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- Inflammatory Process in Chronic Heart Failure: Impact of Cardiac Resynchronization TherapyPublication . Martins, Sílvia Raquel Monteiro; Paiva, Artur Augusto; António, Natália Sofia Cláudio; Tomaz, Cândida Ascensão TeixeiraChronic heart failure (CHF) is a worldwide public health problem. It consists of a complex condition characterized by inadequate cardiac function, accompanied by cardinal symptoms and multiple signs and comorbidities. The pathophysiology of heart failure (HF) is not completely understood; however, it usually culminates in a progressive myocardial dysfunction associated with continuous ventricular remodelling. Nowadays, it is also well established that immune system activation promotes a systemic inflammatory status in this condition. HF patients, independent from prevalent systolic or diastolic dysfunction, present increased levels of several pro-inflammatory cytokines, associated with adverse clinical outcomes. Peripheral blood cells have been suggested as a potential source for the prolonged systemic production of cytokines in CHF. Numerous studies propose the participation of these cells in the pathogenesis of the disease itself, contributing to progressive cardiac remodelling. Cardiac resynchronization therapy (CRT) is a guideline-recommended treatment for patients with drug-refractory HF, reduced left ventricle ejection fraction (LVEF), and left bundle branch block (LBBB). This therapy has beneficial effects on symptoms and cardiac remodelling in responder patients, such as reverse cardiac remodelling (with the reduction of left ventricular volumes and increased LVEF), improvement of New York Heart Association (NYHA)-based functional status, symptoms, and quality of life, reduction of brain natriuretic peptide, improvement in the six-minute walk test, and reduction of mortality and hospitalization for HF. In addition, previous studies have shown a reduction in inflammatory mediators in HF patients treated with CRT. Nonetheless, the connection between reverse cardiac remodelling, and the potential antiinflammatory effect of CRT and peripheral immune cells remains far from fully understood. Therefore, the overall goals of the present research were to elucidate the role of peripheral immune cells in CHF, to investigate the effect of CRT on immune cell dynamics, and to study the possible contribution of those cells to reverse cardiac remodelling. The specific aims included: first, to quantify and functionally characterize circulating innate immune cells, like monocytes and dendritic cells (DC), and cells from adaptive immunity, like the different functional subsets of lymphocytes in patients with advanced HF; second, to study the impact of CRT on those cells by evaluating their frequency of and functional activity in HF patients before and 6 months after CRT; and third, to investigate possible differences between responders and non-responders to CRT. To this end, this research was divided into two phases. First, blood samples were collected from HF patients scheduled for CRT. Subsequently, cells were identified, quantified, and characterized by flow cytometry through direct immunofluorescence membrane and intracytoplasmic staining protocols. Their functional characterization was also evaluated by flow cytometry, but after in vitro stimulation. The quantification of mRNA expression was conducted by real-time polymerase chain reaction (PCR). Statistical analyses were performed to compare data between the control group and HF patients. The second phase comprised a reassessment of patients 6 months after CRT, in which the same variables were analysed. At this time, statistical comparisons were performed not only between the control group and patients, but also between baseline assessment and follow-up, and between responders and non-responders to CRT. Patients with HF presented a significantly lower frequency of plasmacytoid DC (pDC) at baseline and a higher proportion of monocytes and myeloid DC (mDC) producing proinflammatory cytokines than normal individuals. As for adaptive immunity cells, circulating Tc17 cells tended to be higher in patients than in the control group. On the contrary, the level of cells measuring immune tolerance and homeostasis, regulatory T (Treg) cells, was decreased in HF patients. These differences characterize the inflammatory state of HF and support the idea that peripheral immune cells are involved in this inflammatory process. After CRT, a paradigm shift occurred within monocyte subsets: the frequency of classical monocytes (cMo) decreased while that of intermediate monocytes (iMo) increased among responder patients. This group also presented higher non-classical monocytes (ncMo) values at follow-up compared to the non-responder group. These findings suggest the involvement of monocyte subsets in reverse cardiac remodelling and CRT response. In addition, all patients presented a reduction in CD86 expression in all monocyte and DC subpopulations, indicating a compromise in the induction of the adaptive immune response by monocytes and DC. Moreover, in non-responders, the increased frequency of pro-inflammatory cytokines-producing DC persisted after CRT. Regarding T cell subpopulations, the frequency of Tc17 cells decreased after therapy, reaching levels similar to those in the control group. This observation was mainly found among responder patients. Additionally, the expression of IL-17 mRNA was detected in a few responders at initial evaluation and only in one responder at follow-up. These findings showed that IL-17-producing T cells appear to be suppressed after CRT. On the other hand, the level of Treg cells was not restored after treatment, and the production of inflammatory cytokines by CD8+ T cells increased during follow-up. In conclusion, although some cell subpopulations remained pro-inflammatory after CRT, the findings observed in responders indicate that CRT can modulate the behaviour of immune cells, potentially contributing to reverse cardiac remodelling and improving cardiac function. These findings help elucidate the complex relationship between the immune system and cardiac therapy, suggesting that CRT may benefit patients with CHF by improving symptoms, reversing cardiac remodelling, and altering the behaviour of immune cells, thereby potentially reducing the inflammatory response in the heart.