THE DIFFERENTIAL IMPACT OF HEART FAILURE MEDICATIONS ON BASAL INFLAMMATION IN HEART FAILURE PATIENTS

Abstract

Inflammation is a frequent occurrence in individuals suffering from chronic heart failure (CHF) and baseline inflammation can start as early as stage A heart failure. In response to heart failure, compensatory neurohormones are initially activated. These include the renin–angiotensin aldosterone system (RAAS) and the sympathetic nervous system (SNS), along with secretion of inflammatory mediators. The chronic activation of SNS system can increase norepinephrine (NE) acting on beta receptors, subsequently triggering the release of renin, thereby RAAS system chronic activation. Renin, in turn, promotes the formation of the potent vasoconstrictor angiotensin II with both proinflammatory and profibrotic actions. It is also widely recognized that peripheral blood mononuclear cells (PBMCs) express elements of the RAAS. When ACE/ANGII/AT1R activity dominates, PBMCs tend to exhibit a pro-inflammatory state, whereas a preponderance of ACE2/ANG1-7/AT2R activity promotes anti-inflammatory profile. Angiotensin Converting Enzyme inhibitors (ACEIs), Angiotensin Receptor Blockers (ARB) and β-blockers are commonly used medication to manage heart failure patients. ACEIs prevent the conversion of Angiotensin I to Angiotensin II, a peptide hormone that constricts blood vessels and elevates blood pressure. In addition to ARBs that upregulate ACE2 receptors, leading to an increase in Angiotensin 1- 7 levels known for their vasodilation, anti-inflammatory, and anti-fibrotic cardio protective role. As a matter of fact, ACEIs have long been recognized for their direct influence on the immune system by suppressing PBMCs from producing pro-inflammatory cytokines. Finally, β-blockers act by blocking the beta receptors in both the heart and kidneys, have anti-inflammatory effects, contributing to decreased heart rate, decreased contractility, and decreased myocardial O2 demand. Additionally, β-blockers have anti-inflammatory effects leading to the overall therapeutic strategy for heart failure management. Given the importance of the RAAS system in PBMCs inflammatory profile modulation, we hypothesize that patients on ACEIs/ARBs medication exhibit a lower inflammatory profile than β-blockers. We also hypothesize that the combination therapy of ACEIs/ARBs and β-blockers exhibit the strongest lowering effect on basal inflammation in heart failure patients. This study includes both prospective and retrospective components and was approved by the American University of Beirut’s Institutional Review Board (IRB) ID: BIO-2020-0362. A molecular analysis was performed on enrolled patients and a detailed retrospective analysis on patients’ records. As part of the proposed study, collected PBMCs underwent flow cytometry analysis to assess the viability using specific antibodies (CD3+, CD14+, CD19+, CD33+, CD45+, CD56+, CD66-) against various immune cells subsets, which includes lymphocytes, monocytes, NK cells, myeloid cells, and mononuclear cells. ELISA was performed on plasma collected from blood samples to quantify various inflammatory markers including cytokines (IL-1β, IL-2, IL-10, IFN-γ) and ACE2. Linear regression models showed that patients on combination therapy had significantly lower levels of both IL-1b (B=-0.61, p=0.007) and IL-2 (B= -2.04, p=0.007) compared to ACEIs/ARBs after adjusting for age, gender, heart failure stage, smoking status, and number of comorbidities. We also found that for IFN-γ, patients on β-blockers (B=14.19, p=0.011) had significantly higher levels than those on ACEIs/ARBs, and for ACE2 levels, those on combination therapy (B=-1.67, p=0.018) had significantly lower ACE2 levels than those on ACEI/ARBs in unadjusted analysis, and these associations were attenuated when further adjustment was conducted (p=0.07). No significant difference was observed in IL-10 levels before and after linear regression and adjustment in these heart failure patients. In conclusion, the combination therapy of ACEIs/ARB and β-blockers differentially impacts the inflammatory response in heart failure patients. According to our findings, utilizing a combination of ACEIs/ARBs alongside β-blockers proved to be more advantageous when it comes to decreasing inflammatory cytokines (IL-1β and IL-2) in heart failure patients, as opposed to relying on a single medication. Interestingly, this benefit seems to be independent of ACE2. Limitations of the study include the relatively small sample size, indicating the need for expanded recruitment to enhance statistical power and generalizability of the findings. Additionally, a predominant presence of patients in stage A heart failure was noted, potentially limiting the ability to draw comprehensive conclusions across various heart failure stages. Further analyses involving tumor necrosis factor- α (TNF-α), interleukin-6 (IL-6) plasma levels and C-reactive protein (CRP) are pending. Future research incorporating RNA sequencing on PBMCs extracted from heart failure patients is planned, aiming to provide deeper insights into the molecular mechanisms related to inflammatory responses in this population.