Potential of anti-inflammatory agents for treatment of atherosclerosis

Chronic inflammation is a central pathogenic mechanism of atherosclerosis induction and progression. Vascular inflammation is associated with accelerated onset of late atherosclerosis complications. Atherosclerosis-related inflammation is mediated by a complex cocktail of pro-inflammatory cytokines, chemokines, bioactive lipids, and adhesion molecules, and blocking the key pro-atherogenic inflammatory mechanisms can be beneficial for treatment of atherosclerosis. Therapeutic agents that specifically target some of the atherosclerosis-related inflammatory mechanisms have been evaluated in preclinical and clinical studies. The most promising anti-inflammatory compounds for treatment of atherosclerosis include non-specific anti-inflammatory drugs, phospholipase inhibitors, blockers of major inflammatory cytokines, leukotrienes, adhesion molecules, and pro-inflammatory signaling pathways, such as CCL2-CCR2 axis or p38 MAPK pathway. Ongoing studies attempt evaluating therapeutic utility of these anti-inflammatory drugs for treatment of atherosclerosis. The obtained results are important for our understanding of atherosclerosis-related inflammatory mechanisms and for designing randomized controlled studies assessing the effect of specific anti-inflammatory strategies on cardiovascular outcomes.     

The role of Mediterranean type of diet on the development of cancer and cardiovascular disease,in the elderly: A systematic review

Background

The proportion of elderly worlwide is increasing. This increase in life expectancy, is staggering posing tremendous challenges in disease burden, especially, in chronic diseases such as obesity, diabetes, hypertension, hypercholesterolemia, cancer and cardiovascular disease (CVD). Limited studies investigate the effect of Mediterranean diet on cardiovascular risk and cancer in older populations. In this review, findings from observational studies are summarized to evaluate the effect of Mediterranean diet on cancer and cardiovascular disease risk in elderly people.

Methods

Published results from observational studies that assessed food habits on cancer and cardiovascular disease risk in elderly were retreived and summarized.

Results

In all studies diet had an effect on cardiovascular disease risk. The Mediterranean diet, a high-qulaity diet and increased fruit and vegetable consumption were all found to be cardioprotective.

Conclusion

The systematically reviewed studies reveal that a high adherence to a Mediterranean type of diet or “prudent diet” is associated with reduced risk of CVD and some types of cancer, even in the elderly. Also dietary intervention strategies can prevent morbidity, premature mortality and improve quality of life in older persons worldwide.     

Isoflavones and cardiovascular disease

The specific profile of estrogens on cardiovascular risk, with limiting action on atherogenesis but a less clear protection on cardiovascular episodes, might be improved by other agonists of the estrogen receptor, such as isoflavones. By using a systematic search based on the electronic Medline database plus a hand-search of reference lists of selected review papers, we reviewed the rapidly growing body of experimental and clinical data that, on average, follow a pattern of benefit rather similar to estrogens. Experimental models have used endothelial and vascular smooth muscle cells, isolated arteries, and live animals, including monkeys. The clinical evidence arises from studies on the lipid profile and lipid oxidation, insulin resistance, hemostasis, changes in the inflammatory factors, and indicators of endothelial function, including metabolites of nitric oxide and prostacyclin. There are not randomized trials investigating the action of isoflavones on the incidence of clinical episodes, but a few recent, well-designed studies have suggested the association of the ingestion of isoflavones with a reduction in the atherosclerotic burden, as indicated by the measurement of the intima-media thickness in carotid vessels.     

端粒耗损与心血管疾病

心血管疾病一直被认为是与年龄相关的退行性疾病,端粒随年龄增长而变短,是细胞老化的标志.最近,越来越多的研究表明端粒长度缩短与心血管疾病发生发展有关.该文仅就端粒耗损与心血管疾病相关性的研究进展作一综述,旨在为今后心血管疾病的预防和治疗提供新的思路.

Abstract：

Cardiovascular disease (CVD)has been considered as an age-related degenerative diseases. Telomere shortens with age, that is a sign of cell senescence. Currently, more and more researches show that the shortening of telomere length is correlated with the occurrence and progress of cardiovascular diseases. This article reviewed the studies on the relationship of telomere loss and cardiovascular diseases in order to provide new ideas for the prevention and treatment of cardiovascular diseases.     

The effect of hysterectomy or levonorgestrel-releasing intrauterine system on cardiovascular disease risk factors in menorrhagia patients: a 10-year follow-up of a randomised trial

Objective

To compare, whether women with menorrhagia, treated with either hysterectomy or LNG-IUS, differ in their cardiovascular risk profile during 10-year follow-up.

Study design

A total of 236 women were randomized to treatment by hysterectomy (n = 117) or LNG-IUS (n = 119). Their cardiovascular risk factors were analyzed at baseline, at 5 years, and at 10 years. As 55 originally randomized to the LNG-IUS group had hysterectomy during the follow-up, all analyzes were performed by actual treatment modality.

Main outcome measures

Waist circumference, body-mass index (BMI), blood pressure, and the levels of blood lipids, serum high-sensitivity CRP (hsCRP) and tumor necrosis factor alpha (TNF-α) were measured, and the use of medication for hypertension, diabetes, hypercholesterolemia, and ischemic heart disease was analyzed.

Results

After 5 years, an increase in the use of diabetes medication during the follow-up was only detected in the hysterectomy group (from 1.7% to 6.7%, P = 0.008 vs from 5.1% to 8.4%, P = 0.08), as well as they had significantly higher serum levels of TNF-α (108.59 pg/ml vs 49.02 pg/ml, P = 0.001) and hsCRP (1.55 μg/ml vs 0.78 μg/ml, P = 0.038) at 5- and 10-years. There was no difference between the groups in the use of cardiovascular medication, neither was there difference in blood pressure, waist circumference, BMI, or concentrations of blood lipids.

Conclusions

Hysterectomy seems to be associated with increased levels of serum inflammatory markers and increased diabetes medication, which in turn, may predispose individual to future cardiovascular events.     

NOD2 mediates anti-inflammatory signals induced by TLR2 ligands: implications for Crohn's disease

Mutations of the NOD2 gene have been associated with an increased susceptibility to Crohn's disease, but the pathogenetic mechanisms mediated by NOD2 remain elusive. In the present study, we demonstrate that the 3020insC frameshift-mutation in the NOD2 gene associated with Crohn's disease results in defective release of IL-10 from blood mononuclear cells after stimulation with the Toll-like receptor (TLR)2 ligands, peptidoglycan and Pam3Cys-KKKK, but not with bacterial LPS, a TLR4 ligand. The potential pathophysiological significance of this finding in patients with Crohn's disease and who are homozygous for this NOD2 mutation was substantiated by the finding of decreased anti-inflammatory cytokine release when cells from these patients were stimulated with different species of Bacteroides, an enteric microorganism implicated in the pathogenesis of Crohn's disease. In conclusion, defective NOD2 function results in a pro-inflammatory cytokine bias after stimulation of mononuclear cells with TLR2 stimuli, and this could contribute to the overwhelming inflammation seen in Crohn's disease.     

Reduced concentrations of the B cell cytokine interleukin 38 are associated with cardiovascular disease risk in overweight subjects

The IL-1 family member IL-38 (IL1F10) suppresses inflammatory and autoimmune conditions. Here, we report that plasma concentrations of IL-38 in 288 healthy Europeans correlate positively with circulating memory B cells and plasmablasts. IL-38 correlated negatively with age (p = 0.02) and was stable in 48 subjects for 1 year. In comparison with primary keratinocytes, IL1F10 expression in CD19⁺ B cells from PBMC was lower, whereas cell-associated IL-38 expression was comparable. In vitro, IL-38 is released from CD19⁺ B cells after stimulation with rituximab. Intravenous LPS in humans failed to induce circulating IL-38, compared to 100-fold induction of IL-6 and IL-1 receptor antagonist. In a cohort of 296 subjects with body mass index > 27 at high risk for cardiovascular disease, IL-38 plasma concentrations were significantly lower than in healthy subjects (p < 0.0001), and lowest in those with metabolic syndrome (p < 0.05). IL-38 also correlated inversely with high sensitivity C-reactive protein (p < 0.01), IL-6, IL-1Ra, and leptin (p < 0.05). We conclude that a relative deficiency of the B cell product IL-38 is associated with increased systemic inflammation in aging, cardiovascular and metabolic disease, and is consistent with IL-38 as an anti-inflammatory cytokine.     

Nanoparticle theranostics in cardiovascular inflammation

Theranostics, literally derived from the combination of the words diagnostics and therapy, is an emerging field of clinical and preclinical research, where contrast agents, drugs and diagnostic techniques are combined to simultaneously diagnose and treat pathologies. Nanoparticles are extensively employed in theranostics due to their potential to target specific organs and their multifunctional capacity. In this review, we will discuss the current state of theranostic nanomedicine, providing key examples of its application in the imaging and treatment of cardiovascular inflammation.     

Postmenopausal hormone therapy and cardiovascular disease: an overview of main findings

Cardiovascular disease has emerged as a leading cause of death in women. In recent years, significant attention has been paid to the potential benefits of hormone therapy on chronic diseases such as cardiovascular disease. Large prevention trials failed to confirm the cardioprotective effect of estrogen. The divergent findings from observational and randomized clinical studies are summarized and reasons for the different results are postulated. Use of estrogen alone or estrogen opposed with progestins is not indicated for the prevention of cardiovascular disease and may even increase the risk of stroke. Oral estrogen increases venous thromboembolism events. Recent data suggest that transdermal estrogens are safe with respect to venous thromboembolism. Current data have limited ability to investigate the wide variety of hormone treatments available. Clinical research should be continued to assist patients and clinicians in making treatment decisions on the basis of an individual's benefits and risks.     

调节自主神经系统:心血管疾病抗炎治疗的新领域

<正>目前普遍认为高血压、动脉粥样硬化、血脂异常、糖尿病等疾病的发生、发展和转归与炎症免疫反应有着密切联系。同时,心血管疾病中也伴有自主神经病变,表现为交感神经和迷走神经支配紊乱或结构损伤,其主要的病理特征是迷走神经张力减低而交感神经张力亢进。因此,改善自主神经紊乱同时减轻机体低度炎症反应将成为防治心血管疾病的重要方向。近60年的研究表明神经系统可接受免疫系统信号,并可传出神经冲动调节免疫系统活动。     

Risk factors for cardiovascular disease in women

Management of women's health seldom includes cardiovascular disease (CVD) prevention in spite of CVD being the most common cause of death in females being even more common than cancer, HIV/AIDS, malaria and tuberculosis combined. According to the World Heart Federation, CVD is indisputably the most serious, neglected health problem for women in both the developing and the developed worlds. A possible reason may be that CVD has traditionally been perceived as a ‘man's illness’. Since 6 out of 10 deaths from CVD can be prevented, it is of utmost importance that there is more general awareness about CVD in women. The most important factors for developing CVD are dyslipidaemia, hypertension, smoking, stress, diabetes, obesity (especially abdominal fat distribution), physical inactivity, poor eating habits and possibly excessive alcohol intake. Some unique risk factors for CVD exist in women; of which older age at presentation is a major one as they are more likely to suffer from co-morbidities such as diabetes and hypertension.     

Attitudes and cardiovascular disease

Psychological attitudes are prospectively related to cardiovascular disease (CVD), but a causal relationship has not been demonstrated. Trait optimism/pessimism (positive or negative future expectation, respectively), and cynical hostility (mistrust of people), are attitudes with features of personality traits. These attitudes may affect CVD risk in several ways, by influencing an individual's (1) adoption of health behaviors, (2) maladaptive stress responding resulting in direct alteration of physiology (i.e., autonomic dysfunction, thrombosis, arrhythmias), (3) development of traditional CVD risk factors, and (4) lack of adherence to therapy in both primary and secondary prevention. More adaptive attitudes may favorably influence CVD risk at each of these critical junctures. The genetic and environmental (i.e., social, economic, racial/ethnic) determinants of attitudes have not been extensively studied. In addition, it is important to understand how some of these environmental determinants may also moderate the association between attitudes and CVD. Clinical trials to modify attitudes for CVD risk reduction (either by reducing negative attitudes or by increasing positive attitudes) are difficult to conduct, but are necessary to determine whether attitudes can indeed be modified, and if, so, to quantify any CVD-related benefits. To address these questions we present a broad, multidisciplinary research agenda utilizing mixed methods and integrating principles of epidemiology, genetics, psychophysiology, and behavioral medicine over the lifecourse (first figure). This overview focuses on attitudes and CVD, but has broader implications for understanding how psychological factors relate to chronic diseases of adulthood.     

Sleep-disordered breathing and cardiovascular disease in the Bay Area Sleep Cohort

STUDY OBJECTIVES: To examine the relationship between sleep-disordered breathing (SDB) and cardiovascular disease among community-dwelling older adults. Previous studies have suggested relatively stronger associations between SDB and such morbidity in middle-aged, relative to elderly, populations. DESIGN: Cross-sectional analysis of an elderly ambulatory, non-clinic-based cohort (Bay Area Sleep Cohort, BASC) SETTING: Community population studied in a sleep laboratory PARTICIPANTS: One hundred twenty-nine older adults (mean [+/- SD] age = 72.6 [8.3]) (78 women; 51 men). INTERVENTIONS: NA. MEASUREMENTS: Complete clinical history including list of current medications, physical examination, selected blood chemistries, multiple blood pressure measurements, 12-lead electrocardiogram, and 2 consecutive nights of polysomnography. RESULTS: Fifty-one individuals (40%) were taking 1 or more cardiovascular medications and 24 (19%) had an apnea-hypopnea index (AHI) of 10 or more per hour of sleep. Cardiovascular medication use was related to cardiac events or procedures, history of angina, higher systolic or diastolic blood pressure, and abnormal electrocardiogram. Logistic regression showed statistically significant association between cardiovascular medication use and AHI of 10 or greater per hour, independent of age, sex, and body mass index. Supplementary analyses indicated that rapid eye movement AHI of 10 or greater per hour was significantly associated with elevated diastolic blood pressure. CONCLUSIONS: The results suggest that sleep-disordered breathing may contribute to increased cardiovascular morbidity in older adults.     

HRT as secondary prevention of cardiovascular disease

Objective: To review the evidence of the efficacy of postmenopausal hormone replacement therapy (HRT) in secondary prevention of coronary artery disease or stroke. Results: Although a number of rather large and prolonged non-randomized observational studies have produced convincing and consistent evidence of the efficacy of HRT in the prevention of recurrence of cardiac events, the first randomized, placebo controlled trial (RCT) on heart disease and estrogen replacement study (HERS) reported no benefit of conjugated equine estrogen (CEE) and medroxyprogesterone acetate (MPA) in secondary prevention of cardiac events in women with established coronary artery disease. This was supported by RCT reporting no effect of CEE or CEE + MPA on the progress of coronary sclerosis. Similarly, some nonrandomized observational studies have evaluated the risk of recurrent stroke in regard to the use of HRT, and the data are conflicting reporting a reduced or increased risk of recurrence for HRT users. One RCT has shown that low-dose estrogen treatment can only slow down the progression of carotid arteriosclerosis in high-risk postmenopausal women, whereas two other RCTs have shown no benefit (or risk) of using HRT for secondary prevention of ischemic stroke or progression of carotid atherosclerosis. Conclusion: The evidence accumutaed so far shows that HRT has no place in secondary prevention of coronary or carotic artery disease. Its use in these patients must be based on solid nonvascular indications and expected benefits from these causes.     

Gender Differences in the Cross-Sectional Relationships Between Sleep Duration and Markers of Inflammation: Whitehall II Study

Objective:

To examine the relationships between sleep and inflammatory markers because these may be important in the development of cardiovascular disease.

Methods and Results:

The relationship between self-reported sleep duration and interleukin-6 (IL-6) (n = 4642) and high-sensitivity C-reactive protein (hs-CRP) (n = 4677) was examined in individuals from the Whitehall II study. Following multiple adjustments, there were no overall linear or nonlinear trends between sleep duration and IL-6. However, in women but not men (interaction P < 0.05), levels of IL-6 tended to be lower in individuals who slept 8 hours (11% [95% confidence interval 4 to 17]) as compared to 7 hours. With hs-CRP, in the adjusted model, there was no association between hs-CRP and sleep duration in men. However, there was a significant nonlinear association in women, the level of hs-CRP being significantly higher in women short sleepers (5 hours or less) after multiple adjustments (P = 0.04) (interaction P < 0.05).

Conclusions:

No significant variation in inflammatory markers with sleep duration was observed in men. By contrast, both IL-6 and hs-CRP levels varied with sleep duration in women. The observed pattern of variation was different according to the inflammatory marker observed. Further longitudinal studies are required to fully investigate possible temporal relationships between short sleep and markers of inflammation.

Citation:

Miller MA; Kandala NB; Kivimaki M; Kumari M; Brunner EJ; Lowe GDO; Marmot MG; Cappuccio FP. Gender differences in the cross-sectional relationships between sleep duration and markers of inflammation: Whitehall II study. SLEEP 2009;32(7):857-864.     

Impact of obesity on autoimmune arthritis and its cardiovascular complications

Obesity can instigate and sustain a systemic low-grade inflammatory environment that can amplify autoimmune disorders and their associated comorbidities. Metabolic changes and inflammatory factors produced by the adipose tissue have been reported to aggravate autoimmunity and predispose the patient to cardiovascular disease (CVD) and metabolic comorbidities. Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are autoimmune arthritic diseases, often linked with altered body mass index (BMI). Severe joint inflammation and bone destruction have a debilitating impact on the patient's life; there is also a staggering risk of cardiovascular morbidity and mortality. Furthermore, these patients are at risk of developing metabolic symptoms, including insulin resistance resulting in type 2 diabetes mellitus (T2DM). In addition, arthritis severity, progression and response to therapy can be markedly affected by the patient's BMI. Hence, a complex integrative pathogenesis interconnects autoimmunity with metabolic and cardiovascular disorders. This review aims to shed light on the network that connects obesity with RA, PsA, systemic lupus erythematosus and Sj?gren's syndrome. We have focused on clarifying the mechanism by which obesity affects different cell types, inflammatory factors and traditional therapies in these autoimmune disorders. We conclude that to further optimize arthritis therapy and to prevent CVD, it is imperative to uncover the intricate relation between obesity and arthritis pathology.     

Risk of cardiovascular disease morbidity and mortality in frail and pre-frail older adults: Results from a meta-analysis and exploratory meta-regression analysis

Frailty is common and associated with poorer outcomes in the elderly, but its role as potential cardiovascular disease (CVD) risk factor requires clarification. We thus aimed to meta-analytically evaluate the evidence of frailty and pre-frailty as risk factors for CVD. Two reviewers selected all studies comparing data about CVD prevalence or incidence rates between frail/pre-frail vs. robust. The association between frailty status and CVD in cross-sectional studies was explored by calculating and pooling crude and adjusted odds ratios (ORs) ±95% confidence intervals (CIs); the data from longitudinal studies were pooled using the adjusted hazard ratios (HRs). Eighteen cohorts with a total of 31,343 participants were meta-analyzed. Using estimates from 10 cross-sectional cohorts, both frailty and pre-frailty were associated with higher odds of CVD than robust participants. Longitudinal data were obtained from 6 prospective cohort studies. After a median follow-up of 4.4 years, we identified an increased risk for faster onset of any-type CVD in the frail (HR = 1.70 [95%CI, 1.18–2.45]; I² = 66%) and pre-frail (HR = 1.23 [95%CI, 1.07–1.36]; I² = 67%) vs. robust groups. Similar results were apparent for time to CVD mortality in the frail and pre-frail groups. In conclusion, frailty and pre-frailty constitute addressable and independent risk factors for CVD in older adults.