The bone marrow has emerged as a potentially important target in cardiovascular disease as it generates all leukocytes involved in atherogenesis. In the current study, we evaluated whether a change... Show moreThe bone marrow has emerged as a potentially important target in cardiovascular disease as it generates all leukocytes involved in atherogenesis. In the current study, we evaluated whether a change in bone marrow functionality underlies the increased atherosclerosis susceptibility associated with high-density lipoprotein (HDL) deficiency. We found that HDL deficiency in mice due to the genetic lack of hepatocyte-derived apolipoprotein A1 (APOA1) was associated with an increase in the Lin-Sca-1+Kit+ (LSK) bone marrow stem cell population and lymphoid-primed multipotent progenitor numbers, which translated into a higher production and systemic flux of T cell subsets. In accordance with APOA1 deficiency-associated priming of stem cells to increase T lymphocyte production, atherogenic diet-fed low-density lipoprotein receptor knockout mice transplanted with bone marrow from APOA1-knockout mice displayed marked lymphocytosis as compared to wild-type bone marrow recipients. However, atherosclerotic lesion sizes and collagen contents were similar in the two groups of bone marrow recipients. In conclusion, systemic lack of APOA1 primes bone marrow stem cells for T cell lymphopoiesis. Our data provide novel evidence for a regulatory role of HDL in bone marrow functioning in normolipidemic mice. Show less
The first part of this thesis identified patients at low risk for recurrent events or death after STEMI. It was observed that asymptomatic patients with a LVEF>45% after one year can safely be... Show moreThe first part of this thesis identified patients at low risk for recurrent events or death after STEMI. It was observed that asymptomatic patients with a LVEF>45% after one year can safely be referred to the GP with mortality rates after STEMI that come close to the rate in the general population.The second part focused to identify high-risk subpopulations to improve risk stratification. Despite current standards of care aimed at achieving targets for LDLc and other traditional risk factors, STEMI patients remain at high risk of new cardiovascular events. Valuable effort should therefore be made to further reduce residual cardiovascular risk by using additional more discriminating and more refined treatments targets like apoB and apoB/apoA1 ratio. Furthermore, novel biomarkers were identified to improve risk stratification and select high risk sub-populations. GDF-15, a more general marker for disease severity in STEMI patient demonstrated to have an additional prognostic value beyond identified risk factors and other cardiac biomarkers such as cTn and NT-proBNP.Lastly, the third part of this thesis showed that a dedicated pre-hospital triage protocol is an effective tool to select patients for admission at the cardiac emergency department. Overcrowding is a major public health problem and this thesis shows that the introduction of dedicated cardiac emergency departments can potentially reduce the caseload of the general emergency department. Show less
Even, G.; Kiss, M.; Laschet, J.; Ozvar Kozma, M.; Simon, T.; Wigren, M.; ... ; Caligiuri, G. 2018
Phosphorylcholine (PC) is an oxidation-specific epitope present on oxidized LDL and apoptotic cells, as well as the capsular polysaccharide of Streptococcus pneumoniae. PC is bound by naturally... Show morePhosphorylcholine (PC) is an oxidation-specific epitope present on oxidized LDL and apoptotic cells, as well as the capsular polysaccharide of Streptococcus pneumoniae. PC is bound by naturally occurring IgM antibodies and low levels of anti-PC IgM are a risk factor for atherosclerosis. Active immunization of atherosclerosis-prone mice with oxidized LDL, S. pneumoniae or PC conjugated to keyhole lympet hemocyanin (PC-KLH) induces high titers of anti-PC Abs and protects from atherosclerosis. However, it is unknown if existing vaccine preparations can be exploited as preventive vaccine in atherosclerosis. Our aim was to evaluate the potential atheroprotective effect of Prevenar®, a clinical-grade pneumococcal vaccine.Male apolipoprotein E-/-,mice (n=10 per group) were injected subcutaneously with 50μl Prevenar® (diluted 1:10 in PBS) at 8 and 12 weeks of age. PC-KLH and PBS were used as positive and negative controls, respectively. Mice were fed regular chow for the entire study. Serum anti-PC Abs were analyzed at baseline and 15 days after the second injection. After 20 weeks serum lipid levels were measured and atherosclerotic lesion size was quantified in the aortic root.Both vaccination with Prevenar® and PC-KLH induced high titers of anti-PC IgM and IgG Abs and resulted in reduced atherosclerosis compared to PBS injected mice (figure) despite similar serum cholesterol levels.The amount of residual PC in Prevenar® is sufficient to elicit atheroprotective anti-PC responses in apoE-/- mice. Since Prevenar® is already used in humans, its potential to prevent atherosclerosis and/or slow down atherosclerosis progression could readily be tested in clinical trials. Show less
Snip, O.S.C.; Hoekstra, M.; Zhao, Y.; Calpe-Berdiel, L.; Vulve, J.; Carles Escola-Gil, J.; ... ; Eck, M. van 2018
Various studies have shown that leukocyteATP-binding cassette transporter A1 (ABCA1) is an anti-atherogenic factor. It has long been assumed that the increased atherosclerosis susceptibility... Show moreVarious studies have shown that leukocyteATP-binding cassette transporter A1 (ABCA1) is an anti-atherogenic factor. It has long been assumed that the increased atherosclerosis susceptibility observed in leukocyte ABCA1 deficient hyperlipidemic mice was due to an accelerated foam cell formation. However, several studies have suggested that leukocyte ABCA1 may also have a beneficial effect on systemic inflammation. In this study we aim to determine the effect of leukocyte ABCA1 deficiency on atherosclerosis susceptibility in mice that are apolipoprotein A1 (apoA1) deficient.To determine the impact of leukocyte ABCA1 on atherosclerosis outcome, lethally irradiated low-density lipoprotein receptorknock-out (sKO) mice or LDLr/apoA1 double KO (dKO) mice were reconstituted with either ABCA1 KO or wild-type bone marrow. All four groups of chimeric mice were fed a Western-type diet for 6 weeks to induce atherosclerotic lesion development.Leukocyte ABCA1 deficiency in dKO mice resulted in 50-70% larger lesions in the aortic root than those observed in both sKO mice transplanted with ABCA1 KO bone marrow and dKO mice transplanted with wild-type bone marrow. Furthermore, total leukocyte numbers in blood were generally higher in mice lacking apoA1 as compared to those containing apoA1-carrying HDL particles. Two way ANOVA on the different white blood cell sub-populations suggested that the apoA1 deficiency-associated increase in total leukocyte counts was driven by an increase in the number of lymphocytes (P<0.001) and, to a minor extent, monocytes (P<0.01).This study shows that reduced systemic inflammation and increased reverse cholesterol transport together drive macrophage ABCA1-mediated protection against atherosclerosis. Show less
The ATP-binding cassette transporter A1 (ABCA1) facilitates the efflux of cholesterol and phospholipids to lipid-free apolipoprotein A1 and small dense high-density lipoproteins. Various studies... Show moreThe ATP-binding cassette transporter A1 (ABCA1) facilitates the efflux of cholesterol and phospholipids to lipid-free apolipoprotein A1 and small dense high-density lipoproteins. Various studies have shown that leukocyte ABCA1 is an anti-atherogenic factor. Dietary cholesterol lowering stabilizes atherosclerotic lesions, however the role of ABCA1 in this process is unknown. Therefore, this study aims to investigate the effect of leukocyte ABCA1 on diet-induced atherosclerotic lesions after withdrawal of the atherogenic diet. Leukocyte ABCA1 was studied by transplanting bone marrow cells from donor mice that were either knock-out (ABCA1-/-) or wild-type for ABCA1 or that overexpressed ABCA1 (ABCA1Tg) into low-density lipoprotein receptor knock-out (LDLr-/-) mice. All three groups of chimeric mice were fed a Western-type diet (WTD: 0.25%cholesterol, 15Êcao butter) for 6 weeks to induce atherosclerotic lesion development. After this period, a baseline group was sacrificed (ABCA1-/- >LDLr-/- n=12; wild-type >LDLr-/- n=14; ABCA1Tg >LDLr-/- n=9) for lesion assessment. The remainder of chimeric mice was switched to a chow diet (low fat, no added cholesterol) for 3 weeks to lower plasma cholesterol levels (ABCA1-/- >LDLr-/- n=14; wild-type >LDLr-/- n=14; ABCA1Tg >LDLr-/- n=12).Withdrawal of the atherogenic diet normalized plasma cholesterol levels in all three groups. As a result, lesion development was stabilized in both the wild-type >LDLr-/- and ABCA1Tg >LDLr-/- mice, however not in the ABCA1-/- >LDLr-/- mice, which displayed a 1.5-fold increase (p<0.01) in atherosclerotic lesion size. Leukocyte ABCA1 is required to halt atherosclerotic lesion progression after dietary cholesterol lowering. Overexpression of ABCA1 did not result in any additional beneficial effects. Show less
