The current landscape for diabetes treatment: Preventing diabetes-associated CV risk.

Despite the risk of atherosclerosis has progressively declined over the past few decades, subjects with type 2 diabetes mellitus (T2DM) continue to experience substantial excess of atherosclerotic cardiovascular disease (ASCVD)-related events. Therefore, there is urgent need to treat ASCVD disease in T2DM earlier, more intensively, and with greater precision. Many factors concur to increase the risk of atherosclerosis, and multifactorial intervention remains the basis for effective prevention or reduction of atherosclerotic events. The role of anti-hyperglycemic medications in reducing the risk of ASCVD in subjects with T2DM has evolved over the past few years. Multiple cardiovascular outcome trials (CVOTs) with new and emerging glucose-lowering agents, namely SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1-RA), have demonstrated significant reductions of major cardiovascular events and additional benefits. This robust evidence has changed the landscape for managing people with T2DM. In addition to glycemic and ancillary extra-glycemic properties, SGLT2i and GLP1-RA might exert favorable effects on subclinical and clinical atherosclerosis. Therefore, the objective of this review is to discuss the available evidence supporting anti-atherosclerotic properties of SGLT2i and GLP1-RA, with a quick nod to sotagliflozin and tirzepatide.

Association of Interleukin-32 and Interleukin-34 with Cardiovascular Disease and Short-Term Mortality in COVID-19.

BACKGROUND: Excess cardiovascular (CV) morbidity and mortality has been observed in patients with COVID-19. Both interleukin-32 (IL-32) and interleukin-34 (IL-34) have been hypothesized to contribute to CV involvement in COVID-19. METHODS: This prospective, observational study of patients with laboratory-confirmed COVID-19 infection was conducted from 6 June to 22 December 2020 in a tertiary care hospital in Vienna, Austria. IL-32 and IL-34 levels on admission were collected and tested for their association with CV disease and short-term mortality in patients with COVID-19. CV disease was defined by the presence of coronary artery disease, heart failure, stroke or atrial fibrillation and patients were stratified by CV disease burden. RESULTS: A total of 245 eligible patients with COVID-19 were included, of whom 37 (15.1%) reached the primary endpoint of 28-day mortality. Of the total sample, 161 had no CV disease (65.7%), 69 had one or two CV diseases (28.2%) and 15 patients had ≥three CV diseases (6.1%). Median levels of IL-32 and IL-34 at admission were comparable across the three groups of CV disease burden. IL-32 and IL-34 failed to predict mortality upon both univariable and multivariable Cox regression analysis. The two CV disease groups, however, had a significantly higher risk of mortality within 28 days (one or two CV diseases: crude HR 4.085 (95% CI, 1.913-8.725), p < 0.001 and ≥three CV diseases: crude HR 13.173 (95% CI, 5.425-31.985), p < 0.001). This association persisted for those with ≥three CV diseases after adjustment for age, gender and CV risk factors (adjusted HR 3.942 (95% CI, 1.288-12.068), p = 0.016). CONCLUSION: In our study population of hospitalized patients with COVID-19, IL-32 and IL-34 did not show any associations with CV disease or 28-day mortality in the context of COVID-19. Patients with multiple CV diseases, however, had a significantly increased risk of short-term mortality.

A comparison of cardiovascular imaging practices in Africa, North America, and Europe: two faces of the same coin.

Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide. There are significant differences in the burden of cardiovascular disease and associated risk factors, across high-income countries and low- and middle-income countries. Cardiac imaging by echocardiography, cardiac computed tomography, cardiac magnetic resonance imaging, single-photon emission computed tomography, and positron emission tomography myocardial perfusion imaging are well-established non-invasive tests that aid in the diagnosis, risk stratification, and management of various cardiac diseases. However, there are significant inequalities in availability and access to imaging modalities in low- and middle-income countries attributed to financial constraints, disparities in healthcare and technical infrastructure. In the post-COVID-19 pandemic era, these disparities are exaggerated by the continued technological advancements driving innovations in the field of cardiovascular (CV) imaging in high-income countries, while there is an urgent need to provide sustainable access to diagnostic imaging for patients in economically strained healthcare systems in regions like Africa. This review aims to highlight the inequalities in the burden of cardiac disease, associated risk factors, and access to diagnostic CV imaging tests, while also exploring the need for sustainable solutions to implementing CV imaging all over the world.

The Safe and Effective Use of Plant-Based Diets with Guidelines for Health Professionals.

Plant-based diets, defined here as including both vegan and lacto-ovo-vegetarian diets, are growing in popularity throughout the Western world for various reasons, including concerns for human health and the health of the planet. Plant-based diets are more environmentally sustainable than meat-based diets and have a reduced environmental impact, including producing lower levels of greenhouse gas emissions. Dietary guidelines are normally formulated to enhance the health of society, reduce the risk of chronic diseases, and prevent nutritional deficiencies. We reviewed the scientific data on plant-based diets to summarize their preventative and therapeutic role in cardiovascular disease, cancer, diabetes, obesity, and osteoporosis. Consuming plant-based diets is safe and effective for all stages of the life cycle, from pregnancy and lactation, to childhood, to old age. Plant-based diets, which are high in fiber and polyphenolics, are also associated with a diverse gut microbiota, producing metabolites that have anti-inflammatory functions that may help manage disease processes. Concerns about the adequate intake of a number of nutrients, including vitamin B12, calcium, vitamin D, iron, zinc, and omega-3 fats, are discussed. The use of fortified foods and/or supplements as well as appropriate food choices are outlined for each nutrient. Finally, guidelines are suggested for health professionals working with clients consuming plant-based diets.

SARS-CoV-2 Infection and Cardiovascular Disease: COVID-19 Heart.

Coronavirus disease (COVID-19) is a serious illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The symptoms of the disease range from asymptomatic to mild respiratory symptoms and even potentially life-threatening cardiovascular and pulmonary complications. Cardiac complications include acute myocardial injury, arrhythmias, cardiogenic shock and even sudden death. Furthermore, drug interactions with COVID-19 therapies may place the patient at risk for arrhythmias, cardiomyopathy and sudden death. In this review, we summarise the cardiac manifestations of COVID-19 infection and propose a simplified algorithm for patient management during the COVID-19 pandemic.

Cardiovascular Risk in Fatty Liver Disease: The Liver-Heart Axis-Literature Review.

According to the World Health Organization, cardiovascular disease (CVD) remains the leading cause of death worldwide, accounting for approximately 18 million deaths per year. Nevertheless, the worldwide prevalence of metabolic diseases, such as type 2 diabetes mellitus, obesity, and non-alcoholic fatty liver disease (NAFLD), also known to be common risk factors for CVD, have dramatically increased over the last decades. Chronic alcohol consumption is a major cause of chronic liver diseases (CLD) as well as being a major health care cost expenditure accounting for the spending of tremendous amounts of money annually. NAFLD has become one of the major diseases plaguing the world while standing as the most common cause of liver disease in the Western countries by representing about 75% of all CLD. Currently, the most common cause of death in NAFLD remains to be CVD. Several mechanisms have been suggested to be responsible for associating FLD with CVD through several mechanisms including low-grade systemic inflammation, oxidative stress, adipokines, endoplasmic reticulum stress, lipotoxicity and microbiota dysbiosis which may also be influenced by other factors such as genetic and epigenetic variations. Despite of all this evidence, the exact mechanisms of how FLD can causally contribute to CVD are not fully elucidated and much remains unknown. Moreover, the current literature supports the increasing evidence associating FLD with several cardiovascular (CV) adverse events including coronary artery disease, increased subclinical atherosclerosis risk, structural alterations mainly left ventricular hypertrophy, increased epicardial fat thickness, valvular calcifications including aortic valve sclerosis and mitral annular calcification and functional cardiac modifications mainly diastolic dysfunction in addition to cardiac arrhythmias such as atrial fibrillation and ventricular arrythmias and conduction defects including atrioventricular blocks and bundle branch blocks. Patients with FLD should be evaluated and managed accordingly in order to prevent further complications. Possible management methods include non-pharmacological strategies including life style modifications, pharmacological therapies as well as surgical management. This review aims to summarize the current state of knowledge regarding the pathophysiological mechanisms linking FLD with an increased CV risk, in addition to associated CV adverse events and current management modalities.

Association between cardiovascular risk factors and the diameter of the main pulmonary artery in asymptomatic population in the Appalachian region.

BACKGROUND: Pulmonary artery (PA) diameter may be altered in association with cardiovascular (CV) risk factors as noted in aorta in systemic hypertension. The flow of blood from the right ventricle to the PA and all the way to the capillary level depends on the pulmonary vascular resistance and to a lesser extent compliance and impedance of the PA, which are the fundamental conduit for maintenance of the right heart hemodynamics. Our objective is to determine the association between CV risk factors and the main pulmonary artery (MPA) diameter. METHODS: The study population are asymptomatic individuals with no known diagnosis of CV diseases in central Appalachia (n=1,282). Adults aged 18 years or older were eligible for the screening if they were referred by a physician. For self-referral, only males aged ≥45 years and females aged ≥55 years were eligible. Unadjusted and adjusted linear regression analyses were performed. RESULTS: The mean MPA diameter was significantly higher among males compared to females (27.19±4.20 vs. 24.99±3.91 mm, P<0.0001). Participants with diabetes also had wider MPA diameter (26.79±4.56 mm) compared to those without diabetes (25.93±4.11 mm) (P=0.015). Further, hypertensive (26.42±4.15 vs. 25.71±4.21 mm, P=0.002) and obese (27.25±4.11 vs. 25.28±4.07 mm, P<0.0001) participants had significantly wider MPA diameter compared to non-hypertensive and non-obese participants, respectively. Multivariable model showed that age, sex and body mass index (BMI) were significantly associated with MPA diameter. A 1-year increase in age increased MPA diameter by 0.046 mm (P<0.0001). The diameter of MPA was wider among males by 2.16 mm compared to females (P<0.0001). Finally, with one unit increase in BMI, the MPA diameter increased by 0.16 mm (P<0.0001). CONCLUSIONS: MPA diameter was significantly associated with age, sex, and BMI. Further prospective studies are needed to correlate computed tomography (CT) measurement of MPA diameter with pulmonary pressure as assessed by echocardiogram to diagnose pulmonary hypertension (PH).

Analysis from the EMPA-REG OUTCOME® trial indicates empagliflozin may assist in preventing the progression of chronic kidney disease in patients with type 2 diabetes irrespective of medications that alter intrarenal hemodynamics.

In patients with type 2 diabetes mellitus (T2DM) and cardiovascular (CV) disease, empagliflozin (EMPA) decreased progression of chronic kidney disease (CKD), likely via a reduction in intraglomerular pressure. Due to prevalent comorbidities, such as hypertension and albuminuria, patients often receive other agents that alter intrarenal hemodynamics, including angiotensin converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs), calcium channel blockers (CCBs) and diuretics. Nonsteroidal anti-inflammatory drugs (NSAIDs) may also be used by some individuals. In this exploratory, non-prespecified analysis, we investigated whether the kidney benefits of EMPA are altered in individuals already using the medications in these categories. In the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME®) trial, 7020 patients were essentially equally randomized to EMPA 10 mg, 25 mg or placebo added to their standard care. Differences in risk of incident or worsening nephropathy for pooled EMPA vs placebo across subgroups by baseline background medications (to which patients were not randomized) were assessed using a Cox proportional hazards model. Risk reductions in incident or worsening nephropathy with EMPA were consistent across medication subgroups, with no heterogeneity of treatment effect. As a representative example, the risk for acute renal failure was overall slightly increased in patients using ACEi/ARBs in all groups (placebo, EMPA 10 mg or EMPA 25 mg) but incidence rates were numerically lower in those assigned to EMPA. Similar patterns were observed for other medications included in this analysis. Thus, EMPA may assist to prevent CKD progression in patients with T2DM with CV disease, irrespective of common background medications that alter intrarenal hemodynamics, and without increasing acute renal adverse events.

Mouse Models for Atherosclerosis Research-Which Is My Line?

Atherosclerosis is one of the primary causes of cardiovascular disease and mortality. This chronic immunometabolic disease evolves during decades in humans and encompasses different organs and immune cell types, as well as local and systemic processes that promote the progression of the disease. The most frequently used animal model to study these atherogenic processes and inter-organ crosstalk in a short time frame are genetically modified mouse models. Some models have been used throughout the last decades, and some others been developed recently. These models have important differences in cholesterol and lipoprotein metabolism, reverse cholesterol transport pathway, obesity and diabetes as well as inflammatory processes. Therefore, the disease develops and progresses differently in the various mouse models. Since atherosclerosis is a multifaceted disease and many processes contribute to its progression, the choice of the right mouse model is important to study specific aspects of the disease. We will describe the different mouse models and provide a roadmap to facilitate current and future atherosclerosis researchers to choose the right model depending on their scientific question.

Patient Preferences for GLP-1 Receptor Agonist Treatment of Type 2 Diabetes Mellitus in Japan: A Discrete Choice Experiment.

INTRODUCTION: The incidence and prevalence of type 2 diabetes mellitus (T2D) are increasing in Japan, and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are commonly used to treat the disease. The objective of this study was to use a discrete choice experiment (DCE) to characterize patient preferences for clinical treatment features of two GLP-1 RAs-dulaglutide 0.75 mg and semaglutide 0.50 mg-among patients with T2D in Japan. METHODS: Adult patients with T2D in Japan were administered the DCE via a web-based survey. The DCE examined patient preferences for five treatment attributes (each described by two or three levels), including method of administration, HbA1c change, reduction in cardiovascular (CV) risk, weight change, and common side effects (i.e., nausea). Results were analyzed using multinomial and mixed logit models, and predicted choice probability was calculated to determine the overall probability that either dulaglutide or semaglutide DCE levels were preferred. One DCE choice task included a direct comparison of the dulaglutide 0.75 mg versus semaglutide 0.50 mg treatment profiles. RESULTS: 190 subjects completed the survey; 29 were excluded after failing the predefined internal validity assessments. In the final analysis sample (N = 161), the attribute with the largest effect on the subjects' choices was reduction in CV risk, followed by HbA1c change and common side effects. Patients' predicted choice probability for the semaglutide profile was 78%, versus 22% for the dulaglutide profile. 28% of patients were "very willing" to initiate treatment with semaglutide's product profile, versus 6% for dulaglutide. CONCLUSION: In this study, reduction in CV risk and HbA1c change were the key drivers of GLP-1 RA medication preference in Japanese patients with T2D. Overall, the majority of the patients preferred a product with attribute levels reflecting the semaglutide 0.50 mg profile, with a known CV risk reduction benefit and superior HbA1c reduction. FUNDING: Novo Nordisk.

Pharmacologic strategies to reduce cardiovascular disease in type 2 diabetes mellitus: focus on SGLT-2 inhibitors and GLP-1 receptor agonists.

Patients with type 2 diabetes mellitus (T2D) present an increased risk for cardiovascular (CV) complications. In addition to improvement in glycaemic control, glucose-lowering therapies, such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-dependent glucose cotransporter (SGLT)-2 inhibitors, have been shown to significantly reduce CV events. In 2008, the US Food and Drug Administration mandated that all new glucose-lowering drugs undergo CV outcomes trials (CVOTs) to determine their CV safety. These trials have largely demonstrated no major CV safety concerns. Most notably, the GLP-1RAs and SGLT-2 inhibitors have been found to be not only safe, but also cardioprotective compared to placebo. The SGLT-2 inhibitors have opened a new perspective for clinicians treating patients with T2D and established CV disease in light of their 'pleiotropic' effects, specifically on heart failure, while GLP-1RAs seem to present more favourable effects on atherosclerotic events. In this review, we discuss the role of GLP-1RAs and SGLT-2 inhibitors to reduce CV risk in T2D patients and suggest an individualized therapeutic approach in this population based on the presence of metabolic and CV comorbidities.

Emotion regulation moderates the association between chronic stress and cardiovascular disease risk in humans: a cross-sectional study.

Chronic stress is a risk factor for incident cardiovascular (CV) disease. Emotion regulation is the ability to modulate one's state or behavior in response to a given situation or stressor, and may mitigate the effect of chronic stress on CV disease risk. Data from a cohort of 754 community-dwelling young to middle-aged adults who were assessed between 2007 and 2012 on stress, emotion regulation, and CV risk measures were used to test the hypothesis that emotion regulation mitigates the effect of chronic stress on CV risk. Emotion regulation was measured using the Difficulties in Emotion Regulation Scale (DERS). We created a composite stress score using data from the Cumulative Adversity Interview and the Perceived Stress Scale. Our outcomes included blood pressure, body mass index, and insulin resistance separately and combined into a composite CV risk score. Covariates included age, sex, race, years of education, and smoking status. We used multivariable logistic regression to evaluate associations between stress measures and CV risk among participants and the impact of emotion regulation (DERS scores) on this association. We found that composite stress interacted significantly with the DERS score to affect CV risk (p = .007). A median split of the DERS scores indicated that CV risk was associated with the composite stress score in the fully adjusted model (ß = 0.206; p = .005) among participants with low emotion regulation, but not among those with high emotion regulation (ß = 0.048; p = .59). Chronic stress was associated with CV risk only among participants with poor emotion regulation. Emotion regulation is a teachable skill, and may play a role in preventing CV disease.Lay summaryEmotion regulation is the ability to modify one's reaction to a negative or stressful event, and is a teachable skill. Effective emotion regulation dampens the negative effect of chronic stress on the body, which may reduce risk for cardiovascular disease.

Combined Association of Cardiorespiratory Fitness and Body Fatness With Cardiometabolic Risk Factors in Older Norwegian Adults: The Generation 100 Study.

OBJECTIVE: To investigate the independent and combined associations of fitness and fatness with cardiometabolic risk factors in older Norwegian women and men. PATIENTS AND METHODS: We conducted a cross-sectional study of 505 women and 417 men aged 70 to 77 years enrolled in the Generation 100 study in Norway. Fitness was assessed as peak oxygen uptake and fatness as high body mass index (BMI; ≥25 kg/m2), waist circumference (WC) of 88 cm or greater for women and 102 cm or greater for men, and percent body fat (%BF) of 35% or greater and 25% or greater for women and men, respectively. High cardiometabolic risk was defined as the presence of 2 or more of the following risk factors: elevated triglyceride level, reduced high-density lipoprotein cholesterol concentration, elevated blood pressure, and elevated fasting glucose level or pharmacological treatment of these conditions. RESULTS: Receiver operating characteristic curve analyses identified fitness levels of less than 25.7 and less than 30.7 mL/kg per minute in women and men, respectively, as critical thresholds for having high cardiometabolic risk. Individuals with levels below these thresholds had an adjusted odds ratio of 2.77 (95% CI, 2.09-3.66) for having high cardiometabolic risk, while high BMI, WC, and %BF had odds ratios (95% CIs) of 3.58 (2.69-4.77), 3.06 (2.29-4.10), and 3.26 (2.47-4.30), respectively. In our combined analyses, being lean did not attenuate the cardiometabolic risk associated with low fitness, and combinations of low fitness and/or high BMI, WC, or %BF cumulatively increased cardiometabolic risk. CONCLUSION: Low fitness and indication of fatness were independently and cumulatively associated with poor cardiometabolic health. Our results emphasize the importance of including both physical fitness and body fatness in the assessment of cardiometabolic risk and health promotion efforts in older adults.

Implications of the EMPA-REG Trial for Clinical Care and Research.

EMPA-REG OUTCOME was a multicenter, randomized placebo-controlled trial that examined the effect of empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor in addition to standard of care in patients with type 2 diabetes and established cardiovascular (CV) disease. The primary goal was to assess CV safety, as mandated by the US Food and Drug Administration since 2008 for all new glucose-lowering agents. Secondary goals were to examine the effects of empagliflozin on microvascular outcomes and, in particular, kidney disease. This landmark study had several important findings, including striking reductions in the incidence of CV death and heart failure hospitalization and in the progression of renal dysfunction. In this review, we describe the trial's main findings, discuss the possible mechanisms that could explain its results, suggest ways in which clinical care may be influenced, and propose directions for future research.

Uric Acid and Cardiovascular Disease: An Update.

In recent years, serum uric acid (SUA) as a determinant of cardiovascular (CV) risk has gained interest. Epidemiological, experimental and clinical data show that patients with hyperuricaemia SUA are at increased risk of cardiac, renal and vascular damage and CV events. There is now some evidence to suggest that urate-lowering treatment may reduce CV risk in this group and, thus, may represent a new strategy in risk reduction.

Diabetes and cardiovascular disease: let's push forward with translational research.

Albeit advances in therapy have reduced morbidity and mortality in patients with diabetes, cardiovascular (CV) risk is far to be eradicated. This is partially due to the fact that breakthrough therapies have yet to be approved to counteract the atherosclerotic burden in this setting. Therefore, it is very important to understand the molecular mechanisms underpinning diabetes-related CV complications. Growing evidence is supporting the concept that translational research is perhaps the best approach to unveil novel insights into disease etiology and its link with CV phenotypes. The recent employment of high throughput "omics" (i.e., metabolomics, transcriptomics, proteomics) is a clinically relevant approach which may provide insightful interpretations of diabetes-related biological signals. The possibility to analyse thousands or more molecules simultaneously has given "omics" the ability to generate enormous quantities of data which may somehow offer a precious "window on the disease". In the present article, we critically discuss the importance of translational research in diabetes, including potential difficulties which may arise in the implementation and development of promising technologies from the laboratory to the marketplace.

Cause of Death in Patients With Diabetic CKD Enrolled in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT).

BACKGROUND: The cause of death in patients with chronic kidney disease (CKD) varies with CKD severity, but variation has not been quantified. STUDY DESIGN: Retrospective analysis of prospective randomized clinical trial. SETTING & PARTICIPANTS: We analyzed 4,038 individuals with anemia and diabetic CKD from TREAT, a randomized trial comparing darbepoetin alfa and placebo. PREDICTORS: Baseline estimated glomerular filtration rate (eGFR) and protein-creatinine ratio (PCR). OUTCOMES: Cause of death as adjudicated by a blinded committee. RESULTS: Median eGFR and PCR ranged from 20.6 mL/min/1.73 m(2) and 4.1 g/g in quartile 1 (Q1) to 47.0 mL/min/1.73 m(2) and 0.1 g/g in Q4 (P<0.01). Of 806 deaths, 441, 298, and 67 were due to cardiovascular (CV), non-CV, and unknown causes, respectively. Cumulative CV mortality at 3 years was higher with lower eGFR (Q1, 15.5%; Q2, 11.1%; Q3, 11.2%; Q4, 10.3%; P<0.001) or higher PCR (Q1, 15.2%; Q2, 12.3%; Q3, 11.7%; Q4, 9.0%; P<0.001). Similarly, non-CV mortality was higher with lower eGFR (Q1, 12.7%; Q2, 8.4%; Q3, 6.7%; Q4, 6.1%; P<0.001) or higher PCR (Q1, 10.3%; Q2, 7.9%; Q3, 9.4%; Q4, 6.4%; P=0.01). Sudden death was 1.7-fold higher with lower eGFR (P=0.04) and 2.1-fold higher with higher PCR (P<0.001). Infection-related mortality was 3.3-fold higher in the lowest eGFR quartile (P<0.001) and 2.8-fold higher in the highest PCR quartile (P<0.02). The overall proportion of CV and non-CV deaths was not significantly different across eGFR or PCR quartiles. LIMITATIONS: Results may not be generalizable to nondiabetic CKD or diabetic CKD in the absence of anemia. Measured GFR was not available. CONCLUSIONS: In diabetic CKD, both lower baseline GFR and higher PCR are associated with higher CV and non-CV mortality rates, particularly from sudden death and infection. Efforts to improve outcomes should focus on CV disease and early diagnosis and treatment of infection.

Cardiovascular disease in systemic sclerosis.

Cardiovascular (CV) system involvement is a frequent complication of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). It still remains unclear if a premature atherosclerosis (ATS) occurs even in systemic sclerosis (SSc). Although microvascular disease is a hallmark of SSc, in the last few years a number of studies highlighted a higher prevalence of macrovascular disease in SSc patients in comparison to healthy individuals and these data have been correlated with a poorer prognosis. The mechanisms promoting ATS in SSc are not fully understood, but it is believed to be secondary to multi-system organ inflammation, endothelial wall damage and vasculopathy. Both traditional risk factors and endothelial dysfunction have been proposed to participate to the onset and progression of ATS in such patients. In particular, endothelial cell injury induced by anti-endothelial antibodies, ischemia/reperfusion damage, immune-mediated cytotoxicity represent the main causes of vascular injury together with an impaired vascular repair mechanism that determine a defective vasculogenesis. Aim of this review is to analyse both causes and clinical manifestations of macrovascular involvement and ATS in SSc.

Relationship between dimethylarginine dimethylaminohydrolase gene variants and asymmetric dimethylarginine in patients with rheumatoid arthritis.

OBJECTIVE: The aim of our study was to determine whether Dimethylarginine Dimethylaminohydrolase (DDAH) 1 and 2 gene polymorphisms - the main enzyme involved in ADMA degradation - are associated with high Asymmetric Dimethylarginine (ADMA) levels in Rheumatoid Arthritis (RA). METHODS: Serum ADMA levels were measured in 201 individuals with RA [155 females median age 67 (59-73)]. Four tag SNPs in DDAH1 gene and 2 in the DDAH2 gene were genotyped by using the LightCycler™ System. ADMA was initially compared across the genetic variables using one-way ANOVA and then multivariate analysis examined each of the genes after adjustment for parameters of systemic inflammation and insulin resistance, namely erythrocyte sedimentation rate (ESR) and homeostatic model assessment (HOMA), which we have previously shown affect ADMA levels in RA. RESULTS: No significant relationship between DDAH genetic variables and ADMA levels was established in ANOVA analysis. Multivariate model adjusted for age, HOMA and ESR did not demonstrate any significant association between DDAH variants and ADMA. CONCLUSION: The results of our study give no evidence to suggest that increased ADMA levels in RA relate to DDAH genetic polymorphisms. Better understanding of disease-related factors and their interactions with traditional CV risk factors may represent mechanisms responsible for ADMA accumulation in this population.

Metabolic syndrome and nephrolithiasis.

PROBLEM: This review focuses on the association between the metabolic syndrome (MS) and nephrolithiasis. FINDINGS: Associations between nephrolithiasis and systemic diseases are recognized, including atherosclerosis, cardiovascular (CV) disease, hypertension (HNT), diabetes mellitus (DM)-composite risk factors grouped as the MS. Kidney stones incidence is increasing in this particularly high risk group. Those with stones are prone to the disease and those with the systemic disease are at risk for stone formation, with the highest incidence in persons with multiple traits of the MS. Pathophysiologic explanations for the increased stone risk related to MS are likely complex and dynamic. CONCLUSIONS: Kidney stones disproportionately affect persons with some or all traits of MS. One unifying theory may be of a common systemic malfunction of inflammation and tissue damage as an underlying mechanism, but it is unlikely to be the only mechanistic explanation. Further research is needed to investigate this and other hypotheses that go beyond population based and urine physiochemical studies in order to elucidate the mechanisms behind the individual disease states themselves.