Immune Mechanisms of Hypertensive Cardiac Remodeling and Heart Failure

Abstract

Hypertension is a major risk factor for heart failure with preserved ejection fraction, and emerging evidence implicates inflammation as integral to its pathogenesis. Clinical samples from patients admitted with heart failure exacerbations and the mouse model of DOCA-salt hypertensive heart failure were utilized to explore mechanisms underlying immune cell activation in chronic cardiovascular disease. Single cell sequencing of cardiac leukocytes in DOCA-salt treated mice revealed changes in the abundance and transcriptomes of cardiac immune cells, including upregulation of the receptor Trem2 within macrophages. Genetic Trem2 deficiency exacerbated cardiac hypertrophy, renal dysfunction, and diastolic dysfunction after DOCA-salt treatment. Additionally, loss of Trem2 was associated with alterations in expression of pro-inflammatory and angiogenic gene programs. Levels of the cleavage product soluble Trem2 are elevated in the plasma of patients with acute heart failure, suggesting this is one immune regulatory mechanism altered in human heart failure. Further immunophenotyping of circulating leukocytes in human heart failure found increased frequencies of interleukin-17A producing CD4 T cells and increased concentrations of interleukin-1 beta. These studies provide a basis for further work investigating immune alterations in acute and chronic heart failure with preserved ejection fraction.