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Chronic kidney disease is a proinflammatory state associated with increased arterial stiffness. We hypothesized that chronic kidney disease patients on long-term immunosuppression would have lower arterial stiffness and require treatment with less antihypertensive medication compared with non-immunosuppressed patients. A total of 254 patients (97 o...
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Aortic pulse wave velocity (PWV) has been associated with cardiovascular risk in different clinical subsets. This subanalysis of the EDIVA project aimed to establish criteria for normality of PWV based on a statistical definition that considers the fundamental physiological role of aging in arterial stiffness.
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Pulse wave analysis permits non-invasive assessment of arterial elasticity indices. The contour varies in different parts of the circulation. It depends on physiological or pathophysiological conditions of the organism. The pathological events like arteriosclerosis or diabetes have a primary effect to the artery elasticity. Hypertension or some hea...
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... In addition, a significant effect of mycophenolate mofetil on lowering blood pressure has been observed in patients suffering from psoriasis and rheumatoid arthritis (141). Another observational study showed that long-term use of immunosuppressive drugs can alleviate arterial stiffness and lower blood pressure in patients with chronic kidney disease (142). A monoclonal antibody against IL-17A could lower baseline blood pressure in patients with psoriasis (143). ...
Hypertension is regarded as the most prominent risk factor for cardiovascular diseases, which have become a primary cause of death, and recent research has demonstrated that chronic inflammation is involved in the pathogenesis of hypertension. Both innate and adaptive immunity are now known to promote the elevation of blood pressure by triggering vascular inflammation and microvascular remodeling. For example, as an important part of innate immune system, classically activated macrophages (M1), neutrophils, and dendritic cells contribute to hypertension by secreting inflammatory cy3tokines. In particular, interferon-gamma (IFN-γ) and interleukin-17 (IL-17) produced by activated T lymphocytes contribute to hypertension by inducing oxidative stress injury and endothelial dysfunction. However, the regulatory T cells and alternatively activated macrophages (M2) may have a protective role in hypertension. Although inflammation is related to hypertension, the exact mechanisms are complex and unclear. The present review aims to reveal the roles of inflammation, immunity, and oxidative stress in the initiation and evolution of hypertension. We envisage that the review will strengthen public understanding of the pathophysiological mechanisms of hypertension and may provide new insights and potential therapeutic strategies for hypertension.
... 118 Immunosuppression (excluding calcineurin inhibitors) has been shown to be favorable in a clinical trial for patients with chronic kidney disease. 119 In agreement, several pro-inflammatory factors have been found to be upregulated in patients with treatment-resistant hypertension cases of chronic kidney disease. 120 Further clinical studies are needed to verify the efficacy of targeting key immune players in hypertension. ...
Hypertension is the leading cause of cardiovascular disease and the primary risk factor for mortality worldwide. For over half a century, researchers have demonstrated that the immunity plays an important role in the development of hypertension; however, the precise mechanisms are still under investigation. The current body of knowledge indicates that pro-inflammatory cytokines may play an important role in contributing to immune-related pathogenesis of hypertension. Interferon gamma (IFNγ), in particular, as an important cytokine that modulates immune responses, has been recently identified as an critical regulator of blood pressure by several groups including us. In this review, we focus on exploring the role of IFNγ in contributing to the pathogenesis of hypertension, outlining the various immune producers of this cytokine and described signaling mechanisms involved. We demonstrate a key role for IFNγ in hypertension through global knockout studies and related downstream signaling pathways that IFNγ production from CD8+ T cell (CD8T) in the kidney promoting CD8T-stimulated salt retention via renal tubule cells, thereby exacerbating hypertension. We discuss potential activators of these T cells described by the current literature and relay a novel hypothesis for activation.
... Among hypertensives who have undergone medical treatment and brought their blood pressure to a normal level, their cfPWV still tend to be high and they may still have a 50% risk of mortality due to cardiovascular diseases [28]. It has been reported in clinical trials that the use of immunosuppressive agents can reduce aortic PWV in patients with rheumatoid arthritis [29] and chronic kidney disease [30]. Animal models of hypertension have also demonstrated that hypertension-related vascular dysfunction is largely mediated by the invasion of immune cells, especially T lymphocytes, into the vasculature [31][32][33]. ...
Arteriosclerosis is the common pathological basis of hypertension-related target organ damage, and pulse wave velocity
(PWV) is commonly used to assess the degree of arterial stiffness. Previous studies have reported the correlation between
peripheral blood inflammatory indicators and PWV in hypertensives, but few studies examined the role of immune cells in
arteriosclerosis in the context of human hypertension. In order to enrich the understanding of this topic, we conducted a
cross-sectional study on hospitalized hypertensives in Tongji Hospital of Tongji Medical College of Huazhong University of
Science and Technology from January 2015 to February 2017 to investigate the relationship between brachial-ankle pulse
wave velocity (baPWV) and peripheral blood lymphocyte subsets. Sixty-four eligible patients were enrolled in our study.
The patients’ blood pressure, height, body weight, and baPWV were collected, along with the lab results of their peripheral
complete blood count, blood chemistry, and lymphocyte subsets. We studied the Spearman correlation between baPWV and
lymphocyte subsets and other variables. We further used multivariable stepwise linear regression analysis and the results
showed that baPWV was significantly correlated with age, height, systolic blood pressure, and the level of T lymphocytes
(CD3+CD45+) in hypertensive patients (β = 8.77, P = 0.006; β = −17.50, P = 0.001; β = 6.70, P = 0.002, and β = −7.093,
P = 0.024, respectively). According to our findings, baPWV was independently and negatively correlated with the level of
peripheral blood T lymphocytes in hypertensives, and infiltration of T lymphocytes into the vessels wall may be a key part of
the immune mechanism of arteriosclerosis in hypertension.
... Immune cell accumulation occurs in the heart, kidneys, brain, and adventitia of blood vessels, leading to end-organ damage. The prevalence of hypertension is high in patients with autoimmune disease (Shaharir et al. 2015;Taylor and Ryan 2017), and immunosuppression lowers BP in hypertensive subjects (Ferro et al. 2011) and in animal models of hypertension (Rodríguez-Iturbe et al. 2001;Mattson et al. 2006). It is not yet clear what initiates the immune system activation during hypertension; however, oxidation of lipids leads to the formation of isoketaldehydes that form adducts to endogenous proteins, thus transforming them into neoantigens. ...
The lymphatic vessels play an essential role in maintaining immune and fluid homeostasis and in the transport of dietary lipids. The discovery of lymphatic endothelial cell-specific markers facilitated the visualization and mechanistic analysis of lymphatic vessels over the past two decades. As a result, lymphatic vessels have emerged as a crucial player in the pathogenesis of several cardiovascular diseases, as demonstrated by worsened disease progression caused by perturbations to lymphatic function. In this review, we discuss the major findings on the role of lymphatic vessels in cardiovascular diseases such as hypertension, obesity, atherosclerosis, myocardial infarction, and heart failure.
... Cyclophosphamide (CYC) and mycophenolate mofetil (MMF) are the two drugs commonly used as induction therapy for patients diagnosed with diffuse or moderate to severe focal proliferative lupus nephritis (LN) (Chan 2005). MMF has been shown to reduce blood pressure in both humans and in experimental models of hypertension (Rodriguez-Iturbe et al. 2002;Herrera et al. 2006;De Miguel et al. 2010;Ferro et al. 2011;Taylor and Ryan 2017a). Our laboratory recently reported that MMF treatment attenuates the development of hypertension in an established, clinically relevant, experimental model of SLE (female NZBWF1 mice) (Taylor and Ryan 2017a). ...
Abstract Cardiovascular disease is the major cause of mortality among patients with the autoimmune disorder systemic lupus erythematosus (SLE). Our laboratory previously reported that immunosuppression with mycophenolate mofetil, a common therapy in patients with SLE, attenuates the development of hypertension in an experimental model of SLE. Cyclophosphamide (CYC) is another common therapy for patients with SLE that has contributed to improved disease management; however, its impact on the development of hypertension associated with SLE is not clear. We tested whether treatment with CYC (25 mg/kg, once/week, IP injection) for 4 weeks would attenuate hypertension in an established female mouse model of SLE with hypertension (30‐week‐old NZBWF1 females). Plasma anti‐dsDNA IgG levels, pathogenic for the disease, were lower in CYC‐treated SLE mice compared to vehicle‐treated SLE mice, suggesting efficacy of the therapy to suppress aberrant immune system function. Mean arterial pressure (MAP) was assessed by carotid artery catheters in conscious mice. Treatment did not attenuate the development of hypertension when compared to vehicle‐treated SLE mice; however, urinary albumin excretion was lower in CYC‐treated animals. Corresponding with the reduction in autoantibodies, data suggest that CYC treatment lowered circulating CD45R+ B cells. Paradoxically, circulating CD11b+Ly6G+ neutrophils were increased in CYC‐treated SLE mice compared to vehicle treated. Estrus cycling data also suggest that CYC treatment had an impact on ovarian function that may be consistent with reduced circulating estrogen levels. Taken together, these data suggest that CYC treatment attenuates autoantibody production and renal disease during SLE, but that the potential to affect MAP may be blunted by the increase in circulating neutrophils and CYC's impact on ovarian function.
... Whether immunosuppressive drugs can modify PWV, directly or indirectly influencing vasculature, remains largely speculative and difficult to demonstrate for the following reasons [61]. First, transplantation per se ameliorates arterial stiffness [22,62,63], probably as a result of recovery in renal function. ...
Arterial stiffness is a biologic process related to ageing and its relationship with cardiovascular risk is well established. Several methods are currently available for non-invasive measurement of arterial stiffness that provide valuable information to further assess patients' vascular status in real time. In kidney transplantation recipients, several factors could accelerate the stiffness process, such as the use of calcineurin inhibitors (CNIs), the presence of chronic kidney disease and other classical cardiovascular factors, which would explain, at least in part, the high cardiovascular mortality and morbidity. Despite the importance of arterial stiffness as a biomarker of cardiovascular risk, and unlike other cardiovascular risk factors (e.g. left ventricular hypertrophy), only a few clinical trials or retrospective studies of kidney recipients have evaluated its impact. In this review we describe the clinical impact of arterial stiffness as a prognostic marker of cardiovascular disease and the effects of different immunosuppressive regimens on its progression, focusing on the potential benefits of CNI-sparing protocols and supporting the rationale for individualization of immunosuppression in patients with lower arterial elasticity. Among the immunosuppressive drugs, a belatacept-based regimen seems to offer better vascular protection compared with CNIs, although further studies are needed to confirm the preliminary positive results.
... Treatment with cytostatic therapy with cyclophosphamide and/or azathioprine may influence the development of atherosclerotic lesions [18,39]. In patients with chronic kidney disease, treatment with immunosuppressive drugs had a positive effect on blood pressure and PWV [40]. On the other hand, an increase in body weight, hypertension, and diabetes mellitus is well-known side effects of the use of corticosteroids and also risk factors for developing atherosclerosis. ...
Previous studies have suggested an increased risk for cardiovascular events in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). We analyzed the presence of atherosclerotic damage in patients with AAV in relation to the presence of CD4⁺CD28null T cells and antibodies against cytomegalovirus (CMV) and human Heat-Shock Protein 60 (hHSP60). In this cross-sectional study, patients with inactive AAV were compared with healthy controls (HC). Carotid intima-media thickness (IMT) and aortic pulse-wave velocity (PWV) were measured. In addition, CD4⁺CD28null T cells, anti-CMV, and anti-hHSP60 levels were determined. Forty patients with AAV were included. Patients’ spouses were recruited as HC (N = 38). CD4⁺CD28null T cells are present in patients with AAV in a higher percentage (median 3.1, range 0.01–85) than in HC (0.28, 0–36, P < 0.0001). No significant difference in IMT (mm) between patients and controls was detected (mean 0.77 ± standard deviation 0.15 and 0.73 ± 0.11, respectively, P = 0.20). PWV standardized for MAP was increased in AAV patients (9.80 ± 2.50 m/s, compared to 8.72 ± 1.68 in HC, P = 0.04). There was a strong association between a previous CMV infection and the presence and percentage of CD4⁺CD28null T cells (0.33 vs 13.8, P < 0.001). There was no relationship between CD4⁺CD28null T cells and/or a previous CMV infection and IMT or PWV. There was no relation between anti-hHSP60 and CD4⁺CD28null T cells. Increased PWV values suggest atherosclerotic damage in patients with AAV. Plaque size, as determined by IMT, did not differ. CD4⁺CD28null T cells are increased in AAV and related to the previous CMV infection.
... Author Manuscript supported by the fact that treatment with the immunosuppressive drug mycophenolate mofetil in both animal models and essential hypertensive patients reduces blood pressure [Rodriguez-Iturbe et al. 2002;Herrera et al. 2006;De Miguel et al. 2010;Ferro et al. 2011]. ...
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that predominately affects women of reproductive age. Hypertension is an important cardiovascular risk factor that is prevalent in this patient population. Despite the high incidence of hypertension in women with SLE, the pathophysiological mechanisms underlying the development of hypertension remain poorly understood. This review will focus on disease-related factors, including inflammation, autoantibodies, and sex hormones that may contribute to hypertension in patients with SLE. In addition, we will highlight studies performed by our laboratory using the female NZBWF1 (F1 hybrid of New Zealand Black and New Zealand White strains) mouse model, a spontaneous model of SLE that mimics human disease and develops hypertension and renal injury. Specifically, using female NZBWF1 mice, we have demonstrated that multiple factors contribute to the pathogenesis of hypertension, including the inflammatory cytokine, tumor necrosis factor (TNF)-α, oxidative stress, as well as B-cell hyperactivity and autoantibody production.
... For example, a small clinical study showed that immunosuppression lowers blood pressure in patients with rheumatoid arthritis or sarcoidosis. 53,54 Similarly, removing autoantibodies via immunoadsorption in refractory hypertensive patients significantly reduced blood pressure. 55 These studies further underscore the need to understand how autoantibodies might contribute to the pathogenesis of hypertension. ...
Humans have had a long and complex relationship with salt. Although highly valued in many societies, dietary salt has long been associated with high blood pressure1–3 and, more recently, with other diseases.4–6 Some individuals with hypertension often display salt-sensitive blood pressure changes, which is a condition more prevalent among blacks, older people, and individuals with renal insufficiency or diabetes mellitus.7–9 In general, for those with salt-sensitive hypertension, excess sodium intake is associated with higher blood pressure, whereas a low-salt diet decreases blood pressure.3 In spite of this well-known association, the basic molecular and cellular mechanisms underlying the effects of salt on blood pressure regulation are still not well understood. Furthermore, individuals with high blood pressure are at increased risk for multiple diseases (ie, coronary artery disease, heart failure, stroke, and renal disease) although at present whether or not a high dietary salt intake can directly lead to these diseases (ie, in the absence of hypertension) is not known.
Our understanding of the effect of salt on health has grown even more complex recently. Researchers have reported a new connection between salt and autoimmunity: a high-salt diet was shown to accelerate autoimmune activity in a mouse model of multiple sclerosis.10,11 In addition, a close connection between hypertension and the immune system has been revealed.12–16 However, the causal relationships between salt, immunity, and hypertension (eg, how salt could mediate interactions between the immune system and the vasculature, brain, or kidney to increase blood pressure) are not well understood.
The National Heart, Lung, and Blood Institute convened a Working Group (WG) in 2014 to discuss this new emerging scientific area in hypertension research. The WG brought together experts from diverse backgrounds including hypertension, epidemiology, preeclampsia, cardiovascular disease, …
... Another immunosuppressant, tacrolimus, a calcineurin inhibitor which blocks T cell activation, is reported to reduce hypertension in Dahl salt-sensitive rats [125]. Furthermore, chronic kidney disease patients with hypertension and who are on immunosuppressant drugs were found to require less antihypertensive medication than patients who were not taking immunosuppressant drugs [126]. Based on these studies, T cells may be a potential target in treating hypertension. ...
Hypertension is a complex condition and is the most common cardiovascular risk factor, contributing to widespread morbidity and mortality. Approximately 90% of hypertension cases are classified as essential hypertension, where the precise cause is unknown. Hypertension is associated with inflammation; however, whether inflammation is a cause or effect of hypertension is not well understood. The purpose of this review is to describe evidence from human and animal studies that inflammation leads to the development of hypertension, as well as the evidence for involvement of oxidative stress and endothelial dysfunction-both thought to be key steps in the development of hypertension. Other potential proinflammatory conditions that contribute to hypertension-such as activation of the sympathetic nervous system, aging, and elevated aldosterone-are also discussed. Finally, we consider the potential benefit of anti-inflammatory drugs and statins for antihypertensive therapy. The evidence reviewed suggests that inflammation can lead to the development of hypertension and that oxidative stress and endothelial dysfunction are involved in the inflammatory cascade. Aging and aldosterone may also both be involved in inflammation and hypertension. Hence, in the absence of serious side effects, anti-inflammatory drugs could potentially be used to treat hypertension in the future.
