Functional connectivity studies in migraine: what have we learned?

BACKGROUND: Resting-state functional connectivity (FC) MRI has widely been used to understand migraine pathophysiology and to identify an imaging marker of the disorder. Here, we review what we have learned from FC studies. METHODS: We performed a literature search on the PubMed website for original articles reporting data obtained from conventional resting-state FC recording in migraine patients compared with healthy controls or during and outside of migraine attacks in the same patients. RESULTS: We found 219 articles and included 28 in this review after screening for inclusion and exclusion criteria. Twenty-five studies compared migraine patients with healthy controls, whereas three studies investigated migraine patients during and outside of attacks. In the studies of interictal migraine more alterations of more than 20 FC networks (including amygdala, caudate nucleus, central executive, cerebellum, cuneus, dorsal attention network, default mode, executive control, fronto-parietal, hypothalamus, insula, neostriatum, nucleus accumbens, occipital lobe, periaqueductal grey, prefrontal cortex, salience, somatosensory cortex I, thalamus and visual) were reported. We found a poor level of reproducibility and no migraine specific pattern across these studies. CONCLUSION: Based on the findings in the present review, it seems very difficult to extract knowledge of migraine pathophysiology or to identify a biomarker of migraine. There is an unmet need of guidelines for resting-state FC studies in migraine, which promote the use of homogenous terminology, public availability of protocol and the a priori hypothesis in line with for instance randomized clinical trial guidelines.

The multitasking role of macrophages in Stanford type A acute aortic dissection.

OBJECTIVES: The aim of the study was to determine whether the release by macrophages of matrix metalloproteinase (MMP)-12 and vascular endothelial growth factor (VEGF) - leading to inflammation, matrix degradation and neoangiogenesis - represents an effective pathway that underlies aortic wall remodeling in Stanford type A acute aortic dissection (AAD). METHODS: Twenty-one consecutive patients with no genetic predisposition, with Stanford type A AAD were selected. In each patient, the levels of serum VEGF, MMP-12, serum interleukin (IL)-6, IL-8 and monocyte chemoattractant protein (MCP)-1 were evaluated using enzyme-linked immunosorbent assay. Ascending aortic specimens were collected for immunohistochemical identification of any presence of inflammatory infiltrate, VEGF and CD31 expression. RESULTS: A significant increase in serum VEGF (p = 0.044), MMP-12 (p = 0.007), IL-6 (p = 0.0001), IL-8 (p = 0.0001) and MCP-1 (p = 0.0001) levels was observed in the AAD group compared to the control group. Furthermore, all AAD samples were positive for VEGF in the tunica media and showed vessel growth and immune-inflammatory infiltrate. A large number of cases (62.79%) showed inflammation at the edge of the dissection and approximately half (51.42%) showed neovessels growing at the edge of the dissection. CONCLUSIONS: The results suggest that VEGF-mediated angiogenesis and matrix degradation play a role in AAD. Finally, we believe that MMP-12 should be considered a marker of AAD.

Return on Investment (ROI) and Development of a Workplace Disability Management Program in a Hospital-A Pilot Evaluation Study.

The progressive ageing of the working population and the increase in related chronic diseases tend to affect working capacity. The aim of this study was to evaluate a Workplace Disability Management Program (WDMP) within a pediatric hospital. Absenteeism due to healthcare workers' (HCWs) pre- and post- WDMP and the related costs were used for the program evaluation. The Return on Investment (ROI), the Break-Even Analysis (BEA) and the value of the average annual productivity of HCWs who took advantage of the Disability Management (DM) interventions to assess the economic impact of the program, were also used. The HCWs enrolled in the program were 131 (approximately 4% of hospital staff), of which 89.7% females and with an average age of 50.4 years (SD ± 8.99). Sick leave days of the HCWs involved decreased by 66.6% in the year following the end of WDMP compared to the previous one (p < 0.001). The total estimated cost reduction of absenteeism is 427,896€ over a year. ROI was equal to 27.66€. BEA indicated that the break-even point was reached by implementing the program on 3.27 HCWs. The program evaluation demonstrated the particular effectiveness of the implemented WDMP model, acting positively on the variables that affect productivity and the limitation to work.

Tea, flavonoids, and nitric oxide-mediated vascular reactivity.

Epidemiological evidence supports the concept that diets rich in fruits and vegetables promote health and attenuate or delay the onset of cardiovascular disease (CVD). Although a variety of factors contribute to the beneficial effects of plant foods, much attention has been addressed to plant polyphenols. In this regard, in the daily Western diet, both black and green teas contribute to a relevant proportion of total phenol intake. The more abundant class of flavonoids that is present in teas is represented by flavanols, i.e., catechin, epicatechin, epigallocatechin, epicatechin gallate, and epigallocatechin gallate. Studies using animal models of atherosclerosis indicate that dietary flavonoid consumption delays atherosclerotic plaque development. Accordingly, an inverse association between tea intake and CVD has been demonstrated. Further, flavonoids can reduce endothelial dysfunction, i.e., the key step in the development of atherosclerosis. Concordantly, human data suggest that tea may reduce blood pressure levels. Despite this, although they often show that tea may have cardiovascular protective effects, results from epidemiological studies exploring the association between tea and health are controversial. Conflicting results may be caused by disparate study designs and flavonoid contents in different kinds of tea. Thus, because tea is a popular beverage worldwide, and several studies have shown that it is protective against CVD, further studies are needed to determine the role of tea in primary and secondary cardiovascular prevention.

Management of Hypertension in the Elderly and Frail Elderly.

An elevated systolic but not diastolic blood pressure level represents a common finding in elderly patients and is associated with an increased risk for developing coronary artery disease, cerebrovascular disease, peripheral artery disease, progressive cognitive decline and renal failure. Although less frequently, elderly patients manifest not only with systolic but also diastolic hypertension. Also in this case, the elderly patient will present an increased risk for developing hypertension-related abnormalities. Based on several trials conducted in patients ≥65 years and one single trial in patients ≥80 years the most recent European guidelines recommend antihypertensive treatment in elderly hypertensive patients with a systolic blood pressure ≥60 mmHg, with a systolic target between 140 and 150 mmHg. In fit elderly patients <80 years treatment may be considered at a systolic level ≥140 mmHg with a target SBP <140 mmHg if treatment is well tolerated. Despite of the above, at least three issues related to antihypertensive drug treatment in aged individuals are still debated, particularly after the publication of a recent large scale clinical trial that included also 2.636 patients ≥75 years and a study in nursing home residents ≥80 years, i.e. the frailest oldest patients: (1) the blood pressure threshold at which antihypertensive drug should be initiated, (2) the blood pressure targets of the therapeutic intervention, and (3) the approach to frail elderly hypertensive patients. This review will critically review the evidence available so far on these important issues as well as the position of current guidelines and consensus statements.

Regulatory T CD4 + CD25+ lymphocytes increase in symptomatic carotid artery stenosis.

BACKGROUND: Atherosclerosis is a multifactorial disease characterized by an immune-inflammatory remodeling of the arterial wall. Treg and Th17 subpopulations are detectable inside atherosclerotic plaque; however, their behavior in symptomatic carotid artery stenosis (CAS) is not fully elucidated. The aim of this study was to evaluate Th17 and Treg subsets and their ratio in patients affected by symptomatic and asymptomatic CAS. METHODS: 14 patients with symptomatic CAS (CAS-S group), 41 patients with asymptomatic CAS (CAS-A group), 32 subjects with traditional cardiovascular risk factors (RF group), and 10 healthy subjects (HS group) were enrolled. Th17 and Treg frequency was determined by flow cytometry and by histology and immunohistochemistry. Interleukin (IL)-10, IL-17, and metalloproteinase (MMP)-12 levels were measured by ELISA. RESULTS: Th17 were significantly increased in CAS-A versus RF and versus HS. Tregs were significantly increased in CAS-S versus CAS-A. Tregs/Th17 ratio was significantly reduced in CAS-A versus RF and versus HS, whereas it was significantly increased in CAS-S versus CAS-A. CONCLUSIONS: The results of this study suggest that Th17 are related to the late stages of CAS but not to plaque instability. Moreover, Treg expansion seems to represent a specific cellular pattern displayed by patients with symptomatic CAS and associated with brain injury. KEY MESSAGES Tregs expansion seems to represent a specific cellular pattern displayed by patients with symptomatic CAS and associated with CD4+ effector depletion and brain ischemic injury. Th17 lymphocytes are related to the late stages of CAS but not to plaque instability.

Stanford-A acute aortic dissection, inflammation, and metalloproteinases: a review.

Acute aortic dissection (AAD) is a life-threatening disease with an incidence of about 2.6-3.6 cases per 100,000/year. Depending on the site of rupture, AAD is classified as Stanford-A when the ascending aortic thoracic tract and/or the arch are involved, and Stanford-B when the descending thoracic aorta and/or aortic abdominal tract are targeted. It was recently shown that inflammatory pathways underlie aortic rupture in both type A and type B Stanford AAD. An immune infiltrate has been found within the middle and outer tunics of dissected aortic specimens. It has also been observed that the recall and activation of macrophages inside the middle tunic are key events in the early phases of AAD. Macrophages are able to release metalloproteinases (MMPs) and pro-inflammatory cytokines which, in turn, give rise to matrix degradation and neoangiogenesis. An imbalance between the production of MMPs and MMP tissue inhibitors is pivotal in the extracellular matrix degradation underlying aortic wall remodelling in dissections occurring both in inherited conditions and in atherosclerosis. Among MMPs, MMP-12 is considered a specific marker of aortic wall disease, whatever the genetic predisposition may be. The aim of this review is, therefore, to take a close look at the immune-inflammatory mechanisms underlying Stanford-A AAD.

Cocoa, blood pressure, and cardiovascular health.

High blood pressure is an important risk factor for cardiovascular disease and cardiovascular events worldwide. Clinical and epidemiological studies suggest that cocoa-rich products reduce the risk of cardiovascular disease. According to this, cocoa has a high content in polyphenols, especially flavanols. Flavanols have been described to exert favorable effects on endothelium-derived vasodilation via the stimulation of nitric oxide-synthase, the increased availability of l-arginine, and the decreased degradation of NO. Cocoa may also have a beneficial effect by protecting against oxidative stress alterations and via decreased platelet aggregation, decreased lipid oxidation, and insulin resistance. These effects are associated with a decrease of blood pressure and a favorable trend toward a reduction in cardiovascular events and strokes. Previous meta-analyses have shown that cocoa-rich foods may reduce blood pressure. Long-term trials investigating the effect of cocoa products are needed to determine whether or not blood pressure is reduced on a chronic basis by daily ingestion of cocoa. Furthermore, long-term trials investigating the effect of cocoa on clinical outcomes are also needed to assess whether cocoa has an effect on cardiovascular events. A 3 mmHg systolic blood pressure reduction has been estimated to decrease the risk of cardiovascular and all-cause mortality. This paper summarizes new findings concerning cocoa effects on blood pressure and cardiovascular health, focusing on putative mechanisms of action and "nutraceutical " viewpoints.

FGF-23 levels in patients with critical carotid artery stenosis.

The aim of this study was to evaluate fibroblast growth factor (FGF)-23 serum levels and its tissue expression in patients with critical carotid artery stenosis (CAS). We selected 35 patients with critical CAS undergoing carotid thromboendoarterectomy. In each patient, FGF-23 serum levels were evaluated just prior to the surgery (t0) and 30 min (t1) thereafter. Moreover, macrophage cytokines were measured at baselines. Carotid artery specimens were used for immune histochemistry. On the basis of the histology, the patients were divided into 2 groups: A with complicated plaque and B with uncomplicated plaque. Twenty complicated plaques (57.14%, group A,) and 15 uncomplicated (42.86%, group B) were evaluated: calcifications were present in 16/20 (80%) complicated plaques and in 6/15 (40%) uncomplicated plaques. An inflammatory infiltrate was observed in 26/35 carotid samples: 18/26 (69.23%) complicated and 8/26 (30.76%) uncomplicated. FGF-23(+) cells were present in 17/20 complicated (85%) and in 8 uncomplicated (53%) plaques. The double-staining immunofluorescence confirmed that macrophage cells (CD68(+)) were also positive for FGF-23 staining. Serum levels of FGF-23 were significantly higher in group A versus group B at t0 (p < 0.05) and t1 (p 0.0047). Moreover, in group A patients a significant increase of FGF-23 serum levels was observed at t1 in comparison with t0 (p 0.0011). Our results suggest that FGF-23 acts in the late phases of atherosclerotic disease and may potentially represent a marker of complications in critical CAS.

MMP-12 as a new marker of Stanford-A acute aortic dissection.

BACKGROUND: The study evaluated macrophage cytokines and macrophage metalloprotease (MMP)-12 levels in patients with Stanford-A acute aortic dissection (AAD) and in patients with critical carotid artery stenosis (CAS) compared with patients matched for age, sex, and traditional cardiovascular risk factors (RF). The aim was to identify possible early serum markers of risk for atherosclerotic complications. MATERIALS AND METHODS: We selected 65 patients: 23 AAD patients, 21 CAS patients, 21 RF, and 10 healthy subjects (HS). In each patient and control serum, levels of interleukin (IL)-6, IL-8, tumour necrosis factor (TNF)-α, monocyte chemoattractant protein (MCP)-1, vascular endothelial growth factor (VEGF), and MMP-12 were assessed by ELISA. RESULTS: A significant increase of MMP-12, IL-6, and IL-8 levels in AAD versus CAS was found. Moreover, MMP-12 was shown to be significantly higher in AAD versus RF, but not in CAS versus RF. A significant increase of IL-6, IL-8, MCP-1, TNF-α, and VEGF levels was observed both in AAD and CAS versus RF. CONCLUSIONS: The results suggest that MMP-12 may be considered to be a specific marker of Stanford-A AAD. Furthermore, the study confirmed that in AAD and CAS macrophage cytokines play a key role in the progression of the atherosclerotic disease towards complications.

Chronic hyperuricemia, uric acid deposit and cardiovascular risk.

Hyperuricemia is commonly associated with traditional risk factors such as dysglicemia, dyslipidemia, central obesity and abnormal blood pressure, i.e. the metabolic syndrome. Concordantly, recent studies have revived the controversy over the role of circulating uric acid, hyperuricemia, and gout as an independent prognostic factor for cardiovascular morbidity and mortality. In this regard, different studies also evaluated the possible role of xanthine inhibitors in inducing blood pressure reduction, increment in flow-mediated dilation, and improved cardiovascular prognosis in various patient settings. The vast majority of these studies have been conducted with either allopurinol or its active metabolite oxypurinol, i.e. two purine-like non-selective inhibitors of xanthine oxidase. More recently, the role of uric acid as a risk factor for cardiovascular disease and the possible protective role exerted by reduction of hyperuricemia to normal level have been evaluated by the use of febuxostat, a selective, non purine-like xanthine oxidase inhibitor. In this review, we will report current evidence on hyperuricemia in cardiovascular disease. The value of uric acid as a biomarker and as a potential therapeutic target for tailored old and novel "cardiometabolic" treatments will be also discussed.

Tea, flavonoids, and cardiovascular health: endothelial protection.

Several studies have suggested that tea consumption might protect against the development and progression of cardiovascular disease, one of the leading causes of morbidity and mortality worldwide. The endothelium plays a pivotal role in arterial homeostasis. Reduced nitric oxide (NO) bioavailability with endothelial dysfunction is considered the earliest step in the pathogenesis of atherosclerosis. Endothelial dysfunction has been considered an important and independent predictor of future development of cardiovascular risk and events. The association between brachial NO-dependent flow-mediated dilation (FMD) and cardiovascular disease risk has been investigated in several prospective studies, suggesting that FMD is inversely associated with future cardiovascular events. Dietary flavonoids and tea consumption have been described to improve endothelial function and FMD. A proposed mechanism by which dietary flavonoids could affect FMD is that they improve the bioactivity of the endothelium-derived vasodilator NO by enhancing NO synthesis or by decreasing superoxide-mediated NO breakdown. This could be of clinical relevance and may suggest a mechanistic explanation for the reduced risk of cardiovascular events and stroke observed among tea drinkers in the different studies. The purpose of this article is to provide an overview of the relation between tea consumption and cardiovascular disease, with a focus on clinical implications resulting from the beneficial effects of tea consumption on endothelial function.

Benefits in cognitive function, blood pressure, and insulin resistance through cocoa flavanol consumption in elderly subjects with mild cognitive impairment: the Cocoa, Cognition, and Aging (CoCoA) study.

Flavanol consumption is favorably associated with cognitive function. We tested the hypothesis that dietary flavanols might improve cognitive function in subjects with mild cognitive impairment. We conducted a double-blind, parallel arm study in 90 elderly individuals with mild cognitive impairment randomized to consume once daily for 8 weeks a drink containing ≈990 mg (high flavanols), ≈520 mg (intermediate flavanols), or ≈45 mg (low flavanols) of cocoa flavanols per day. Cognitive function was assessed by Mini Mental State Examination, Trail Making Test A and B, and verbal fluency test. At the end of the follow-up period, Mini Mental State Examination was similar in the 3 treatment groups (P=0.13). The time required to complete Trail Making Test A and Trail Making Test B was significantly (P<0.05) lower in subjects assigned to high flavanols (38.10±10.94 and 104.10±28.73 seconds, respectively) and intermediate flavanols (40.20±11.35 and 115.97±28.35 seconds, respectively) in comparison with those assigned to low flavanols (52.60±17.97 and 139.23±43.02 seconds, respectively). Similarly, verbal fluency test score was significantly (P<0.05) better in subjects assigned to high flavanols in comparison with those assigned to low flavanols (27.50±6.75 versus 22.30±8.09 words per 60 seconds). Insulin resistance, blood pressure, and lipid peroxidation also decreased among subjects in the high-flavanol and intermediate-flavanol groups. Changes of insulin resistance explained ≈40% of composite z score variability through the study period (partial r(2)=0.4013; P<0.0001). To the best of our knowledge, this is the first dietary intervention study demonstrating that the regular consumption of cocoa flavanols might be effective in improving cognitive function in elderly subjects with mild cognitive impairment. This effect appears mediated in part by an improvement in insulin sensitivity.

Cognitive decline as a consequence of essential hypertension.

Hypertension is a leading cardiovascular risk for cardiovascular morbidity and mortality. Age is the strongest risk factor for dementia and with the increasing life expectancy the number of patients living with dementia worldwide is estimated to progressively rise. A number of studies support an association between hypertension, particularly in midlife, and the development of cognitive disorders and dementia, including Alzheimer's disease. According to this, considering hypertension as a possible modifiable risk factor for the cognitive decline is of great clinical interest. Treatment of hypertension in midlife seems to promote considerable benefits with regard to cardiovascular outcomes. Longitudinal studies examining the possible benefit of anti-hypertensive treatments on cognitive decline have produced promising results. Nevertheless, the results from randomised controlled clinical trials on treatment of hypertension are not conclusive for the effect on cognitive decline and dementia. New randomized controlled trials are needed to definitively clarify clinical advantages and specifically elucidate the relationship between anti-hypertensive treatments and cognitive function or dementia.

Oxidative stress and endothelial dysfunction: say NO to cigarette smoking!

Smoking is a significant independent risk factor for cardiovascular disease and is a leading cause of structural and functional alterations of the cardiovascular system. Increasing evidence supports the hypothesis that oxidative stress and endothelial dysfunction are the fundamental pathophysiological mechanisms linking cigarette smoking to cardiovascular disease. The cardiovascular system is a rich source of NADPH oxidase-derived reactive oxygen species, which under pathological conditions play a fundamental role in vascular damage. Endothelium-derived nitric oxide (NO) plays a major role in the regulation of vascular tone, structure, and function, and endothelial dysfunction could be considered the first step in the pathogenesis of atherosclerosis and cardiovascular disease. Indeed, the bioavailability of NO is modulated by reactive oxygen species that degrade NO, uncouple NO synthase, and inhibit synthesis. Reduced bioavailability of NO and consequent endothelial dysfunction are involved in the initiation, progression and complications of atherosclerosis and also are predictive of future cardiovascular events. Thus, although data from clinical trials exploring the role of antioxidants on cardiovascular risk and disease are equivocal as yet, the role of oxidative stress in cardiovascular disease is an important area of research, which is likely to continue to be fruitful. This review focuses on possible interactions between oxidative stress, endothelial dysfunction and cigarette smoking--favouring the atherosclerotic process and cardiovascular disease--also focusing on the potential role for antioxidants in the prevention of adverse cardiovascular outcomes.