Introduction: Heart failure (HF) remains one of the leading causes of death globally, primarily driven by common risk factors like obesity and hypertension. These cardiometabolic risk
factors are often linked to cardiac dysfunction, cardiac inflammation and elevated circulatory cytokine levels. Recent evidences indicate that these risk factors can also trigger myeloid-skewing in the bone marrow hematopoietic stem and progenitors (HSPCs), followed by increased myelopoiesis which lead to immune-priming in the differentiated myeloid cells like macrophages. This primed phenotype of the bone-marrow derived macrophages (BMDM) might contribute to an enhanced pro-inflammatory microenvironment after infiltrating to the failing heart, thereby exacerbating HF progression.
Objective: We have investigated whether obesity and hypertension trigger myeloid-skewing and immune priming in the bone marrow of a HF mouse model. Secondly, we studied the
effects of these risk factors on the cardiac immune microenvironment and different cardiac macrophage subsets during HF.
Methods: 7-8-week-old C57BL6/N mice underwent 5-weeks of high-fat diet (HFD) in combination with eNOS-inhibitor L-NAME treatment to induce HF. Flow-cytometric profiling
was done to characterise the HSPCs from isolated bone marrow cells from healthy and HF mice. Thereafter these cells were cultured and differentiated into BMDMs using M-CSF. After
6 days, BMDMs were stimulated with LPS (20 ng/ml) for 24 h, followed by RNA extraction and qPCR analysis. Flow-cytometry was used to analyse different cardiac myeloid subpopulations and isolated cardiac macrophages from the digested whole hearts of the non-failing and failing mice.
Results: After treatment with HFD/L-NAME, mice exhibited an increase in body weight and blood pressure as well as a reduction in diastolic heart function. Interestingly, these diseased
mice also displayed myeloid-bias in HSPCs alongside an increased number of granulocyte-and monocyte-restricted progenitors. The LPS-stimulated BMDMs from failing mice exhibited
increased inflammatory responses compared to those from healthy mice, displaying a prominent upregulation of IL-1β, TNF-α and CCR2 expression levels after LPS challenge. In the cardiac tissue, higher numbers of pro-inflammatory (Ly6C
hi), recruited monocytes and macrophages (CCR2
+) were observed in the diseased mice. In addition, resident cardiac macrophage subsets differed between non-failing and failing mice.
Conclusion: Obesity and hypertension leads to myeloid-skewing and immune priming in the bone marrow and BMDMs of the diseased mice. This primed phenotype in the bone marrow might contribute to adverse cardiac immune remodelling in the failing hearts, indicating further HF progression due to chronic sub-clinical inflammation.
