A case report: 'happy heart' syndrome in a patient treated with atomoxetine for attention deficit hyperactivity disorder.

BACKGROUND: Takotsubo syndrome (TS) is an acute cardiac disease entity with a clinical presentation resembling that of an acute coronary syndrome. Numerous physical stress factors including pheochromocytoma, epinephrine, and norepinephrine administration, and even physiological exercise have been reported to induce TS. Takotsubo syndrome induced by medications causing elevation of plasma norepinephrine as serotonin-norepinephrine reuptake inhibitor or selective norepinephrine reuptake inhibitor (atomoxetine) has been reported. CASE SUMMARY: We report on the case of a 49-year-old woman who was on atomoxetine treatment for attention deficit hyperactivity disorder, developed TS in association with sexual intercourse. DISCUSSION: The TS pattern in this patient was the type of mid-apical ballooning with apical tip-sparing at presentation. Two days later, TS evolved to mid-ventricular pattern. Takotsubo syndrome resolved completely 1 month after the index presentation.

Blood dendritic cell levels and phenotypic characteristics in relation to etiology of end-stage heart failure: implications for dilated cardiomyopathy.

BACKGROUND: Dysregulation of dendritic cell (DC) mediated immune responses towards auto-antigens, is considered an important feature in the maintenance of experimentally induced heart failure (HF). In order to evaluate the role of blood DCs in cardiomyopathies of different origins, we examined myeloid (mDC) and plasmacytoid (pDC) subset levels and maturation characteristics, according to HF severity and etiology in humans. METHODS: Absolute numbers of mDCs and pDCs in 12 New York Heart Association (NYHA) class-II, 28 NYHA class III-IV HF patients and 18 healthy controls, were studied by 4-colour whole blood flow cytometry. RESULTS: End-stage (NYHA III-IV) HF patients had comparable circulating DC subset levels to NYHA-II patients and controls. However, within the NYHA III-IV group total DC levels in patients with non-ischemic dilated cardiomyopathy (DCM) were higher (P<0.001) than in patients with coronary artery disease (CAD), hypertrophic cardiomyopathy (HCM) or other HF etiology. This was due to a significant increase of primarily mDCs (P<0.0001) and to a lesser extent of pDCs (P<0.05) in idiopathic DCM patients, independent of systolic or diastolic cardiac dysfunction. Maturation marker CD83 and lymphoid homing chemokine receptor CCR7 surface expression was enhanced only on mDCs, but not pDCs from DCM patients (P<0.05), compared to patients with CAD, HCM or other underlying cardiac pathophysiology. CONCLUSIONS: Total blood DC levels in end-stage HF are elevated in patients with DCM. Whole blood DC characterisation may lead to new insights into the pathophysiology of idiopathic DCM in humans.

Peripheral blood manipulation significantly affects the result of dendritic cell monitoring.

It has been postulated that the plasmacytoid/myeloid dendritic cell ratio (pDC/mDC) reflects immune reactivity, and can therefore be used to monitor transplant recipients. We investigated the influence of Ficoll-Paque separation and PBMC cryopreservation on the pDC/mDC ratio and the expression of maturation markers, e.g. chemokine receptors (CKRs) CCR7, CXCR4, and CCR5, in comparison to fresh blood cells. Fractions of pDCs and mDCs, and CKR expression were measured by flow cytometry in fresh blood, in Ficoll-isolated PBMCs and in cryopreserved PBMCs from healthy individuals and kidney transplant recipients. Ficoll-isolation of PBMCs resulted in higher pDC/mDC ratios in both groups compared to fresh blood cells resulting from a relatively large increase in pDCs compared to mDCs. The pDC/mDC ratio increased further after cryopreservation of PBMCs from kidney transplant recipients. Ficoll-isolation and cryopreservation of PBMCs affected the proportion of mDCs and pDCs positive for CKRs, and their expression levels resulting in a more mature phenotype. In conclusion, the pDC/mDC ratio and pDC or mDC maturation status based on CKR expression, is dependent on manipulation of PBMCs. Therefore, fresh blood is preferable for monitoring purposes in transplant patients, as only these cells reflect the in vivo immune-status of patients accurately.

Altered chemokine receptor profile on circulating leukocytes in human heart failure.

Chemokines and their receptors have been implicated in the pathogenesis of different forms of heart failure (HF). We examined CC- and CXC-chemokine receptor expression in fresh peripheral blood leukocyte populations from 24 end-stage HF patients consisting of coronary artery disease (CAD; n = 6) and hypertrophic cardiomyopathy (HCM; n = 7) or idiopathic dilated cardiomyopathy (IDCM; n = 8) or valvular disease (VD; n = 3) and compared the data with 18 healthy controls. Levels of CCR1, 2, 3, 4, 5, and 7, and CXCR1, 2, 3, and 4 were measured by flow cytometry, and the expression profile was assessed as molecules of equivalent soluble fluorochrome units as well as frequency (percentage) of CD3+, CD4+, and CD8+ T cells and monocytes or granulocytes. Frequency of CD3+ CXCR4+, CD3+ CXCR1+, and CD3+ CXCR3+ cells was significantly increased in HF patients, whereas only CCR7 and CXCR4 expression levels were elevated on CD3+ cells. Both CD4+ CXCR4+ and CD8+ CXCR4+ cell frequencies were significantly increased irrespective of cardiac disease etiology. Elevated CCR7 expression was less pronounced on CD4+ than CD8+ cells in patients with CAD and IDCM. Expression of CXCR4 on CD8+ cells was upregulated substantially, regardless of the cause of disease. CD8+ CXCR1+ and CD8+ CXCR3+ but not CD4+ CXCR1+ or CD4+ CXCR3+ cells were increased in the HF patients with IDCM and CAD, respectively. Expression of CXCR1 or CXCR3 on both CD4+ and CD8+ cells did not differ in all the groups. For monocytes, frequency of CD14+ CCR1+ and CD14+ CCR2+ cells was significantly decreased in CAD patients, whereas, increase in CD14+ CXCR4+ cell frequency was accompanied with elevated CXCR4 expression. On granulocytes, CXCR1 and CXCR2 receptors were downregulated in all patients, compared with controls. Our results suggest that the altered expression profile of CC- and CXC-chemokine receptors on circulating leukocyte populations involves enhanced activation of the immune system, perhaps as part of the pathogenic mechanisms in HF. Modulation of the chemokine network could offer interesting novel therapeutic modalities for end-stage HF.

The effects of chronic kidney disease and renal replacement therapy on circulating dendritic cells.

BACKGROUND: The mechanisms underlying the immunodeficiency of chronic kidney disease (CKD) are incompletely understood. Recently, we described decreased numbers of myeloid (m) and plasmacytoid (p) dendritic cells (DCs), considered the most important antigen-presenting cells, in peripheral blood of patients on chronic intermittent haemodialysis (CIHD). In this study, we analysed whether this reduction resulted from CKD or from renal replacement therapy (RRT). METHODS: Using flowcytometry, we quantified mDCs and pDCs in peripheral blood of patients maintained on CIHD (n = 37), continuous ambulatory peritoneal dialysis (CAPD; n = 29), and patients with CKD not receiving RRT (n = 37). Twenty-nine healthy volunteers served as controls. RESULTS: Patients with CKD (n = 103) had lower pDC and mDC counts compared with volunteers: 4.2 vs 8.3 and 10.0 vs 13.8 x 10(6) cells/l, respectively (P < or = 0.001). Within the CKD group, pDC counts did not differ between patients on CIHD, CAPD and those not receiving RRT (3.6 vs 5.0 vs 4.9 x 10(6) cells/l, respectively). In the latter group, pDC numbers correlated with the glomerular filtration rate (GFR; Spearman's r = 0.49; P<0.01). In contrast, mDC counts of patients on CIHD were lower compared with patients on CAPD (7.5 vs 10.1 x 10(6) cells/l; P = 0.039) and patients not receiving RRT (13.7 x 10(6) cells/l; P<0.001). Among non-dialyzing patients, no correlation existed between GFR and mDC numbers, which were comparable to those of volunteers, even when only non-dialyzing patients with a GFR below 15 ml/min were analysed. CONCLUSIONS: Circulating DC counts are decreased in patients with CKD; for pDCs, this reduction is primarily related to the loss of GFR, whereas the dialysis treatment appears to affect mDC numbers.

Impaired circulating dendritic cell reconstitution identifies rejecting recipients after clinical heart transplantation independent of rejection therapy.

OBJECTIVE: Dendritic cell (DC) mediated allo-antigen presentation to host antigen specific T-lymphocytes initiates acute allograft rejection. We investigated peripheral blood DC (PBDC) incidence and DC subset reconstitution in relation to histological diagnosis of acute cellular rejection (AR) and administration of rejection therapy after clinical heart transplantation (post-HTx). METHODS: Venous blood from 20 HTx recipients under standard immunosuppression was collected during serial endomyocardial biopsy (EMB) prior to administration of rejection therapy in a 9-month follow-up post-HTx. Echocardiographic assessment of allograft function during EMB was performed to distinguish clinical necessity for rejection therapy within histologically rejecting patients (R). Myeloid (mDC) and plasmacytoid (pDC) subsets identified by flow-cytometry were analysed for different ISHLT rejection grades. Circulating PBDC incidence and mDC/pDC ratio were compared sequentially between non-rejecting (NR) recipients and R patients treated (3A(+)) or not-treated (3A(-)) with rejection therapy during follow-up. RESULTS: Eleven samples from biopsy-proven AR episodes (AR(+): ISHLT>or=3) were compared to 89 samples from non-rejection episodes (AR(-): ISHLT grade 0, n=52; grade 1, n=29; grade 2, n=8). We observed an inverse correlation of mDCs (P<0.05) but not pDCs with increasing rejection grade. PBDC incidence and mDC/pDC ratio were low in blood samples obtained during AR (P<0.05 and P<0.01, respectively). Both PBDCs and mDC/pDC ratio decreased during each AR episode (P<0.05). Comparison of 3A(+) and 3A(-) rejectors with NR patients after 12 weeks post-HTx revealed lower PBDC incidence (P<0.01) and mDC/pDC ratio (P<0.05) for R patients, independent of rejection therapy. CONCLUSIONS: Defective DC subset reconstitution by dendritic cell profiling identifies patients at risk for AR after 3 months post-HTx. This finding may contribute to further optimization of immunosuppressive treatment strategies after clinical heart transplantation.

Preferential depletion of blood myeloid dendritic cells during acute cardiac allograft rejection under controlled immunosuppression.

Allo-Ag presentation to Ag-specific T-lymphocytes by donor or recipient dendritic cells (DCs) induces acute rejection (AR) after solid organ transplantation. It is postulated that myeloid (mDC) and plasmacytoid (pDC) subsets circulate differentially between bone marrow, heart and lymphoid tissues after cardiac transplantation (HTx). We investigated peripheral blood DC subset distribution, maturation and lymphoid homing properties in relation to endomyocardial biopsy (EMB) rejection grade after clinical HTx. Twenty-one HTx recipients under standard immunosuppression were studied in a 9-month follow-up. mDC and pDC numbers were analyzed by flow cytometry in fresh venous whole blood samples collected during the EMB procedures and before histological diagnosis of AR. Subsets were further characterized for maturation marker CD83 and lymphoid homing chemokine receptor CCR7. Although numbers of both DC subsets remained low for the whole post-HTx period, we observed a negative association of mDCs with rejection grade. Repeated measurements analysis revealed that only mDCs decreased during AR episodes. Rejectors had lower mDC numbers after a 3-month follow-up compared to nonrejectors. Furthermore, patients during AR exhibited low proportions of mDCs positive for CD83 or CCR7. These findings suggest peripheral blood mDC depletion in association with selective lymphoid homing of this subset during AR after clinical HTx.

Peripheral blood dendritic cells in human end-stage heart failure and the early post-transplant period: evidence for systemic Th1 immune responses.

OBJECTIVES: Dendritic cells (DCs) are antigen presenting cells that play a central role in inflammation, allograft rejection and immune tolerance. Myeloid (mDC) and plasmacytoid (pDC) subsets regulate immune reactions by polarising naive T-helper cells into a Th1 or Th2 response, respectively. In this study we examined total peripheral blood DCs, mDC and pDC subsets in chronic heart failure (CHF) and clinical heart transplantation (HTx). METHODS: We compared 16 heart transplant patients before and after HTx to 14 healthy controls. Whole blood was collected pre-HTx and 1-week post-HTx from patients and at corresponding time-points from controls. All patients received induction and maintenance immunosuppression post-HTx. mDCs and pDCs were measured by flow cytometry and were further characterised for maturation and homing potential to the secondary lymphoid organs with CD83 and CCR7, respectively. Data were expressed as absolute numbers/microl whole blood, percentage (%) mDC or pDC of total blood DCs and % positive DCs for CD83 and CCR7. RESULTS: CHF patients had more peripheral blood DCs compared to controls (P<0.01) while only the mDC fraction was increased compared to controls (P=0.01). Percentage CD83(+) and CCR7(+) mDCs was also higher than control levels (P<0.05). One week post-HTx, total DCs, mDCs and pDCs decreased below controls (P<0.001). At the same time % mDCs in peripheral blood increased markedly compared to CHF and control levels (P<0.001). The %CD83(+) mDC, %CD83(+) pDC and %CCR7(+) mDC also returned to control levels and only %CCR7(+) pDC decreased below control levels (P=0.005). CONCLUSIONS: Total peripheral blood DCs are elevated during CHF due to an increase in the mature fraction of the mDC subset suggesting a possible Th1 response in end-stage heart failure. The decrease in total DCs and mature mDCs and pDCs seen post-HTx, probably reflects immunological quiescence through adequate immunosuppression. Peripheral blood DC monitoring may provide a new insight into mechanisms of heart failure and allograft rejection by safe weaning from immunosuppression after clinical HTx.