HIV-Related Myocardial Fibrosis: Inflammatory Hypothesis and Crucial Role of Immune Cells Dysregulation

Figures

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  Figure 1. The role of myocardial fibrosis in CVD pathogenesis. The inflammatory hypothesis is considered a main driver of CVD complications in HIV-positive individuals. Persistent immune activation leads to a chronic inflammatory state that includes relatively high levels of inflammatory and pro-fibrotic cytokines (IL-10, TGF-β), together with RAAS activation. This subsequently enhances pro-fibrotic pathways (increased collagen I and III deposition), while also lowering collagen degradation. The increased collagen leads to LV stiffness and diastolic dysfunction (early sign of myocardial fibrosis). Myocardial fibrosis is a contributor to diastolic and systolic dysfunction, HF, and sudden cardiac death. LV: left ventricle, RAAS: renin-angiotensin aldosterone system, ROS: reactive oxygen species, IL: interleukin, and TGF: transforming growth factor.

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  Figure 2. HIV infection causes the persistent activation and immune dysfunction. Effective healing is usually characterized by a dominant T helper 1 response, whereas a shift of the balance towards T helper 2 cells leads to chronic inflammation, which can eventually result in fibrosis. There are two types of macrophage activation, i.e., M1 based on the T helper 1-type response, and M2 that is based on the T helper 2-type response. The shift to T helper 2 cells, M2 responses, and platelet activation with HIV is involved in fibrotic pathway activation. HIV: human immunodeficiency virus, IFN-γ: interferon-γ, IL: interleukin, PDGF: platelet-derived growth factor, Th: T helper, TGF-β: transforming growth factor-β, TF: tissue factor.

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  Figure 3. The inflammatory hypothesis and cardiac fibrosis. Failed resolution during early HIV infection leads to persistent immune activation and a chronic inflammatory status, together with thrombosis, increased levels of ROS and proinflammatory and profibrotic cytokines. Immune dysregulation (e.g., platelet activation, macrophage polarization, and shift of T helper cells) results in increased fibroblast activation and profibrotic signaling, which leads to myocardial fibrosis. The culmination of such factors increases the risk for heart failure and sudden cardiac death. ROS: reactive oxygen species, cART: combination antiretroviral therapy, HIV: human immunodeficiency virus, HF: heart failure, SCD: sudden cardiac death, Th: T helper, TGF-β: transforming growth factor-β.