Abstract
Both animal models and 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, and rituximab, lower blood pressure and reduce organ damage. Mechanistically targeted immune interventions include isolevuglandin scavengers to prevent neo-antigen formation, co-stimulation blockade (abatacept, belatacept), and anti-cytokine therapies (e.g. 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 anti-hypertensive effects. Evidence of immunomodulatory drugs influencing hypertension-mediated organ damage are also discussed. The reviewed animal models, 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.
Highlights
No change in blood pressure (BP) occurred in 58 liver transplant patients treated with a tacrolimus/Mycophenolate mofetil (MMF) (P = 0.88, baseline average 129/70 mmHg) whilst a group treated with tacrolimus/steroid showed an 8 mmHg rise in systolic BP (SBP).[180]
This study reported a reduction in cardiovascular risk in response to numerous immunomodulatory drugs, including biologic agents (HR: 0.42; 95% CI: 0.21–0.81), MTX (HR: 0.85; 95% CI: 0.81–0.89), sulfasalazine (HR: 0.92; 95% CI: 0.87–0.98), and leflunomide (HR: 0.59; 95% CI: 0.43–0.79); P < 0.05.265 Baseline BP values were not reported in either paper
Genetic, and clinical evidence supports the role of inflammation and immune system involvement in hypertension and associated vascular, renal, and cardiac pathology, immunomodulatory approaches are not currently considered therapeutic options in BP lowering and cardiovascular disease reduction
Summary
The role of inflammation is well defined,[1,2,3,4,5] and a coexisting chronic inflammatory condition such as rheumatoid arthritis (RA), inflammatory bowel disease, ankylosing spondylitis, or psoriasis is considered an additional risk factor, including in ESC Cardiovascular Disease Prevention guidelines.[6,7,8] Anti-inflammatory therapies are recommended in such patients,[6] and targeting inflammation to improve cardiovascular outcomes has been supported by recent clinical trials such as CANTOS, COLCOT, and LoDoCo2.9–12 Hypertension is the most common cardiovascular risk factor worldwide.[13]. It is essential to identify the clinically permissible therapeutic interventions that address inflammatory targets in hypertension, and patient populations that would benefit from such treatment. While basic and translational evidence suggests that interfering in immuneinflammatory processes may aid in control of blood pressure (BP) and prevention of target organ damage,[14,15,16,17] the clinical evidence for these interventions has not been systematically analysed. We review potential immune therapeutic targets to identify approaches for which well-designed clinical studies may prove fruitful
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