was used to measure the amount of calcium within the valve cusps.The mean weight of aortic valves was higher in men than in women (2·83 ± 0·09 vs. 1·91 ± 0·09 g, P0·0001), in patients with bicuspid vs. tricuspid valves (3·21 ± 0·15 vs. 2·23 ± 0·07 g, P0·0001), and in patients with higher remodelling score (score 2: 1·86 ± 0·19 g; score 3: 2·08 ± 0·12 g; score 4: 3·08 ± 0·1 g, P0·0001). The remodelling score was higher in men (3·35 ± 0·05 vs. 2·94 ± 0·07, P0·0001) and in bicuspid valves (3·38 ± 0·07 vs. 3·14 ± 0·05, P = 0·006). Both valve weight (r = 0·44, P0·0001) and remodelling score (r = 0·23, P = 0·002) correlated with calcium content within the aortic valve. Patients under ARBs medication (n = 47, 22·6%) had lower aortic valve weights (2·14 ± 0·13 g vs. 2·63 ± 0·09 g, P = 0·001) and remodelling scores (3·01 ± 0·09 vs. 3·26 ± 0·04, P = 0·009). On multivariate analyses, ARBs were significantly associated with a lower aortic valve remodelling score (P = 0·04) and weight (P = 0·02).ARBs were associated with lower aortic valve weight and less pronounced tissue remodelling. Further studies are needed to determine if ARBs could be used as a therapeutic avenue in AS.