New insights to the mechanisms underlying atherosclerosis in rheumatoid arthritis

Rheumatoid arthritis (RA) is an inflammatory circumstance, which has been associated with increased risk of cardiovascular disease (CVD). Although RA management has been promoted, mortality rate due to CVD remains remarkable. Approximately, 50% of premature death cases in RA are attributable to CVD. RA patients develop atherosclerosis in a greater amount than the general population. Moreover, atherosclerotic lesions develop rapidly in RA patients and might be more susceptible to rupture. The inflammatory condition of RA, such as cytokines, abnormally activated immune cells, play a role in the initiation, perpetuation and exacerbation of atherosclerosis. RA and CVD have genetic and environmental contributing risk factors in common, implying to potential coincidence of both disorders. Accelerated atherosclerosis in RA is attributed to inflammation, which carries its role out both through modulation of traditional risk factors and direct effect on the vessel wall. Hence, anti‐inflammatory medications in RA like tumor necrosis factor blockers might have a beneficial effect on preventing cardiovascular development. Increasing age, smoking, hypertension, male gender, hypercholesterolemia and diabetes are enumerated as traditional CVD risk factors. Hopefully, further understanding of the cardiovascular risk factors by perceiving the disease conditions behind CVD, will improve management of cardiovascular risks in patients with RA.     

Intestinal Microbiota in Cardiovascular Health and Disease: JACC State-of-the-Art Review

Despite major strides in reducing cardiovascular disease (CVD) burden with modification of classic CVD risk factors, significant residual risks remain. Recent discoveries that linked intestinal microbiota and CVD have broadened our understanding of how dietary nutrients may affect cardiovascular health and disease. Although next-generation sequencing techniques can identify gut microbial community participants and provide insights into microbial composition shifts in response to physiological responses and dietary exposures, provisions of prebiotics or probiotics have yet to show therapeutic benefit for CVD. Our evolving understanding of intestinal microbiota-derived physiological modulators (e.g., short-chain fatty acids) and pathogenic mediators (e.g., trimethylamine N-oxide) of host disease susceptibility have created novel potential therapeutic opportunities for improved cardiovascular health. This review discusses the roles of human intestinal microbiota in normal physiology, their associations with CVD susceptibilities, and the potential of modulating intestinal microbiota composition and metabolism as a novel therapeutic target for CVD.     

Food factors for atherosclerosis prevention: Asian perspective derived from analyses of worldwide dietary biomarkers

Worldwide epidemiological surveys covering 61 populations in 25 countries have shown that fish and soybean diets contribute to healthy longevity through the prevention of cardiovascular diseases in the Japanese population, particularly in Okinawans who consume a lot of fish and soy products. This is supported by the finding that 24 h urinary excretions of taurine and isoflavones, which are rich in fish and soybeans, are inversely related to mortality rates of coronary artery disease (CAD). Immigrant studies of Okinawans in Hawaii (USA) and Brazil showed that dietary factors were more important determinants of cardiovascular diseases than genetic factors. Intervention studies in these immigrants and Scottish people, whose CAD mortality rates are among the highest in the world, confirmed that diets fortified with fish oil (docosahexaenoic acid) and soy protein (isoflavone) alleviated the risks of CAD and osteoporosis. Asian eating patterns, consisting of daily seafood and/or soy consumption, confer protection against CAD despite a Westernized life style; moreover, dietary biomarkers indicate that approximately 100 g of soybean curd (tofu) or fish may contribute to lower CAD mortality, as low as that found among the Japanese.     

Chronic kidney disease in postmenopausal women

Menopause is derived from the Greek words men (month) and pauses (cessation) and means permanent cessation of menstruation after the loss of ovarian activity. Chronic kidney disease (CKD) has recently been associated with cardiovascular events in several studies. CKD patients have a heavy burden of traditional cardiovascular risk factors in addition to a range of nontraditional risk factors such as inflammation and abnormal metabolism of calcium and phosphate. In this review, the association of CKD and cardiovascular disease (CVD), as well as of osteoporosis in postmenopausal women is discussed. CKD mineral and bone disorder, characterized by disturbances of calcium/phosphate/parathyroid hormone, bone abnormalities and vascular and soft tissue calcification, is highly prevalent in CKD and is a strong, independent predictor of bone fracture, CVD and death. Estrogen has been shown to: (a) decrease the expression of angiotensin type 1 receptors in vasculature and kidneys; (b) reduce the expression and activity of angiotensin-converting enzyme, and (c) cause the release of angiotensinogen substrate from the liver. However, the degree of activation or suppression of the renin-angiotensin-aldosterone system by estrogen has not been clearly established. Clinical data on the effects of estrogen therapy on bone mineral densities are extremely limited in the ESRD population. CVD is the most common cause of death in postmenopausal women with CKD and many contributing factors have been explored. Future research for prevention of CVD in postmenopausal women with CKD would focus on the biology of vascular calcification as well as bone loss.     

Consensus recommendations on managing the selected comorbidities including cardiovascular disease,osteoporosis, and interstitial lung disease in rheumatoid arthritis

Background:Rheumatoid arthritis (RA)-related comorbidities, including cardiovascular disease (CVD), osteoporosis (OP), and interstitial lung disease (ILD), are sub-optimally managed. RA-related comorbidities affect disease control and lead to impairment in quality of life. We aimed to develop consensus recommendations for managing RA-related comorbidities.Methods:The consensus statements were formulated based on emerging evidence during a face-to-face meeting of Taiwan rheumatology experts and modified through three-round Delphi exercises. The quality of evidence and strength of recommendation of each statement were graded after a literature review, followed by voting for agreement. Through a review of English-language literature, we focused on the existing evidence of management of RA-related comorbidities.Results:Based on experts’ consensus, eleven recommendations were developed. CVD risk should be assessed in patients at RA diagnosis, once every 5 years, and at changes in DMARDs therapy. Considering the detrimental effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids on CVD risks, we recommend using the lowest possible dose of corticosteroids and prescribing NSAIDs cautiously. The OP/fragility fracture risk assessment includes dual-energy X-ray absorptiometry and fracture risk assessment (FRAX) in RA. The FRAX-based approach with intervention threshold is a useful strategy for managing OP. RA-ILD assessment includes risk factors, pulmonary function tests, HRCT imaging and a multidisciplinary decision approach to determine RA-ILD severity. A treat-to-target strategy would limit RA-related comorbidities.Conclusions:These consensus statements emphasize that adequate control of disease activity and the risk factors are needed for managing RA-related comorbidities, and may provide useful recommendations for rheumatologists on managing RA-related comorbidities.     

Polycystic ovary syndrome and cardiometabolic risk: Opportunities for cardiovascular disease prevention

Although polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders affecting women, its etiology is not entirely understood. Clinical symptoms of PCOS include acne, amenorrhea or oligomenorrhea, hirsutism, infertility, and mood disorders, which tend to be the primary focus of clinical management. However, the impact of PCOS on future cardiovascular disease (CVD) risk should not be overlooked, and opportunities to implement CVD prevention strategies in these women should be given high priority. The pathogenesis of PCOS commonly involves insulin resistance which leads to several cardiometabolic abnormalities (e.g., dyslipidemia, hypertension, glucose intolerance, diabetes, and metabolic syndrome), thereby putting women at an increased risk for CVD. Prior studies have found that subclinical CVD markers such as coronary artery calcium scores, C-reactive protein, carotid intima-media thickness, and endothelial dysfunction are more likely to be increased in women with PCOS. While the associations between PCOS and cardiometabolic abnormalities have been well established, whether PCOS is associated with subclinical and clinical CVD, independently of these CVD risk factors, is not entirely clear. Lifestyle interventions and weight management may mitigate some of these future CVD risks and should be encouraged. This review summarizes the literature on PCOS and CVD risk factors and provides recommendations that would aid clinicians in the management of these risk factors.     

Dietary Factors,Dietary Patterns,and Cardiovascular Disease Risk in Representative Japanese Cohorts: NIPPON DATA80/90

Diet is one of the most important factors affecting healthy life expectancy through the onset of cardiovascular disease (CVD) risk as well as various chronic diseases. Because dietary habits and disease structure differ depending on the country, region, and/or race, evidence from each population is required. NIPPON DATA80/90 is a long-term cohort study of a representative Japanese population that participated in national nutrition surveys. Among the many findings of this cohort study, a dietary pattern with higher intake of fruits, vegetables, fish (n-3 polyunsaturated fatty acids), and dietary fiber and lower intake of salt as well as sodium-to-potassium ratio was found to be associated with a lower risk of CVD mortality. The results from our cohort study would be useful for effectively preventing CVD. This article reviews the published studies from the NIPPON DATA80/90 to highlight the significant findings that may be used to develop risk prevention strategies for CVD.     

Cardiovascular Risk Factors and Prevention: A Perspective From Developing Countries

By the beginning of the 21st century, cardiovascular disease (CVD) had become the leading cause of premature mortality and morbidity worldwide, with 80% originating from less developed lower-income countries in line with societal and economic developments. Extensive research on causes and risk factors have been carried out since the mid-20th century and have established individual factors such as smoking, hypertension, diabetes, and dyslipidemia as CVD risk factors, followed by others. Two recent major case-control studies have summarized the role of common major CVD risk factors in determining the risk of myocardial infarction (INTERHEART study) and stroke (INTERSTROKE study). They showed that 9 and 10 common risk factors accounted for > 90% of the risk of myocardial infarction and stroke, respectively, and established the focus in prevention of these common CVDs. The efficacy of lowering blood pressure, blood glucose, and lipid-lowering therapies has been shown to reduce subsequent morbidity and mortality. Leading international health organizations have published guidelines that are updated regularly to set the standards for providing guidance for implementation and management of risk factors. Interventions can also be costly and long-term adherence, essential to be effective in reducing risks, tends to decrease drastically with time. Dietary recommendations have been incorporated into national and professional guidelines for CVD prevention since the 1960s. On the basis of new research, some existing dietary recommendation might be outdated and should be reviewed, and revised, if necessary. A perspective of CVD prevention and treatment in developing countries is highlighted.     

Molecular Basis of Obesity and the Risk for Cardiovascular Disease

Atherosclerosis and cardiovascular disease (CVD) are the main causes of death in the Western world, for both men and women. The onset and development of diseases of the cardiovascular and cerebrovascular system are strongly dependent on multiple risk factors that promote pathologic conditions like atherosclerosis, hypertension and thrombosis. Besides genetic factors also environmental influences such as diet composition are known to be closely related to CVD. In this context obesity has been postulated as an independent cardiovascular risk factor. Data from the Framingham Heart Study have consistently shown that increasing degrees of obesity are accompanied by greater rates of CVD. At present, obesity affects 10-35% of the European and US population and increases steadily. As obesity is a serious health problem which promotes metabolic abnormalities (insulin resistance, hyperinsulinemia and dyslipidemia) and dramatically increases the risk for CVD, this review will focus on the epidemiologic and genetic background of obesity. Furthermore, the molecular mechanisms involved in obesity development and their contribution to CVD will be discussed.     

Pathology supported genetic testing and treatment of cardiovascular disease in middle age for prevention of Alzheimer’s disease

Chronic, multi-factorial conditions caused by a complex interaction between genetic and environmental risk factors frequently share common disease mechanisms, as evidenced by an overlap between genetic risk factors for cardiovascular disease (CVD) and Alzheimer's disease (AD). Single nucleotide polymorphisms (SNPs) in several genes including ApoE, MTHFR, HFE and FTO are known to increase the risk of both conditions. The E4 allele of the ApoE polymorphism is the most extensively studied risk factor for AD and increases the risk of coronary heart disease by approximately 40%. It furthermore displays differential therapeutic responses with use of cholesterol-lowering statins and acetylcholinesterase inhibitors, which may also be due to variation in the CYP2D6 gene in some patients. Disease expression may be triggered by gene-environment interaction causing conversion of minor metabolic abnormalities into major brain disease due to cumulative risk. A growing body of evidence supports the assessment and treatment of CVD risk factors in midlife as a preventable cause of cognitive decline, morbidity and mortality in old age. In this review, the concept of pathology supported genetic testing (PSGT) for CVD is described in this context. PSGT combines DNA testing with biochemical measurements to determine gene expression and to monitor response to treatment. The aim is to diagnose treatable disease subtypes of complex disorders, facilitate prevention of cumulative risk and formulate intervention strategies guided from the genetic background. CVD provides a model to address the lifestyle link in most chronic diseases with a genetic component. Similar preventative measures would apply for optimisation of heart and brain health.     

Overview: Studies on Spontaneous Hypertension - Development from Animal Models Toward Man

The development of genetic rat models for research on hypertension, stroke and other cardiovascular diseases (CVD) such as spontaneously hypertensive rats (SHR) and strokeprone SHR (SHRSP) have contributed not only to the elucidation of the pathogenesis of hypertension-related CVD but also to their prediction and prevention. Since both genetic and environmental factors are involved in the pathogenesis of CVD as extensively studied so far on these models, the detection of the early pathogenic mechanisms related to the genetic factors and the control of environmental factors such as dietary improvement are useful as predictive and preventive measures against CVD. Sympathetic overresponsiveness, early development of cardiovascular hypertrophy, increased salt sensitivity and membrane or transport abnormalities in vascular smooth muscle cells (VSMC) from SHR and SHRSP, possibly related to the pathogenesis of hypertension, are so far regarded as predictors for hypertension partly applicable to human hypertension. Genetic pathogenic mechanisms of stroke in SHRSP which have been proven to be greatly influenced also by dietary factors are hypertension-induced VSMC degeneration and necrosis of intracerebral arteries due to local nutritional disturbance. One of predictors of stroke related to the pathogenic mechanisms is reduction of regional cerebral blood flow. On the other hand, the control of environmental factors, especially nutrition and diets such as intakes of animal and vegetable proteins, some amino acids and fatty acids, potassium, calcium, magnesium, dietary fibers, etc., have been experimentally demonstrated to be effective for the prevention of CVD in these genetic models, and the applicability of these experimental findings to the CVD prevention in man is now supported from our world-wide epidemiological studies (WHO CARDIAC Study).     

Relevance of genetics and genomics for prevention and treatment of cardiovascular disease: a scientific statement from the American Heart Association Council on Epidemiology and Prevention, the Stroke Council, and the Functional Genomics and Translational Biology Interdisciplinary Working Group

Atherosclerotic cardiovascular disease (CVD) is a major health problem in the United States and around the world. Evidence accumulated over decades convincingly demonstrates that family history in a parent or a sibling is associated with atherosclerotic CVD, manifested as coronary heart disease, stroke, and/or peripheral arterial disease. Although there are several mendelian disorders that contribute to CVD, most common forms of CVD are believed to be multifactorial and to result from many genes, each with a relatively small effect working alone or in combination with modifier genes and/or environmental factors. The identification and the characterization of these genes and their modifiers would enhance prediction of CVD risk and improve prevention, treatment, and quality of care. This scientific statement describes the approaches researchers are using to advance understanding of the genetic basis of CVD and details the current state of knowledge regarding the genetics of myocardial infarction, atherosclerotic CVD, hypercholesterolemia, and hypertension. Current areas of interest and investigation--including gene-environment interaction, pharmacogenetics, and genetic counseling--are also discussed. The statement concludes with a list of specific recommendations intended to help incorporate usable knowledge into current clinical and public health practice, foster and guide future research, and prepare both researchers and practitioners for the changes likely to occur as molecular genetics moves from the laboratory to clinic.     

提高对非酒精性脂肪性肝病的认识,早期防治代谢紊乱

非酒精性脂肪性肝病(NAFLD)十分常见,在普通人群中患病率为10%～24%,在糖尿病人群中高达70%～80%,近年来在亚太地区和我国呈上升趋势,我国上海城市社区人群中NAFLD患病率已达15%.大量研究表明NAFLD是代谢综合征在肝脏的表现,NAFLD不仅与代谢综合征密切伴随,而且还可预测2型糖尿病和心血管疾病的发生.由于肝脏是调节和控制糖脂代谢的中枢器官,肝脏脂肪沉积在代谢紊乱相关疾病的发病中起着关键作用.对专科医生尤其是内分泌科医生来说,认识到NAFLD与糖尿病和心血管疾病的密切关系至关重要.对NAFLD应该及早正确诊断,并且及时评估这些患者糖尿病和心血管疾病的风险,这对于预防糖尿病和心血管疾病具有重要意义.     

Vitamin D, cardiovascular disease and mortality

A poor vitamin D status, i.e. low serum levels of 25-hydroxyvitamin D [25(OH)D], is common in the general population. This finding is of concern not only because of the classic vitamin D effects on musculoskeletal outcomes, but also because expression of the vitamin D receptor (VDR) and vitamin D metabolizing enzymes in the heart and blood vessels suggests a role of vitamin D in the cardiovascular system. VDR-knockout mice suffer from cardiovascular disease (CVD), and various experimental studies suggest cardiovascular protection by vitamin D, including antiatherosclerotic, anti-inflammatory and direct cardio-protective actions, beneficial effects on classic cardiovascular risk factors as well as suppression of parathyroid hormone (PTH) levels. In epidemiological studies, low levels of 25(OH)D are associated with increased risk of CVD and mortality. Data from randomized controlled trials (RCTs) are sparse and have partially, but not consistently, shown some beneficial effects of vitamin D supplementation on cardiovascular risk factors (e.g. arterial hypertension). We have insufficient data on vitamin D effects on cardiovascular events, but meta-analyses of RCTs indicate that vitamin D may modestly reduce all-cause mortality. Despite accumulating data suggesting that a sufficient vitamin D status may protect against CVD, we still must wait for results of large-scale RCTs before raising general recommendations for vitamin D in the prevention and treatment of CVD. In current clinical practice, the overall risks and costs of vitamin D supplementation should be weighed against the potential adverse consequences of untreated vitamin D deficiency.     

Nonconventional genetic risk factors for cardiovascular disease

Despite numerous advances made in identifying the genes for rare mendelian forms of cardiovascular disease (CVD), relatively little is known about the common, complex forms at the genetic level. Moreover, most genes that have been associated with CVD, whether they are single gene forms or more common forms of the disease, have primarily been involved in biochemical pathways related to what are considered “conventional” risk factors. However, recent genetic studies have begun to identify genes and pathways associated with CVD that would not be considered to underlie conventional risk factors. In this review, we discuss the evidence for this latter notion based on recent linkage and association studies in humans. As an example, we also illustrate how a combination of mouse and human genetics led to identification of the 5-lipoxygenase pathway for CVD, with potentially important implications for its treatment and diagnosis. We conclude with a discussion of the prospects for identifying CVD genes in the future and for potentially developing more effective therapeutic strategies.     

Targeting Inflammation as a Therapeutic Strategy in Accelerated Atherosclerosis in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is an autoimmune disease affecting approximately 1% of the population. Patients have reduced life expectancy and the leading cause of death is cardiovascular disease (CVD), with patients experiencing at least a 2‐fold increased risk of myocardial infarction. RA is recognized as an independent risk factor for CVD. Inflammation is a key contributor to the pathogenesis of atherosclerosis and cardiovascular events. As a common catalyst of both diseases, inflammation is the likely cause of increased prevalence of CVD in the RA population. Abating disease‐related inflammation in RA may be an effective strategy in reducing CVD risk. Several other therapies used to modify cardiovascular risk factors in the general population such as statins and angiotensin‐converting enzyme inhibitors are under investigation in patients with RA. This review discusses the parallels in the pathology of RA and atherosclerosis and discusses current therapies for RA and how they affect cardiovascular risk.     

Genetic factors in cardiovascular disease. 10 questions

The common forms of cardiovascular disease (CVD) have a complex etiology, involving multiple genetic influences and important environmental interactions. Because of this complexity, it has proved difficult to apply the positional cloning approaches that have revolutionized understanding of Mendelian (single-gene) disorders; and the understanding of the genetics of CVD and its underlying cause, atherosclerosis, remains poor. This review, organized into 10 broad questions, summarizes the understanding of the genetics of common, complex forms of CVD. Implications for DNA-based diagnosis, pharmacogenetics, and risk assessment are also discussed.     

Cardiovascular Disease in Systemic Lupus Erythematosus: The Role of Traditional and Lupus Related Risk Factors

Atherosclerosis is a chronic inflammatory disorder characterized by immune cell activation, inflammation driven plaque formation and subsequent destabilization. In other disorders of an inflammatory nature, the chronic inflammatory state per se has been linked to acceleration of the atherosclerotic process which is underlined by an increased incidence of cardiovascular disease (CVD) in disorders such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and antiphopholipid (Hughes) syndrome (APS). SLE is an autoimmune disease that may affect any organ. Premature coronary heart disease has emerged as a major cause of morbidity and mortality in SLE. In addition to mortality, cardiovascular morbidity is also markedly increased in these patients, compared with the general population. The increased cardiovascular risk can be explained only partially by an increased prevalence of classical risk factors for cardiovascular disease; it also appears to be related to inflammation. Inflammation is increasingly being considered central to the pathogenesis of atherosclerosis and an important risk factor for vascular disease. Recent epidemiologic and pathogenesis studies have suggested a great deal in common between the pathogenesis of prototypic autoimmune disease such as SLE and that of atherosclerosis.We will review traditional risk factors for CVD in SLE. We will also discuss the role of inflammation in atherosclerosis, as well as possible treatment strategies in these patients.Key Words: Cardiovascular disease, systemic lupus erythematosus, atherosclerosis.     

Osteoporosis and cardiovascular disease: brittle bones and boned arteries, is there a link?

Both osteoporosis and cardiovascular disease (CVD) are major public health problems leading to increased morbidity and mortality. Although traditionally viewed as separate disease entities that increase in prevalence with aging, accumulating evidence indicates that there are similar pathophysiological mechanisms underlying both diseases. In addition to menopause and advanced age, other risk factors for CVD such as dyslipidemia, oxidative stress, inflammation, hyperhomocystinemia, hypertension, and diabetes have also been associated with increased risk of low bone mineral density (LBMD). Elevated LDL and low HDL cholesterol are associated with LBMD, altered lipid metabolism is associated with both bone remodeling and the atherosclerotic process, which might explain, in part, the co-existence of osteoporosis and atherosclerosis in patients with dyslipidemia. Similarly, inflammation plays a pivotal role in both atherosclerosis and osteoporosis. Elevated plasma homocysteine levels are associated with both CVD and osteoporosis. Nitric oxide (NO), in addition to its known atheroprotective effects, appears to also play a role in osteoblast function and bone turnover. Supporting this notion, in a small randomized controlled trial, nitroglycerine (an NO donor) was found to be as effective as estrogen in preventing bone loss in women with surgical menopause. Statins, agents that reduce atherogenesis, also stimulate bone formation. Furthermore, bisphosphonates, used in the treatment of osteoporosis, have been shown to inhibit atherogenesis. Intravenous bisphosphonate therapy significantly decreases serum LDL and increases HDL in postmenopausal women. The exciting possibilities of newer pharmacological agents that effectively treat both osteoporosis and CVD hold considerable promise. However, it is important to emphasize that the current evidence linking both of these diseases is far from conclusive. Therefore, additional research is necessary to further characterize the relationship between these two common illnesses.     

Hemostatic abnormalities and relationships to metabolic and hormonal status in polycystic ovarian syndrome

Polycystic ovarian syndrome (PCOS), diagnosed based on hyperandrogenism, ovulatory dysfunction, and polycystic ovaries, is one of the most common disorders of reproductive-aged females. Etiology includes both genetic and environmental/lifestyle factors contributing to both insulin resistance and hyperandrogenism. Clinically, PCOS has reproductive, psychological, and metabolic features, the latter predisposing to cardiovascular disease (CVD). Hemostatic abnormalities have an association with and a demonstrated pathophysiological role in CVD in non-PCOS populations but have not been adequately explored in PCOS. This review focuses on the hemostatic system in PCOS, exploring also relationships to the metabolic and hormonal abnormalities of the syndrome, and aims to identify whether hemostatic abnormalities are present as potential contributors to increased cardiovascular risk. Ultimately, this area may reveal preventative and therapeutic opportunities, which could improve the cardiovascular health of women with PCOS.