Dendritic Cells and Their Role in Cardiovascular Diseases: A View on Human Studies

Table 2

Clinical studies on the role of dendritic cells in cardiovascular diseases.

Study	Type of cardiovascular disease	Study population	Major findings
	Atherosclerosis
Cherian et al., 2000 [107]	Atherosclerosis	Patients with aortocoronary bypass ()	(i) DCs present in stenotic aortocoronary saphenous vein bypass grafts
Cherian et al., 2001 [35]	Atherosclerosis	Patients with aortocoronary bypass () and healthy controls ()	(i) CD1a^+/S100^+ DCs present in stenotic saphenous vein bypass grafts but not in normal saphenous veins
Ozmen et al., 2001 [38]	Atherosclerosis	Patients with stenotic aortocoronary saphenous vein grafts () and control carotid arteries ()	(i) CD40^+ cells detected in stenotic grafts and carotid plaques; (ii) CD40^+/S100^+ cells clustered within the intima, the media, and the adventitia
Yilmaz et al., 2006 [29]	Atherosclerosis	Patients with carotid endarterectomy ()	(i) Lower DC numbers in initial lesions than in advanced plaques; (ii) DC number higher in stable than in vulnerable plaques; (iii) 70% of DCs in advanced plaques with mature phenotype indicate functional activity of DCs
Van Vré et al., 2006 [30]	Atherosclerosis	CAD patients () and controls ()	(i) Lower numbers and percentage of pDCs and mDCs in patients with CAD than in controls
Niessner et al., 2006 and 2007 [24, 25]	Atherosclerosis	Patients with carotid endarterectomy ()	(i) 53% of carotid samples with CD123^+ pDCs and with CD11c^+ DC-Sign^+ fascin^+ mDCs; (ii) DCs localized in the shoulder region and at the base of the plaque; (iii) pDCs are localized in the shoulder region and produce IFN-α; (iv) IFN-α transcript concentrations correlated with plaque instability; (v) mDC : pDC ratio of 2.7 in the plaques
Erbel et al., 2007 [28]	Atherosclerosis	Patients with carotid artery plaques ()	(i) Plaques from patients with ischemic complications with elevated levels of CD83, CCL19, and CCL21; (ii) Presence of CD83^+ DCs in the shoulder region of unstable plaques
Yilmaz et al., 2009 [31]	Atherosclerosis	CAD patients ()	(i) Reduction of pDCs, mDCs, and DCs in advanced CAD patients; (ii) Reduction of pDCs, mDCs, and DCs in patients with required percutaneous coronary intervention or coronary artery bypass grafting
Van Vré et al., 2010 [32]	Atherosclerosis	CAD patients () and controls ()	(i) Decrease of total blood DCs, mDCs, and pDCs in CAD patients compared to controls; (ii) Inverse association of IL-6 and hs-CRP with mDCs
Van Vré et al., 2011 [27]	Atherosclerosis	Patients with carotid endarterectomy () or autopsy ()	(i) Accumulation of BDCA-1 and BDCA-2 near microvessels; (ii) S100^+ and fascin^+ DCs increased from intimal thickening via pathological thickening, fibrous cap atheroma to complicated plaques
Van Brussel et al., 2011 [33]	Atherosclerosis	CAD patients () and controls ()	(i) Circulating mDCs and pDCs declined in CAD patients; (ii) Frequencies of CD86^+ and CCR7^+ mDCs, but not pDCs, declined in CAD patients; (iii) Plasma Flt3L positively correlated with blood DC counts
Abbas et al., 2015 [34]	Atherosclerosis	Patients with carotid atherosclerosis () and healthy controls ()	(i) pDCs with increased mRNA levels of IL-23 and IL-23R in atherosclerosis
Rohm et al., 2015 [26]	Atherosclerosis	Patients with carotid endarterectomy ()	(i) Higher numbers of fascin^+, S100^+, or CD83^+ mDCs are unstable compared with stable plaques; (ii) No differences between stable and unstable plaques for pDCs
	Hypertension
Kirabo et al., 2014 [47]	Hypertension	Hypertensive patients () and normotensive controls ()	(i) Elevated levels of isoketal-modified proteins in circulating monocytes and DCs in patients with hypertension; (ii) Hypertension activates DCs, in large part by promoting the formation of isoketals
	Heart failure associated diseases
Yokoyama et al., 2000 [5]	Myocarditis	Acute myocarditis patients () and patients that died from noncardiac disease ()	(i) Cardiac DCs increase in the acute phase of myocarditis; (ii) Cardiac DCs with long, slender dendritic processes and positive for HLA-DR, but negative for CD68
Athanassopoulos et al., 2004 [72]	HF, transplantation	HF/HTx patients () and healthy controls ()	(i) Increase of blood DCs and mDCs in CHF patients; (ii) Increase of mature DC subsets compared to controls
Yilmaz et al., 2006 [29]	MI	Angina pectoris () and MI () patients	(i) Reduced circulating mDCs in patients with angina pectoris and acute myocardial infarction compared to controls; (ii) mDCs inversely correlated with C-reactive protein or IL-6; (iii) More mDC precursors in vulnerable carotid plaques than in stable ones
Athanassopoulos et al., 2009 [73]	HF	NYHA II patients (), NYHA III/IV patients (), and healthy controls ()	(i) NYHA III/IV patients with comparable percentage of circulating DC subsets; (ii) Within NYHA III/IV patients: total DC levels in patients with nonischemic DCM higher than in patients with CAD, HF, and HCM; (iii) Mature mDCs, but not pDCs, in DCM patients compared to patients with CAD, HCM, or other cardiac pathophysiologies
Sugi et al., 2011 [74]	HF	Patients with decompensated HF ()	(i) Circulating DC subsets lower in decompensated HF patients compared to controls; (ii) HF treatment restored reduction and activation of circulating mDCs and pDCs; (iii) Numbers of circulating DCs correlated with decreases of BNP and troponin-T; (iv) Poor recovery of circulating DC numbers predictive of recurrence of decompensated HF
Kofler et al., 2011 [60]	MI	STEMI patients (), NSTEMI patients (), stable CAD patients (), and controls ()	(i) Downregulation of immature (CD1a^+) DCs in STEMI, NSTEMI, and CAD patients; (ii) Upregulation of mature (CD86^+) DCs in CAD patients
Fukui et al., 2012 [64]	MI	AMI patients (), SAP patients (), and controls ()	(i) Circulating mDCs and pDCs lower in AMI group than in SAP or control group; (ii) Numbers of circulating mDCs and pDCs returned to control levels 7 days after AMI and were stable until the next 3 months; (iii) % CD40^+ and CD83^+ mDCs higher in AMI patients than in SAP group or controls; (iv) % CD40^+ and CD83^+ pDCs were similar between the three groups
Carvalheiro et al., 2012 [63]	MI	AMI patients () and healthy controls ()	(i) Lower frequency of circulating mDCs
Kretzschmar et al., 2012 [59]	MI	STEMI patients (), NSTEMI patients (), and controls ()	(i) Decrease of circulating mDCPs, pDCPs, and tDCPs in AMI patients with pronounced reduction in STEMI patients; (ii) Higher DC number in infarcted myocardium than in control
Wen et al., 2013 [61]	MI	AMI patients (), SAP patients (), UAP patients (), and controls ()	(i) % circulating mDC precursors reduced in AMI and UAP patients compared to SAP patients and controls; (ii) % circulating pDC precursors not different between the groups; (iii) % circulating mDC precursors negatively correlated with severity and extent of coronary artery lesions
Pistulli et al., 2013 [71]	DCM	DCM patients ()	(i) Myocardial DCs of all subtypes and maturation stages decreased in DCM compared to controls; (ii) , apoptosis, and CCR7 overexpressed in DCM; (iii) mDCs reduced in virus-positive endomyocardial biopsies; (iv) mDC number correlated with positive change in EF at follow-up
Nagai et al., 2014 [58]	MI	STEMI patients with present () or absent () cardiac rupture	(i) CD209^+ DC and CD11c^+ DC infiltration increased in the rupture group; (ii) Positive correlation between the number of infiltrating CD209^+ DCs and CD11c^+ DCs and the extent of reparative fibrosis
	Transplantation
Athanassopoulos et al., 2004 [72]	Transplantation, HF	HTx patients () and healthy controls ()	(i) Decrease of total DCs, mDCs, and pDCs one week after HTx; (ii) % of circulating mDCs higher after HTx compared to CHF patients and controls; (iii) Maturation status of DC subsets comparable to controls (but not the CCR7^+ pDCs)
Athanassopoulos et al., 2005 [76]	Transplantation	HTx patients ()	(i) Reduced DC numbers up to week 38 after HTx; (ii) Negative association of mDCs with rejection grade; (iii) mDCs and their mature states decreased during AR episodes and are lower in rejectors than in nonrejectors
Athanassopoulos et al., 2005 [77]	Transplantation	HTx patients ( venous blood analyses; EMB analyses)	(i) Total DC numbers decreased at the first week after HTx and remained lower than the pre-HTx condition until week 38; (ii) Negative association between mDCs, but not pDCs, and the diagnosed ISHLT rejection grade for the follow-up period
Barten et al., 2006 [95]	Transplantation	HTx patients () and healthy controls ()	(i) Higher % of mDCs in HTx patients compared to controls; (ii) % of pDCs were different in patients with conversion from calcineurin inhibitors to everolimus compared to healthy controls; (iii) Mature mDCs did not differ between HTx patients and controls
John et al., 2014 [94]	Transplantation	HTx patients ()	(i) mDCs higher and pDCs lower in cyclosporine A-treated patients than in tacrolimus-treated patients; (ii) pDC/mDC ratio higher at day 0, month 3, and month 6 in tacrolimus-treated patients than in cyclosporine A-treated patients
Dieterlen et al., 2015 [75]	Transplantation	HTx patients ()	(i) Increase of pDCs, but not for mDCs, in the first year after HTx; (ii) No significant changes of the pDC/mDC ratio in the first year after HTx

AMI: acute myocardial infarction; AR: acute rejection; BDCA-1/BDCA-2/BDCA-3/BDCA-4: blood dendritic cell antigen-1/antigen-2/antigen-3/antigen-4; BNP: B-type natriuretic peptide; CAD: coronary artery disease; CD1a/CD11c/CD40/CD68/CD83/CD123/CD209: Cluster of Differentiation 1a/11c/40/68/83/123/209; CHF: chronic heart failure; CCL19/CCL21: chemokine ligands 19/21; DCM: dilative cardiomyopathy; DC/DCs: dendritic cell/dendritic cells; EF: ejection fraction; EMB: endomyocardial biopsy; Flt3L: FMS-like tyrosine kinase 3 ligand; HCM: hypertrophic cardiomyopathy; HF: heart failure; HLA-DR: human leukocyte antigen DR; hs-CRP: high sensitivity C-reactive protein; HTx: heart transplantation; IFN-α: interferon-α; IL-6/IL-23/IL-23R: interleukin 6/interleukin 23/interleukin 23-receptor; ISHLT: International Society of Heart and Lung Transplantation; mDCs: myeloid dendritic cells; mDCPs: myeloid dendritic cell precursors; MI: myocardial infarction; NSTEMI: non-ST-elevation myocardial infarction; NYHA II/III/IV: New York Heart Association grade II/III/IV; pDCs: plasmacytoid dendritic cells; pDCPs: plasmacytoid dendritic cell precursors; SAP: stable angina pectoris; STEMI: ST-elevation myocardial infarction; S100: calcium-binding protein with low molecular weight, marker for DCs; tDCPs: total dendritic cell precursors; : regulatory T cells; UAP: unstable angina pectoris.