Investigating Experimental and Standard of Care Heart Failure Therapies in Modulating Macrophage-Mediated Myocardial Inflammation

Abstract

Acute myocardial infarction (AMI) and hypertension continue to be major contributors to heart failure, yet current pharmacological interventions fail to fully address or cure this disease. In experimental models of AMI, hemin, an inducer of heme oxygenase-1 (HMOX1), has been shown to reduce inflammation in the heart. This effect is mediated via macrophages and other immune cells in the peri-infarct and infarct zones. Candesartan or valsartan (both angiotensin receptor blockers, ARBs), or sacubitril/valsartan (angiotensin receptor blocker with neprilysin inhibitor, ARNI) are standard-of-care heart failure therapeutics with anti-inflammatory effects that may be independent of their AT1 blockade effect or natriuretic peptide breakdown ability. Whether hemin, ARB, or ARNI treatment in heart failure are effective in resolving inflammation via macrophages in cardiac tissues is not fully known. In this thesis, we tested if hemin, ARB, and ARNI could alter the accumulation of M2 macrophages in vivo; if these compounds influenced macrophage polarity in an in vitro model, and if cytokines in media from these macrophages could protect AC16 cardiomyocytes from oxidative stress.