Therapeutic targeting of inflammation in hypertension: from novel mechanisms to translational perspective

Abstract

Animal models, human observational and genetic studies have shown that immune and inflammatory mechanisms play a key role in hypertension and its complications. We review the effects of immunomodulatory interventions on blood pressure, target organ damage and cardiovascular risk in humans. In experimental and small clinical studies both non-specific immunomodulatory approaches, such as mycophenolate mofetil and methotrexate, and medications targeting T and B lymphocytes, such as tacrolimus, cyclosporine, everolimus, rituximab, lower blood pressure and reduce organ damage. Mechanistically targeted immune interventions include isolevuglandin (isoLG) scavengers to prevent neo-antigen formation, co-stimulation blockade (abatacept, belatacept), and anti-cytokine therapies (secukinumab, tocilizumab, canakinumab, TNF-α inhibitors). In many studies, trial designs have been complicated by a lack of blood pressure related endpoints, inclusion of largely normotensive study populations, polypharmacy, and established comorbidities. Among a wide range of interventions reviewed, TNF-α inhibitors have provided the most robust evidence of blood pressure lowering. Treatment of periodontitis also appears to deliver non-pharmacological antihypertensive effects. Evidence of immunomodulatory drugs influencing hypertension-mediated organ damage are discussed. Animal model, observational studies, and trial data in humans support the therapeutic potential of immune targeted therapies in blood pressure lowering and in hypertension-mediated organ damage. Targeted studies are now needed to address their effects on blood pressure in hypertensive individuals.

Endothelial Dysfunction in Hypertension: Current Concepts and Clinical Implications

“…Essential hypertension is characterized by functional and structural alterations in resistance arteries which lead to increased peripheral vascular resistance ( 7 ). Endothelial dysfunction may contribute to the increased peripheral resistance by several mechanisms that leads to the enhanced constriction and vascular remodeling (i.e., structural, mechanical, and functional alterations) of resistance arteries, which is associated to the development and complications of hypertension ( 6 , 8 ). In particular, endothelial dysfunction may participate to the increased myogenic tone of resistance arteries through the activation of the renin-angiotensin system (RAS), endothelin-1, catecholamines, and growth factors production, leading to vasoconstriction, vascular remodeling and then to increased resistance to blood flow and ultimately to increased peripheral blood pressure.…”

Periodontitis as an inflammatory trigger in hypertension: From basic immunology to clinical implications

“…Moreover, recent epidemiological evidence revealed the link between lifetime exposure to oral inflammation and future cardiovascular risk [8]. Angiotensin II (Ang II), salt, and other pro-hypertensive stimuli cause the increase of the expression and accumulation of immune cells including Th17, effector T cells producing Th1 type cytokines [93,95]. In line with this, animal studies indicated that hypertension was exacerbated by exposure to Porphyromonas gingivalis antigens, which are commonly present in periodontal diseases [30].…”

Mechanisms Underlying Antiarrhythmic Properties of Cardioprotective Agents Impacting Inflammation and Oxidative Stress

“…The cardiovascular risk factors that predispose to arrhythmias are accompanied by low grade inflammation and oxidative stress. These factors include hypertension, obesity, insulin resistance, metabolic syndrome, ageing, neurological disorders and circadian rhythm disruption [16,38,40,63,[69][70][71][72][73][74][75][76][77][78][79][80]. These conditions cause pro-arrhythmic load and predisposition to acute heart attack and stroke.…”