Dietary modulation of endothelial function: implications for cardiovascular disease

The vascular endothelium is the primary site of dysfunction in many diseases, particularly cardiovascular disease. A variety of risk factors, including smoking, hypercholesterolemia, hyperhomocysteinemia, hypertension, and diabetes mellitus, adversely affect endothelial function. Emerging evidence suggests an important role of dietary factors in modulating endothelial function. In particular, n-3 fatty acids, antioxidant vitamins (especially vitamins E and C), folic acid, and L-arginine appear to have beneficial effects on vascular endothelial function, either by decreasing endothelial activation or by improving endothelium-dependent vasodilation in patients at high risk of cardiovascular disease as well as in healthy subjects. These effects may serve as one potential mechanism through which these nutrients reduce the risk of cardiovascular disease, as observed in epidemiologic studies and several clinical trials. This article reviews clinical and experimental evidence regarding the role of these nutrients in modulating endothelial function and their potential to prevent cardiovascular disease.     

Vascular dementia. Advances in nosology, diagnosis, treatment and prevention

Ischemic or hemorrhagic cerebrovascular disease (CVD) produces injury of brain regions important for executive function, behavior, and memory leading to decline in cognitive functions and vascular dementia (VaD). Cardiovascular disease may cause VaD from hypoperfusion of susceptible brain areas. CVD may worsen degenerative dementias such as Alzheimer disease (AD). Currently, the global diagnostic category for cognitive impairment of vascular origin is vascular cognitive disorder (VCD). VCD ranges from vascular cognitive impairment (VCI) to VaD. The term VCI is limited to cases of cognitive impairment of vascular etiology, without dementia; VCI is equivalent to vascular mild cognitive impairment (MCI). Risk factors for VaD include age, hypertension, diabetes, smoking, cardiovascular disease (coronary heart disease, congestive heart failure, peripheral vascular disease), atrial fibrillation, left ventricular hypertrophy, hyperhomocysteinemia, orthostatic hypotension, cardiac arrhythmias, hyperfibrinogenemia, sleep apnea, infection, and high C-reactive protein. Research on biomarkers revealed increased CSF-NFL levels in VaD, whereas CSF-tau was normal. CSF-TNF-alpha, VEGF, and TGF-beta were increased in both AD and VaD. VaD shows low CSF acetylcholinesterase levels. This condition responds to acetylcholinesterase inhibitors, confirming the central role of cholinergic deficit in its pathogenesis. Evidence strongly suggests that control of vascular risk factors, in particular hypertension, could prevent VaD.     

Aspirin for the primary prevention of cardiovascular diseases in diabetic patients. A review of currently available tests

The benefits of aspirin treatment in reducing the risk of myocardial infarction, cerebrovascular accidents and vascular death is well-documented among individuals having prior cardiovascular disease, including the subgroup with diabetes mellitus. The role of aspirin in primary prevention is less clear and debatable: the results of the clinical trials currently available are not consistent, although the meta-analyses are favorable in some aspects. There seems to be a disparity between the type of benefit (when found to exist) and gender, the findings being particularly contradictory for diabetic subjects, totalling a minor percentage of the population sample included in the studies. Despite this fact, in 1997, the American Diabetes Association and more recently other scientific societies (including several Spanish societies) have been recommending the use of aspirin in low doses in primary prevention in all type 1 or type 2 diabetic patients over 40 years of age and in all those within the 21-40 age range having any other cardiovascular risk factor in addition to diabetes (family history of vascular disease, hypertension, smoking, dyslipidemia or albuminuria). This study reviews the findings of the randomized, controlled clinical trials on primary cardiovascular prevention with aspirin, on which the official American Diabetes Association guidelines might be based, the conclusion being reached that there is not currently sufficient scientific evidence to uphold these guidelines.     

Vascular risk factors, alcohol intake, and cognitive decline

Since the therapeutic options currently available have demonstrated limited efficacy, the search for preventive strategies for cognitive decline and dementia is mandatory. A possible role of vascular and lifestyle-related factors was recently proposed for age-related changes of cognitive function, predementia syndromes, and cognitive decline of degenerative (Alzheimer’s disease, AD) or vascular origin. At present, cumulative evidence suggested that vascular risk factors may be important in the development of mild cognitive impairment (MCI), dementia, and AD. Among vascular-related factors, metabolic syndrome has been associated with the risk of cognitive decline and overall dementia. Moderate alcohol drinking has been proposed as a protective factor against MCI and dementia in several longitudinal studies, but contrasting findings also exist. However, in most cases, these were only observational studies, and results are awaited from large multicenter randomized clinical trials in older persons. At present, vascular risk factor management, lifestyle changes, and drugs could be employed together to delay the onset of dementia syndromes.     

A Multifactorial Approach to Reduce Cardiovascular Disease in Type 2 Diabetes Mellitus: Now More Than Ever

Managing cardiovascular (CV) risk is an important part of caring for patients with type 2 diabetes mellitus, as the disease itself confers CV risk. Many CV risk factors (such as hypertension, dyslipidemia, and obesity) have been found to be more common among individuals with diabetes than in the general population. A growing body of evidence provides guidance for clinicians on how to balance control of hyperglycemia with management of these risk factors. Newer classes of antihyperglycemic agents have been associated with beneficial effects on several CV risk factors; several studies evaluating the effect of these newer diabetic medications on CV outcomes have been published, and several more are in progress. While evidence continues to unfold about the benefits of risk factor control in patients with type 1 diabetes mellitus, this article reviews evidence related to risk-factor control in patients with type 2 diabetes mellitus as well as recent findings on the effect of newer drug classes on CV risk factors and outcomes. Favorably altering CV risk factors appears to improve outcomes, and is more important now than ever before.     

Endothelial dysfunction in diabetes mellitus

Diabetes mellitus is associated with an increased risk of cardiovascular disease, even in the presence of intensive glycemic control. Substantial clinical and experimental evidence suggest that both diabetes and insulin resistance cause a combination of endothelial dysfunctions, which may diminish the anti-atherogenic role of the vascular endothelium. Both insulin resistance and endothelial dysfunction appear to precede the development of overt hyperglycemia in patients with type 2 diabetes. Therefore, in patients with diabetes or insulin resistance, endothelial dysfunction may be a critical early target for preventing atherosclerosis and cardiovascular disease. Microalbuminuria is now considered to be an atherosclerotic risk factor and predicts future cardiovascular disease risk in diabetic patients, in elderly patients, as well as in the general population. It has been implicated as an independent risk factor for cardiovascular disease and premature cardiovascular mortality for patients with type 1 and type 2 diabetes mellitus, as well as for patients with essential hypertension. A complete biochemical understanding of the mechanisms by which hyperglycemia causes vascular functional and structural changes associated with the diabetic milieu still eludes us. In recent years, the numerous biochemical and metabolic pathways postulated to have a causal role in the pathogenesis of diabetic vascular disease have been distilled into several unifying hypotheses. The role of chronic hyperglycemia in the development of diabetic microvascular complications and in neuropathy has been clearly established. However, the biochemical or cellular links between elevated blood glucose levels, and the vascular lesions remain incompletely understood. A number of trials have demonstrated that statins therapy as well as angiotensin converting enzyme inhibitors is associated with improvements in endothelial function in diabetes. Although antioxidants provide short-term improvement of endothelial function in humans, all studies of the effectiveness of preventive antioxidant therapy have been disappointing. Control of hyperglycemia thus remains the best way to improve endothelial function and to prevent atherosclerosis and other cardiovascular complications of diabetes. In the present review we provide the up to date details on this subject.     

B-vitamins and prevention of dementia

Elevated plasma homocysteine (Hcy) concentrations have been implicated with risk of cognitive impairment and dementia, but it is unclear whether low vitamin B12 or folate status is responsible for cognitive decline. Most studies reporting associations between cognitive function and Hcy or B-vitamins have used a cross-sectional or case-control design and have been unable to exclude the possibility that such associations are a result of the disease rather than being causal. The Hcy hypothesis of dementia has attracted considerable interest, as Hcy can be easily lowered by folic acid and vitamin B12, raising the prospect that B-vitamin supplementation could lower the risk of dementia. While some trials assessing effects on cognitive function have used folic acid alone, vitamin B12 alone or a combination, few trials have included a sufficient number of participants to provide reliable evidence. An individual-patient-data meta-analysis of all randomised trials of the effects on cognitive function and vascular risk of lowering Hcy with B-vitamins will maximise the power to assess the epidemiologically-predicted differences in risk. Among the twelve large randomised Hcy-lowering trials for prevention of vascular disease, data should be available on about 30 000 participants with cognitive function. The principal investigators of such trials have agreed to combine individual-participant data from their trials after their separate publication.     

Risk factors and neurodegenerative mechanisms in stroke related dementia

Considerable evidence indicates that systemic vascular diseases are associated with neurodegenerative processes preceding cognitive decline and dementia. Conditions such as hypertension, diabetes, atrial fibrillation, ischemic heart disease, dyslipidaemia and obesity have propensity to induce strokes, which increase risk of dementia up to five-fold in the elderly. The link between vascular diseases and clinical Alzheimer's disease (AD) also exists but pathological confirmation has often been lacking. However, more than 30% of stroke survivors will develop dementia within two years. Transient ischaemic attacks and silent infarcts may unmask neurodegenerative processes characterized by primary pathologies such as those found in AD. Cerebral infarction and neurodegenerative pathologies are additive and accelerate dementia. Medial temporal atrophy is a strong predictor of dementia and also appears a feature in demented stroke survivors with minimal AD pathology. The atrophy is attributed to selective smaller cell volumes in the hippocampus and likely frontal lobe that may reflect loss of neuronal arborization and connectivity. Therapeutic strategies that maintain or restore functional morphology in surviving neurons could prevent further cognitive decline in post stroke and ageing related dementias.     

Management of Hypertension in Patients with Diabetes Mellitus

Hypertension and diabetes mellitus are significant and independent risk factors for cardiovascular disease.Antihypertensive therapy reduces cerebrovascular and cardiovascular morbidity and mortality in patients with hypertension. Tight blood pressure (BP) control [target diastolic BP (DBP) ≤80mm Hg] reduced the incidence of major cardiovascular events by 51% compared with less tight control (DBP ≤90mm Hg) in patients with diabetes mellitus in the Hypertension Optimal Treatment (HOT) study. Similarly, in the UK Prospective Diabetes Study (UKPDS), tight BP control [mean systolic BP (SBP)/DBP = 144/82mm Hg] with captopril or atenolol reduced diabetes mellitus-related morbidity and mortality by 24% compared with less tight control (mean SBP/DBP = 154/87mm Hg). Importantly, the frequency of microvascular disease (including retinopathy) was reduced by 37% among those randomised to tight BP control in the UKPDS.In the diabetic subgroup in the Heart Outcomes Prevention Evaluation (HOPE) study, there was a 25% reduction in the composite end-point of death due to cardiovascular causes, or myocardial infarction or stroke during 5 years of treatment with ramipril 10 mg/day relative to placebo.Lisinopril is an ACE inhibitor indicated for use in hypertension, heart failure and post-myocardial infarction. As an antihypertensive agent the drug is effective and generally well tolerated in patients with type 1 or 2 diabetes mellitus and in those with early or overt nephropathy.In the Swedish Treatment of Old People (STOP) Hypertension 2 trial, there was no difference in the relative risk of cardiovascular death between those assigned to ACE inhibitors (lisinopril or enalapril), calcium channel blockers (felodipine or isradipine) or ‘conventional’ antihypertensive therapy (thiazide diuretics or β blockers); treatment effects did not differ significantly between diabetic and nondiabetic patients (10.9% of the 6614 patients had diabetes mellitus). Importantly, lower frequencies of nonfatal or fatal myocardial infarction [relative risk (RR) 0.77; 95% confidence interval (CI) 0.61 to 0.96] and congestive heart failure (RR 0.78; CI 0.83 to 0.97) were detected during 4 years’ treatment with lisinopril or enalapril than felodipine or isradipine in this study.Lisinopril reduced albumin excretion rates in patients with type 1 or 2 diabetes mellitus. In the 2-year EURODIAB Controlled Trial of Lisinopril in IDDM (EUCLID) study, albumin excretion rates decreased by 49.7% relative to placebo in normotensive patients with type 1 diabetes mellitus and microalbuminuria during treatment with lisinopril 10 to 20 mg/day. Progression of retinopathy was attenuated in normotensive patients with type 1 diabetes mellitus during treatment with lisinopril in this study.In conclusion, lisinopril, like other ACE inhibitors should be considered a first-line agent for reducing BP and attenuating nephropathy in patients with type 1 or 2 diabetes mellitus.     

瑞典斯德哥尔摩市社区人群老年痴呆和阿尔茨海默病的危险因素队列研究

目的探讨老年痴呆和阿尔茨海默病（AD）的危险因素。方法在6年问（1991-1996年）对斯德哥尔摩市一个社区非痴呆老年人群（n=1301，年龄≥75岁）进行两次随访检查，并按照美国老年精神病协会制订的DSM—Ⅲ—R标准诊断随访期间痴呆和AD新发病例。研究对象在基线调查时对有关因素暴露情况系经问卷调查、临床检查和查阅住院病例登记资料库等方法确定。采用Cox比例风险模型对资料进行统计分析。结果随访期间共有350例被诊断为痴呆，包括260例AD患者。多因素分析结果显示，痴呆和AD发病的危险因素有年龄大、文化程度低、认知功能损害、体力活动障碍、低舒张压、糖尿病、缺血性心脏病和携带APOEa4基因。脑卒中和心房纤维颤动亦能增加痴呆的危险性，而服用抗高血压药物则可降低痴呆和AD发病的危险性。结论某些人口统计学因素、认知和体力功能障碍、血管性疾病及遗传易感性是老年痴呆和AD的重要危险因素；使用抗高血压药物及控制高血压相关的血管性疾病可能会降低痴呆发病的危险性。     

关于2型糖尿病并发末梢神经病变危险因素的病例对照研究

糖尿病末梢神经病变(Diabetic Peripheral Neuropathy,DPN)是糖尿病常见并发症之一,不仅本身严重危害健康,有很高的病死率,而且与其他慢性并发症的发生发展关系密切。目的探讨2型糖尿病病人并发DPN的危险因素。方法采用以医院为基础的1:1配对病例对照研究方法。运用条件Logistic回归分析,建立主效应方程分析讨论DPN的危险因素。结果单因素Logistic回归分析表明,DPN发生的保护性因素包括:文化程度高、治疗方法力度大、现患冠心病、饮茶;危险因素包括:糖尿病病程长、血糖控制(HbAlc%)不良、使用胰岛素、合并糖尿病肾病、合并糖尿病视网膜病变、主诉眩晕症状、皮肤干燥、现患高血压、既往酮症、患糖尿病前肉类食物的摄入较多、既往吸烟(调查时已戒烟)、创伤经历、腰臀比WHR超标、血胆固醇(Chol)水平高。多因素Logistic回归分析示DPN发生的危险因素有6个:糖尿病病程、使用胰岛素、主诉眩晕症状、糖尿病前肉类食物摄入较多、饮酒以及既往创伤经历(手术、冻伤等)。结论DPN与多种因素相关,在2型糖尿病患者中,糖尿病病程长、使用胰岛素、主诉眩晕症状、糖尿病前肉类食物摄入较多、饮酒、既往创伤史会增加糖尿病神经病变的发生危险,我们应在DPN的防治过程中特别予以注意。     

Cerebral small vessel disease, cognitive impairment and vascular dementia

In recent years, accumulating evidence has suggested that vascular risk factors (especially hypertension, and also diabetes, high level of cholesterol and smoking) contribute to Alzheimer disease. Vascular dementia had been traditionally considered secondary to stroke and vascular disease. However it appears that there is a continuous spectrum of disease, composed of a gradient of features of both types of dementia. The brain is an early target for organ damage due to high blood pressure. Hypertension is the major modifiable risk factor for stroke and small vessel disease and is known to be the most-important factor for macrovascular cerebral complications such as atherotrombotic stroke and, consequently, vascular dementia. Hypertension may also predispose to more subtle cerebral processes based on arteriolar narrowing or microvascular pathological changes. The term cerebral small vessel disease refers to a group of pathological processes with various etiologies that affect the small arteries, arterioles, venules, and capillaries of the brain. Age-related and hypertension-related small vessel diseases and cerebral amyloid angiopathy are the most common forms. It has been suggested that cerebral microvascular disease contributes to vascular cognitive impairment. The mechanisms underlying hypertension-related cognitive changes are complex and not yet fully understood. Both high and, especially in the elderly, low blood pressure have been linked to cognitive decline and dementia. There is some evidence that antihypertensive drug treatment could play a role in the prevention of cognitive impairment or vascular dementia through BP control. The BP levels that should be targeted to achieve optimal perfusion while preventing cognitive decline are still under debate.     

The relationship between parental history of vascular disease and cardiovascular disease risk factors in children: the Bogalusa Heart Study

The relationship between parental history of vascular disease (heart attack, stroke, diabetes mellitus, and hypertension) and risk factor variables for cardiovascular disease was assessed in 3,312 offspring aged 5-17 years during the 1981-1982 school year in the biracial community of Bogalusa, Louisiana. Risk factors studied included systolic blood pressure, diastolic blood pressure, serum total cholesterol, triglycerides, and individual lipoprotein cholesterol (beta-, low density lipoprotein (LDL) cholesterol; pre-beta, very low density lipoprotein (VLDL) cholesterol; and alpha-, high density lipoprotein (HDL) cholesterol). Risk factors were adjusted for age, race, sex, and height (blood pressure only) prior to testing parental history effects. Univariate comparisons between risk factors in children and vascular disease in parents resulted in statistically significant increases in systolic and diastolic pressures associated with the presence of maternal or paternal hypertension (p less than 0.001). Paternal heart attack was also associated with elevations in diastolic pressure (p less than 0.01) of children. Maternal diabetes mellitus was associated with an increase in serum total cholesterol (p less than 0.05). Paternal diabetes mellitus and maternal heart attack (for female progeny only) were associated with increases in mean triglyceride levels of children. VLDL cholesterol results were similar to those for triglycerides. For HDL cholesterol, paternal diabetes mellitus was associated with a small decrease in mean levels (p less than 0.05). Dramatic increases to the highest decile of risk were found in association with the following parental disease combinations: paternal heart attack-paternal diabetes for serum total cholesterol (p less than 0.0001), maternal heart attack-paternal diabetes (p less than 0.001) and paternal stroke-maternal diabetes (p less than 0.0001) for LDL cholesterol. Multivariate analysis detected no significant effects of single parental vascular disease. However, paternal heart attack in combination with either diabetes mellitus or hypertension was statistically significant in their relationship to the risk factors overall.     

Homocysteine and Alzheimer's disease

In a recent case-control study of 164 patients with clinically diagnosed Alzheimer's disease (AD), including 76 patients with the AD diagnosis confirmed postmortem, mean total serum homocysteine concentration was found to be significantly higher than that of a control group of elderly individuals with no evidence of cognitive impairment. Because homocysteine is considered an independent risk factor for vascular disease, this finding is consistent with the emerging hypothesis that vascular disease is a contributing factor in the pathogenesis of AD.     

Vitamin D and cardiovascular disease and cancer: not too much and not too little? The need for clinical trials

Low vitamin D levels are more common in women than in men. Low vitamin D levels have been implicated in numerous disease processes including fracture risk, falls, cardiovascular disease, hypertension, diabetes mellitus and cancers. In this article we review recent evidence regarding associations between low vitamin D levels and cancers and cardiovascular disease. We also review evidence regarding associations between high vitamin D levels and vascular calcifications and pancreatic cancer. It appears that there is probably an optimal level of vitamin D that is neither too high nor too low that is required to maximize health. On going clinical trials should aid in elucidating the optimal levels of 25-hydroxyvitamin D for numerous health outcomes.     

Shared Neuropathological Characteristics of Obesity,Type 2 Diabetes and Alzheimer’s Disease: Impacts on Cognitive Decline

In the past few decades, the prevalence of obesity and type 2 diabetes mellitus (T2DM), as well as older individuals at risk for Alzheimer’s disease (AD), has increased. While the consumption of diets high in fat (total and saturated) have been linked to increased risk of AD, diets rich in antioxidants, polyunsaturated fats, and omega-3 fatty acids are associated with decreased risk. Additionally, AD patients are at increased risk for developing T2DM. Recent research suggests that there are stronger similarities between AD and T2DM than have previously been considered. Here we review the neurocognitive and inflammatory effects of high-fat diet consumption, its relationship to AD, and the treatment potential of dietary interventions that may decrease risk of cognitive decline and other associated neuropathological changes, such as insulin resistance, oxidative stress, and chronic inflammatory processes.     

Can vitamin D deficiency cause diabetes and cardiovascular diseases? Present evidence and future perspectives

Several studies have shown that vitamin D may play a role in many biochemical mechanisms in addition to bone and calcium metabolism. Recently, vitamin D has sparked widespread interest because of its involvement in the homeostasis of the cardiovascular system. Hypovitaminosis D has been associated with obesity, related to trapping in adipose tissue due to its lipophilic structure. In addition, vitamin D deficiency is associated with increased risk of cardiovascular disease (CVD) and this may be due to the relationship between low vitamin D levels and obesity, diabetes mellitus, dyslipidaemia, endothelial dysfunction and hypertension. However, although vitamin D has been identified as a potentially important marker of CVD, the mechanisms through which it might modulate cardiovascular risk are not fully understood. Given this background, in this work we summarise clinical retrospective and prospective observational studies linking vitamin D levels with cardio-metabolic risk factors and vascular outcome. Moreover, we review various randomised controlled trials (RCTs) investigating the effects of vitamin D supplementation on surrogate markers of cardiovascular risk. Considering the high prevalence of hypovitaminosis D among patients with high cardiovascular risk, vitamin D replacement therapy in this population may be warranted; however, further RCTs are urgently needed to establish when to begin vitamin D therapy, as well as to determine the dose and route and duration of administration.     

老年2型糖尿病合并高血压患者认知功能改变特点及危险因素研究

目的分析老年2型糖尿病合并高血压患者认知功能的改变特点和相关危险因素。方法选取2016年9月—2017年6月在上海市普陀区真如镇社区卫生服务中心门诊和住院诊治的225例老年患者为研究对象,其中单纯糖尿病患者78例为A组,单纯高血压患者84例为B组,糖尿病合并高血压患者63例为C组,收集患者的一般资料,测定生化指标。采用蒙特利尔认知评估量表(Montreal Cognitive Assessment,Mo CA)、简易智能状态量表(Mini-Mental State Examination,MMSE)对三组患者进行认知功能评价,了解患者认知功能的改变特点。根据Mo CA评分,将225例患者筛选出轻度认知障碍(MCI)组86例和非MCI组139例,分析两组患者认知功能的改变特点和相关危险因素。结果 C组Mo CA评分明显低于A组、B组,C组命名、注意力明显低于B组,三组之间抽象思维差异有统计学意义;C组患者MCI发生率明显高于A组和B组(P0.05)。MCI组与非MCI组患者在年龄、受教育年限、FPG、Hb A1c和HCY的差异有统计学意义(P0.05)。多元回归分析结果显示:年龄、HCY和Hb A1c是老年患者发生认知功能损害的危险因素,受教育年限是发生认知功能损害的保护因素(P0.05)。结论老年2型糖尿病合并高血压患者MCI发生率明显高于单纯糖尿病组和单纯高血压组。     

Diabetic nephropathy: the role of blood pressure and extra-cellular volume in its pathogenesis and treatment

Hypertension is an important risk factor for the development of cardiovascular disease and for the progression of renal insufficiency. In the pathophysiology of hypertension in diabetes mellitus, expansion of the extracellular fluid volume has a pivotal role. Coinciding derangements are probably responsible for this expansion: increased proximal tubular reabsorption, inadequate activation of the renin-angiotensin system and impaired renal autoregulation. Together, these lead to glomerular hypertension and resultant glomerular damage. Many clinical trials emphasise the importance of the renin-angiotensin system in the treatment of diabetics with hypertension. There are strong indications that correction of the excess volume is pivotal in the treatment of hypertension in patients with diabetic nephropathy. However, many recent studies have omitted consideration of the role of extracellular fluid-volume expansion. Many questions remain unanswered about the pathophysiology of hypertension in diabetes mellitus. More insight into the pathophysiology could well result in improved treatment of the hypertension and thus help to delay the progression of diabetic nephropathy.