Dendritic Cells in Human Atherosclerosis: From Circulation to Atherosclerotic Plaques

Background. Atherosclerosis is a chronic inflammatory disease with atherosclerotic plaques containing inflammatory infiltrates predominantly consisting of monocytes/macrophages and activated T cells. More recent is the implication of dendritic cells (DCs) in the disease. Since DCs were demonstrated in human arteries in 1995, numerous studies in humans suggest a role for these professional antigen-presenting cells in atherosclerosis. Aim. This paper focuses on the observations made in blood and arteries of patients with atherosclerosis. In principal, flow cytometric analyses show that circulating myeloid (m) and plasmacytoid (p) DCs are diminished in coronary artery disease, while immunohistochemical studies describe increased intimal DC counts with evolving plaque stages. Moreover, mDCs and pDCs appear to behave differently in atherosclerosis. Yet, the origin of plaque DCs and their relationship with blood DCs are unknown. Therefore, several explanations for the observed changes are postulated. In addition, the technical challenges and discrepancies in the research field are discussed. Future. Future studies in humans, in combination with experimental animal studies will unravel mechanisms leading to altered blood and plaque DCs in atherosclerosis. As DCs are crucial for inducing but also dampening immune responses, understanding their life cycle, trafficking and function in atherosclerosis will determine potential use of DCs in antiatherogenic therapies

Targeting Endothelial Function to Treat Heart Failure with Preserved Ejection Fraction: The Promise of Exercise Training

Although the burden of heart failure with preserved ejection fraction (HFpEF) is increasing, there is no therapy available that improves prognosis. Clinical trials using beta blockers and angiotensin converting enzyme inhibitors, cardiac-targeting drugs that reduce mortality in heart failure with reduced ejection fraction (HFrEF), have had disappointing results in HFpEF patients. A new “whole-systems” approach has been proposed for designing future HFpEF therapies, moving focus from the cardiomyocyte to the endothelium. Indeed, dysfunction of endothelial cells throughout the entire cardiovascular system is suggested as a central mechanism in HFpEF pathophysiology. The objective of this review is to provide an overview of current knowledge regarding endothelial dysfunction in HFpEF. We discuss the molecular and cellular mechanisms leading to endothelial dysfunction and the extent, presence, and prognostic importance of clinical endothelial dysfunction in different vascular beds. We also consider implications towards exercise training, a promising therapy targeting system-wide endothelial dysfunction in HFpEF

Late gadolinium enhancement CMR in primary mitral regurgitation.

AIMS: The appropriate timing for surgery in severe asymptomatic primary mitral regurgitation (MR) remains controversial. It has been shown that late gadolinium enhancement on cardiovascular magnetic resonance (LGE CMR), which may identify myocardial fibrosis, is associated with a worse outcome in various cardiomyopathies. We sought to investigate the prevalence and significance of delayed enhancement in primary MR. METHODS: We prospectively included 41 patients with at least moderate primary MR and without overt signs of left ventricular (LV) dysfunction. Patients with evidence of coronary artery disease, arrhythmias or significant concomitant valvular disease were excluded. All patients were scheduled for transthoracic echocardiography and LGE CMR. RESULTS: A total of 39 patients had interpretable LGE CMR images. Among them, 12 (31%) had late contrast uptake of the LV wall. LGE CMR showed an infarct pattern in three patients, a pattern of mid-wall fibrosis in seven patients and two patients had a combined pattern. Patients with delayed enhancement on CMR had significant higher LV diameters (LV end-systolic diameter 39 +/- 4 vs. 34 +/- 5 mm, P = 0.002; LV end-diastolic diameter 57 +/- 5 vs. 50 +/- 5 mm, P = 0.001). There was a trend towards a higher indexed left atrial volume (55 +/- 21 vs. 44 +/- 13 mL/m(2), P = 0.06). By contrast, there was no significant association between myocardial contrast uptake and age, LV ejection fraction and MR severity. CONCLUSION: Left ventricular remodelling seems to be associated with the presence of delayed enhancement on CMR in primary MR. Further data are needed to determine whether LGE CMR can predict a less favourable outcome or could improve risk stratification in asymptomatic primary MR

Impact of Lifestyle Intervention on HDL-Induced eNOS Activation and Cholesterol Efflux Capacity in Obese Adolescent

Background. Endothelial dysfunction occurs in obese children and adolescent and is regarded as a key step in the development of atherosclerosis. Important components for the development of endothelial dysfunction are reduced activity of endothelial nitric oxide synthase (eNOS) and an increase in cholesterol deposition in the vessel wall, due to reduced reverse cholesterol transport (RCT) activity. High density lipoprotein (HDL) exhibits antiatherosclerotic properties including modulation of eNOS activity and cholesterol efflux capacity. Lifestyle intervention programs can modify endothelial dysfunction in obese adolescents, but their impact on HDL-mediated eNOS activation and RCT is unknown so far. Methods. Obese adolescents (15±1 years, BMI > 35 kg/m2) where randomized either to an intervention group (IG, n=8; restricted diet and exercise) or to a usual care group (UC, n=8). At the beginning and after 10 months of treatment HDL-mediated eNOS phosphorylation and cholesterol efflux capacity were evaluated. Results. Ten months of treatment resulted in a substantial weight loss (−31%), an improvement of endothelial function, and an increase in HDL-mediated eNOS-Ser1177 phosphorylation and RCT. A correlation between change in eNOS-Ser1177 phosphorylation or RCT and change in endothelial function was noted. Conclusion. A structured lifestyle intervention program improves antiatherosclerotic HDL functions, thereby positively influencing endothelial function

Circulating CD34 + /KDR + endothelial progenitor cells are reduced in chronic heart failure patients as a function of Type D personality

A B S T R A C T The aim of the present study was to assess whether EPC (endothelial progenitor cell) number/function might be an explanatory factor for the observed relationship between Type D personality (a joint tendency towards negative affectivity and social inhibition) and poor cardiovascular prognosis. We also assessed whether the effect of a single exercise bout on EPC number/function was affected by Type D personality. A total of 35 sedentary men with CHF (chronic heart failure; left ventricular ejection fraction 45 %) underwent CPET (cardiopulmonary exercise testing) and personality assessment with the 14-item Type D scale. CD34 + /KDR (kinase insert domain-containing receptor) + cells were quantified by flow cytometry before and immediately after CPET. Migration of early EPC towards VEGF (vascular endothelial growth factor) and SDF-1α (stromal-cell-derived factor-1α) was investigated. Type D (n = 10) and non-Type D (n = 25) patients were comparable with regards to demographics, disease severity and Framingham risk factor score. Circulating EPC numbers were reduced by 54 % in Type D compared with non-Type D patients (0.084 + − 0.055 and 0.183 + − 0.029 % of lymphocytes respectively; P = 0.006). Exercise led to a 60 % increase in EPC in Type D patients, whereas the EPC number remained unchanged in the non-Type D group (P = 0.049). Baseline migratory capacity was related to disease severity, but was not different between Type D and non-Type D patients. Exercise induced a highly significant enhancement of migratory capacity in both groups. In conclusion, reduced EPC numbers might explain the impaired cardiovascular outcome in Type D patients. The larger increase in circulating EPCs observed in these patients suggests that acute exercise elicits a more pronounced stimulus for endothelial repair

Endothelial Microparticles (EMP) for the Assessment of Endothelial Function: An In Vitro and In Vivo Study on Possible Interference of Plasma Lipids

BACKGROUND: Circulating endothelial microparticles (EMP) reflect the condition of the endothelium and are of increasing interest in cardiovascular and inflammatory diseases. Recently, increased numbers of EMP following oral fat intake, possibly due to acute endothelial injury, have been reported. On the other hand, the direct interference of lipids with the detection of EMP has been suggested. This study aimed to investigate the effect of lipid-rich solutions, commonly administered in clinical practice, on the detection, both in vitro and in vivo, of EMP. METHODS: For the in vitro assessment, several lipid-rich solutions were added to whole blood of healthy subjects (n = 8) and patients with coronary heart disease (n = 5). EMP (CD31+/CD42b-) were detected in platelet poor plasma by flow cytometry. For the in vivo study, healthy volunteers were evaluated on 3 different study-days: baseline evaluation, following lipid infusion and after a NaCl infusion. EMP quantification, lipid measurements and peripheral arterial tonometry were performed on each day. RESULTS: Both in vitro addition and in vivo administration of lipids significantly decreased EMP (from 198.6 to 53.0 and from 272.6 to 90.6/µl PPP, respectively, p = 0.001 and p = 0.012). The EMP number correlated inversely with the concentration of triglycerides, both in vitro and in vivo (r = -0.707 and -0.589, p<0.001 and p = 0.021, respectively). The validity of EMP as a marker of endothelial function is supported by their inverse relationship with the reactive hyperemia index (r = -0.758, p = 0.011). This inverse relation was confounded by the intravenous administration of lipids. CONCLUSION: The confounding effect of high circulating levels of lipids, commonly found in patients that receive intravenous lipid-based solutions, should be taken into account when flow cytometry is used to quantify EMP