Distinct roles of resident and nonresident macrophages in nonischemic cardiomyopathy

Area of Science:

• Cardiovascular Biology
• Immunology
• Heart Failure Pathophysiology

Background:

• Nonischemic cardiomyopathy (NICM) is a leading cause of heart failure globally, often stemming from hypertension, valvular disease, or genetic factors.
• The precise roles of tissue-resident versus circulating myeloid cells in NICM development are not fully elucidated.
• Understanding these cellular dynamics is crucial for developing novel therapeutic strategies for heart failure.

Purpose of the Study:

• To investigate the distinct roles of cardiac resident and blood-borne myeloid cells in the progression of nonischemic heart failure.
• To identify key molecular regulators of myeloid cell function in the failing heart.
• To determine the therapeutic potential of modulating myeloid cell infiltration in heart failure models.

Main Methods:

• Utilized a pressure overload hypertrophy (POH) mouse model to simulate heart failure conditions.
• Employed lineage tracing and cell-specific analyses to distinguish resident and recruited myeloid cells.
• Investigated the role of Kruppel-like factor 4 (KLF4) in cardiac macrophage function using genetic manipulation.
• Assessed the impact of blocking blood-borne macrophage recruitment on cardiac angiogenesis and function.

Main Results:

• Cardiac resident macrophage proliferation was observed early in POH and was essential for adaptive cardiac remodeling.
• Kruppel-like factor 4 (KLF4) was identified as a critical transcription factor regulating resident macrophage proliferation and pro-angiogenic activities.
• Recruitment of blood-borne macrophages in later stages of POH proved detrimental to cardiac function.
• Blocking the infiltration of these late-phase macrophages enhanced myocardial angiogenesis and preserved cardiac function.

Conclusions:

• Cardiac resident macrophages play a beneficial, adaptive role early in heart failure, regulated by KLF4.
• Conversely, blood-borne macrophages recruited later in the disease process exert harmful effects on the heart.
• Targeting the infiltration of detrimental blood-borne macrophages represents a promising therapeutic avenue for preserving cardiac function in heart failure.