Warfarin, but not rivaroxaban, promotes the calcification of the aortic valve in ApoE-/- mice.

SummaryIntroductionVitamin K antagonists, such as warfarin, are known to promote arterial calcification through blockade of gamma‐carboxylation of Matrix‐Gla‐Protein. It is currently unknown whether other oral anticoagulants such as direct inhibitors of Factor Xa can have protective effects on the progression of aortic valve calcification.AimsTo compare the effect of warfarin and rivaroxaban on the progression of aortic valve calcification in atherosclerotic mice.Results42 ApoE−/− mice fed with Western‐type Diet (WTD) were randomized to treatment with warfarin (n = 14), rivaroxaban (n = 14) or control (n = 14) for 8 weeks. Histological analyses were performed to quantify the calcification of aortic valve leaflets and the development of atherosclerosis. The analyses showed a significant increase in valve calcification in mice treated with warfarin as compared to WTD alone (P = .025) or rivaroxaban (P = .005), whereas no significant differences were found between rivaroxaban and WTD (P = .35). Quantification of atherosclerosis and intimal calcification was performed on the innominate artery of the mice and no differences were found between the 3 treatments as far as atherogenesis and calcium deposition is concerned. In vitro experiments performed using bovine interstitial valve cells (VIC) showed that treatment with rivaroxaban did not prevent the osteogenic conversion of the cells but reduce the over‐expression of COX‐2 induced by inflammatory mediators.ConclusionWe showed that warfarin, but not rivaroxaban, could induce calcific valve degeneration in a mouse model of atherosclerosis. Both the treatments did not significantly affect the progression of atherosclerosis. Overall, these data suggest a safer profile of rivaroxaban on the risk of cardiovascular disease progression

Lipoprotein-associated phospholipase A2 Mass and Activity and PLA2G7 gene polymorphisms as Markers for Cardiovascular Risk Stratification In High Risk Coronary Artery Disease Patients.

Objective. We investigated if Lp-PLA2 titer predicts cardiovascular (CV) events in a prospective cohort study and we sought to investigate if LpPLA2 mass and activity bear any prognostic information in high-risk coronary artery disease patients We also analyzed the association of three polymorphisms ( Arg92His, Ile198Thr, Ala379Val) and related haplotypes at the PLA2G7 locus with angiographic coronary artery disease (CAD), plasma LpPLA2 mass, LpPLA2 activity, and long-term survival. Background Lipoprotein-associated phospholipase A2 (Lp-PLA2), which is secreted by different cell types (e.g. monocytes, macrophages and T lymphocytes) and in plasma is associated with low-density lipoprotein (LDL) place a controversial function in the atherosclerotic process : the degradation of pro-inflammatory phospholipids in LDL would suggest anti-atherogenic properties, while the production of pro-inflammatory species (lysoPC and NEFA) would support a pro-atherogenic role Methods. The titer of Lp-PLA2 was measured in 749 randomly selected Caucasian patients of the GENICA Study, who underwent coronary angiography and were followed-up for incident CV events. Patients were classified including the last and the first three quartiles, respectively by Lp-pLA2 and after we determined the best cut-off value in predicting CV deaths and MACE with ROC curves and into a high and a low titer group. Finally we analyzed the association of three polymorphisms (Arg92His, Ile198Thr, and Ala379Val) and related haplotypes at the PLA2G7 locus with angiographic coronary artery disease (CAD), plasma LpPLA2 activity and mass and long-term survival in the same cohort of high risk patients Results. Complete follow-up data were obtained in 78% of the patients with a median follow-up of 7.2 years. Patients in the high Lp-PLA2 activity group again showed a worse CV death-free survival includes AMI, ACS, stroke, death from other cardiovascular causes (17.64% vs. 8.4%, respectively, p=0.1) and a significantly worse CV events-free survival (33.3% vs. 20.5%, respectively, p=0.023) than those in the low Lp-PLA2 activity group at the Kaplan-Meyer plot. The 92His and 198Thr polymorphisms those are associated with a modest change in plasma LpPLA2 activity. However, these alleles are neither associated with CAD nor with long-term survival. Conclusions The analysis performed to correct for the imbalance of variables distribution between the patients with low and high Lp-PLA2 with the propensity score matching has somewhat reduced the role of Lp-PLA2 mass for the prediction of CV events and confirm the role of Lp-PLA2 activity in CV events-free survival and a borderline significance for AMI and ACS events. The genetic approach has allowed us in an important way of there are at least two coding variants 92His and 198Thr that are associated with a modest change in plasma LpPLA2 activity. However, these alleles are neither associated with CAD nor with long-term survival.Premesse: La lipoproteina associata alla fosfolipasi A2 (Lp-PLA2), che è secreta da diversi tipi di cellule (monociti, macrofagi e linfociti T) e che nel plasma è associato alle lipoproteine a bassa densità (LDL), mantiene ancora una funzione controversa nel processo eziopatogenico dell’aterosclerosi. Se da un lato l’induzione da lei mediata della degradazione di fosfolipidi infiammatori in LDL suggerisce proprietà anti-aterogeniche, la produzione di specie pro-infiammatorie (lysoPC e NEFA) sosterrebbe un ruolo pro-aterogenico. Obiettivo: Ho cercato di studiare se l’enzima Lp-PLA2 è capace di predire gli eventi cardiovascolari (CV) in uno studio prospettico di coorte andando a indagare se i valori di massa e di attività corrispondevano con le stime prognostiche nei pazienti ad alto rischio coronarico Ho anche analizzato l'associazione di tre polimorfismi (Arg92His, Ile198Thr, Ala379Val) e degli aplotipi correlati al locus PLA2G7 negli stessi pazienti, e rapportato i valori plasmatici di massa e attività enzimatica di LpPLA2 per valutare se la presenza o meno di queste variazioni genotipiche possano essere a loro volta predittive nella sopravvivenza a lungo termine. Metodi: Valori di massa e attività di Lp-PLA2 sono stati misurati in 749 pazienti dello studio GENICA (Genetic and ENvironmental factors InCoronary Atherosclerosis ), sottoposti ad angiografia coronarica e seguiti in lungo follow-up monitorandone l’incidenza degli eventi cardiovascolari. I pazienti sono stati classificati in base al titolo di Lp-PLA2, ed è stato determinato il miglior cut-off utile nel predire le mortalità CV e gli eventi (MACE). Infine ho analizzato l'associazione di tre polimorfismi (Arg92His, Ile198Thr e Ala379Val) e gli aplotipi correlati al locus PLA2G7 con gli stessi livelli di attività e di massa di LpPLA2 ed è stata valutata la sopravvivenza a lungo termine nella stessa coorte di pazienti ad alto rischio. Risultati: I dati completi di follow-up sono stati ottenuti nel 78% dei pazienti con un follow-up mediano di 7,2 anni. I pazienti con alta Lp-PLA2 dimostravano una peggior sopravvivenza per end-point morte (17,64% vs 8,4%, rispettivamente, p = 0,1) e inoltre una maggiore incidenza di MACE (33,3% vs 20,5%, rispettivamente, p = 0,023) rispetto a quelli con bassa attività di Lp-PLA2. I polimorfismi 92His e 198Thr si sono dimostrati associati ad un modesto cambiamento nell’attività plasmatica di LpPLA2. Tuttavia, questi alleli non sono associati a significative differenze nella sopravvivenza a lungo termine. Conclusioni: L'analisi effettuata per correggere lo squilibrio della distribuzione delle variabili tra i pazienti con bassa e alta Lp-PLA2 tramite il Propensity Score ha, in qualche modo, ridotto il ruolo di Lp-PLA2 massa per la previsione di eventi cardiovascolari e ma confermando il ruolo dell’attività enzimatica di Lp-PLA2 come variabile indipendente predittiva per MACE. L'approccio genetico invece mi ha permesso di considerare che almeno due varianti polimorfiche come 92His e 198Thr sono associate a un cambiamento modesto nell’attività plasmatica di Lp-PLA2. Tuttavia, questi alleli non sono associati alla prognosi di malattia coronarica né alle sopravvivenze a lungo termine

Stepwise linear regression analysis of determinants of Lp-PLA2 mass and activity.

<p>Significant predictors of Lp-PLA2 mass were creatinine, HDL- and LDL. Significant predictors of Lp-PLA2 activity were gender, HDL- and LDL-cholesterol, and homocysteinemia.</p

Cardiovascular events by Lp-PLA2 mass.

<p>The bar graphs show cardiovascular death and events rate by quartiles of Lp-PLA2 mass (the absolute number of events is shown above each column). Cardiovascular deaths (p = 0.020) were significantly different across Lp-PLA2 mass quartiles. AMI: acute myocardial infarction.</p

Cardiovascular events by Lp-PLA2 activity.

<p>The bar graphs show cardiovascular death and events rate by quartiles of Lp-PLA2 activity (the absolute number of events is shown above each column). Cardiovascular deaths (p = 0.012), events (p = 0.016), acute myocardial infarction (AMI) (p = 0.019) were significantly different across Lp-PLA2 activity quartiles.</p

Demographic and clinical characteristics of the subjects classified by Lp-PLA2 activity quartiles.

<p>Results are expressed as mean ± SD. BMI, body mass index; K⁺, potassium; Na⁺, sodium; BP, Blood Pressure; HDL, high density lipoprotein; LDL, low density lipoprotein; EF, ejection fraction; CAD, coronary artery disease.</p

RANKL Expression Is Increased in Circulating Mononuclear Cells of Patients with Calcific Aortic Stenosis

We aimed to investigate whether the expression of the OPG/RANK/RANKL triad in peripheral blood mononuclear cells (PBMC) and circulating levels of markers of ectopic mineralization (OPG, FGF-23, PPi) are modified in patients with calcific aortic valve disease (CAVD). We found that patients affected by CAVD (n\u2009=\u200950) had significantly higher circulating levels of OPG as compared to control individuals (p\u2009=\u20090.003). No differences between the two groups were found in FGF-23 and PPi levels. RANKL expression was higher in the PBMC from CAVD patients (p\u2009=\u20090.018) and was directly correlated with the amount of valve calcification (p\u2009=\u20090.032). In vitro studies showed that treatment of valve interstitial cells (VIC) with RANKL plus phosphate was followed by increase in matrix mineralization (p\u2009=\u20090.001). In conclusion, RANKL expression is increased in PBMC of patients with CAVD, is directly correlated with the degree of valve calcification, and promotes pro-calcific differentiation of VIC

Demographic and clinical characteristics of the subjects classified by Lp-PLA2 mass quartiles.

<p>Results are expressed as mean ± SD. BMI, body mass index; K⁺, potassium; Na⁺, sodium; BP, Blood Pressure; HDL, high density lipoprotein; LDL, low density lipoprotein; EF, ejection fraction; CAD, coronary artery disease.</p