Leukocyte behavior in atherosclerosis, myocardial infarction, and heart failure

Abstract

Cardiovascular diseases claim more lives worldwide than any other. Etiologically, the dominant trajectory involves atherosclerosis, a chronic inflammatory process of lipid-rich lesion growth in the vascular wall that can cause life-threatening myocardial infarction (MI). Those who survive MI can develop congestive heart failure, a chronic condition of inadequate pump activity that is frequently fatal. Leukocytes (white blood cells) are important participants at the various stages of cardiovascular disease progression and complication. This Review will discuss leukocyte function in atherosclerosis, MI, and heart failure.

Figure 1. Leukocytes in experimental atherosclerosis

The cartoon depicts leukocyte flux and function in experimental atherosclerosis. Monocytes are made in bone marrow (medullary hematopoiesis) and spleen (extramedullary hematopoiesis). Ly-6C^high monocytes accumulate preferentially in the lesion and differentiate to macrophages, which ingest lipids or cholesterol crystals, and become lipid-rich “foam cells”. Ly-6C^low monocytes patrol the vasculature and enter lesions less frequently. Concurrently, other leukocytes and platelets participate in inflammation and lesion growth in various consequential ways (see main text). The scanning electron and transmission electron microscope images show, from left to right, monocytes (M) adhering to the endothelium (E), monocytes extending into lumen (Lu) trapped in junctions of the endothelium, endothelium overlying foam cells (FC) in intima, and ruptured endothelium revealing numerous foam cells. Images are from a classic study using Yorkshire pigs (6, 7).

Figure 2. Biphasic monocyte response during early myocardial remodeling

(A) Optical projection tomography of a murine heart with myocardial infarction after injection of molecular imaging reporters for major function of myeloid cells, including protease activity (red) and phagocytic activity (yellow). Unpublished, image courtesy of Dr. Claudio Vinegoni. (B) Magnetic resonance images of murine hearts. The upper panel shows a normal short axis view, while the lower panel depicts a severely dilated and remodeled heart after coronary ligation. Unpublished own data. (C) Cartoon of biphasic monocyte subset activity in the infarct as a function of time. In a first phase, inflammatory Ly-6C^high monocytes are recruited via MCP-1 and remove necrotic debris. In a second phase, Ly-6C^low monocytes accumulate via CX3CL1 and pursue repair functions that result in a stable scar.

Figure 3. Organ networks that lead to acceleration of atherosclerotic disease after myocardial infarction

The cartoon depicts events observed in mice acutely after MI that lead to accelerated disease progression in atherosclerotic plaque. The enlarged inset depicts processes in the bone marrow microenvironment. Here, niche cells provide signals that regulate HSC activity, retention and leukocyte production. After MI, increased sympathetic nervous signaling releases noradrenalin in the bone marrow niche, which binds to beta-3 adrenoreceptors on niche cells. These withdraw the soluble factor CXCL12 which results in increased HSC activity and emigration to extramedullary sites. Increased production of leukocytes then feeds an expanded pool of circulating monocytes which are recruited to atherosclerotic plaque in higher numbers, accelerating plaque growth and inflammation. This feedback loop may cause the high re-infarction rates observed clinically. The dotted arrow refers to currently unknown cross-talk between the cardiac wound and the hematopoietic system via alarmins (danger associated molecular patterns, DAMPs), which may also activate the bone marrow after MI. HSC: hematopoietic stem cell. HSPC: hematopoietic stem and progenitor cells. CAR: CXCL12 abundant reticular cell, MΦ: macrophage.