Trained immunity: new paradigm in the immunological memory of cardiovascular disease

Cardiovascular disease (CVD) remains the leading cause of death worldwide, despite significant progress in identifying and managing traditional risk factors such as hyperlipidemia, hypertension, and diabetes. While targeted therapies addressing these factors reduce the risk of primary and secondary cardiac events, a substantial "residual risk" persists even after successful clinical intervention. This residual risk has prompted renewed interest in understanding the long-term biological effects of cardiovascular risk factors, particularly through the lens of chronic inflammation. Recent advances highlight a pivotal role for trained immunity-a form of innate immune memory driven by epigenetic and metabolic reprogramming-in driving this inflammation. Unlike adaptive immune memory, trained immunity occurs in innate immune cells and enhances their responsiveness to subsequent, unrelated stimuli. Emerging evidence suggests that various cardiovascular risk states, including hypercholesterolemia, obesity, and diabetes, can induce trained immunity, leading to heightened inflammatory tone that persists over time. Cardiac macrophages, as central mediators of tissue homeostasis and inflammation in the heart, are increasingly recognized as critical targets of this phenomenon. In this review, we explore how established cardiovascular risk factors can induce trained immunity on cardiac macrophages and examine the implications for disease progression, myocardial remodeling, and post-injury repair. Finally, we discuss emerging therapeutic strategies aimed at modulating trained immunity to reduce residual cardiovascular risk, offering a new frontier in the prevention and treatment of CVD.