Rationale The role of mononuclear phagocytes in chronic heart failure (HF) is unknown. Objective Our aim was to delineate monocyte, macrophage, and dendritic cell trafficking in HF and define the contribution of the spleen to cardiac remodeling. Methods and Results We evaluated C57Bl/6 mice with chronic HF 8 weeks after coronary ligation. As compared with sham-operated controls, HF mice exhibited: (1) increased proinflammatory CD11b+F4/80+CD206− macrophages and CD11b+F4/80+Gr-1hi monocytes in the heart and peripheral blood, respectively, and reduced CD11b+F4/80+Gr-1hi monocytes in the spleen; (2) significantly increased CD11c+B220− classical dendritic cells and CD11c+/lowB220+ plasmacytoid dendritic cells in both the heart and spleen, and increased classic dendritic cells and plasmacytoid dendritic cells in peripheral blood and bone marrow, respectively; (3) increased CD4+ helper and CD8+ cytotoxic T-cells in the spleen; and (4) profound splenic remodeling with abundant white pulp follicles, markedly increased size of the marginal zone and germinal centers, and increased expression of alarmins. Splenectomy in mice with established HF reversed pathological cardiac remodeling and inflammation. Splenocytes adoptively transferred from mice with HF, but not from sham-operated mice, homed to the heart and induced long-term left ventricular dilatation, dysfunction, and fibrosis in naive recipients. Recipient mice also exhibited monocyte activation and splenic remodeling similar to HF mice. Conclusions Activation of mononuclear phagocytes is central to the progression of cardiac remodeling in HF, and heightened antigen processing in the spleen plays a critical role in this process. Splenocytes (presumably splenic monocytes and dendritic cells) promote immune-mediated injurious responses in the failing heart and retain this memory on adoptive transfer.

Background Inappropriately sustained inflammation is a hallmark of chronic ischemic heart failure (HF); however, the pathophysiological role of T-lymphocytes is unclear. Methods and Results Permanent coronary ligation was performed in adult C57BL/6 mice. As compared with sham-operated mice, mice with HF (8 w after ligation) exhibited the following features: 1) significant (p<0.05) expansion of circulating CD3+CD8+ cytotoxic and CD3+CD4+ helper (Th) T-lymphocytes, together with increased Th1, Th2, Th17, and regulatory T-cell (Treg) CD4+ subsets; 2) significant expansion of CD8+ and CD4+ T-cells in failing myocardium, with increased Th1, Th2, Th17, and Treg CD4+ subsets, marked reduction of the Th1/Th2 ratio, augmentation of the Th17/Treg ratio, and upregulation of Th2 cytokines; and 3) significantly increased Th1, Th2, Th17 cells, and Tregs, in the spleen and mediastinal lymph nodes, with increased expansion of splenic antigen-experienced effector and memory CD4+ T cells. Antibody-mediated CD4+ T-cell depletion in HF mice (starting 4 w after ligation) reduced cardiac infiltration of CD4+ T-cells and prevented progressive LV dilatation and hypertrophy whereas adoptive transfer of splenic CD4+ T-cells (and, to a lesser extent, cardiac CD3+ T-cells) from donor mice with HF induced long-term LV dysfunction, fibrosis, and hypertrophy in naïve recipient mice. Conclusions CD4+ T-lymphocytes are globally expanded and activated in chronic ischemic HF, with Th2 (vs Th1) and Th17 (vs Treg) predominance in failing hearts, and with expansion of memory T-cells in the spleen. Cardiac and splenic T-cells in HF are primed to induce cardiac injury and remodeling, and retain this memory upon adoptive transfer.

From ancient times, chemopreventive agents have been used to treat/prevent several diseases, including cancer. They are found to elicit a spectrum of potent responses including anti-inflammatory, anti-oxidant, anti-proliferative, anti-carcinogenic, and anti-angiogenic activity in various cell culture and some animal studies. Research over the past four decades has shown that chemopreventives affect a number of proteins involved in various molecular pathways that regulate inflammatory and carcinogenic responses in a cell. Various enzymes, transcription factors, receptors, and adhesion proteins are also affected by chemopreventives. Although, these natural compounds have shown significant efficacy in cell-culture studies, they elicited limited efficacy in various clinical studies. Their introduction into the clinical setting is hindered largely by their poor solubility, rapid metabolism, or a combination of both, ultimately resulting in poor bioavailability upon oral administration. Therefore, to circumvent these limitations and to ease their transition to clinics, alternate strategies should be explored. Drug delivery systems such as nanoparticles, liposomes, microemulsions, and polymeric implantable devices are emerging as one of the viable alternatives that have been demonstrated to deliver therapeutic concentrations of various potent chemopreventives such as curcumin, ellagic acid, green tea polyphenols, and resveratrol into the systemic circulation. In this review article, we have attempted to provide a comprehensive outlook for these delivery approaches, using curcumin as a model agent, and discussed future strategies to enable the introduction of these highly potent chemopreventives into a physician’s armamentarium.

Visual Abstract