New insight in molecular mechanisms regulating SIRT6 expression in diabetes: Hyperglycaemia effects on SIRT6 DNA methylation.

Conflicting data are reported on the relationship between hyperglycaemia, diabetes and SIRT6 expression. To elucidate hyperglycaemia-induced molecular mechanisms regulating SIRT6 expression, the effect of hyperglycaemia on DNA methylation and SIRT6 expression has been evaluated in human aortic endothelial cells exposed to high glucose. DNA methylation of SIRT6 and any potential clinical implication was also evaluated in type 2 diabetic patients and compared with healthy controls. Endothelial cells exposed to high glucose showed lower methylation levels in SIRT6 promoter and increased SIRT6 and TET2 expression. The high glucose-induced epigenetic changes persisted after 48 h of glucose normalization. Diabetic patients showed lower levels of SIRT6 DNA methylation compared with nondiabetic patients. SIRT6 DNA methylation levels inversely correlated with plasma glucose. Our results firstly demonstrate the involvement of epigenetic mechanisms in regulating SIRT6 expression. Further experiments are necessary to clarify metabolic memory mechanisms driving to diabetic complications and how SIRT6 is potentially involved.

Non-ST-elevation myocardial infarction outcomes in patients with type 2 diabetes with non-obstructive coronary artery stenosis: Effects of incretin treatment.

There are insufficient data on the prognosis and management of people with type 2 diabetes who experience a non-obstructive coronary artery stenosis (NOCS)-non-ST-elevation myocardial infarction (NSTEMI) event. We evaluated the 12-month prognosis of patients with diabetes and NOCS (20%-49% luminal stenosis) who experience a first NSTEMI as compared with patients without diabetes. In addition, we investigated the 12-month prognosis in patients with diabetes and NSTEMI-NOCS previously treated with incretin-based therapy compared with a matched cohort of patients with NSTEMI-NOCS never treated with such therapy. We categorized the patients with diabetes as current incretin users (6 months' treatment with glucagon-like peptide-1 agonists or dipeptidyl peptidase-4 inhibitors) and non-users of incretins. The endpoint was all-cause mortality, cardiac death, recurrent acute coronary syndrome (ACS), and heart failure. The unadjusted Kaplan-Meier analysis, and a risk-adjusted hazard analysis showed that, all-cause mortality, cardiac death, readmission for ACS and heart failure rates during the 12-month follow-up were higher in patients with diabetes and NOCS-NSTEMI than in those with NOCS-NSTEMI without diabetes. Among the patients with diabetes, the current incretin users had a significantly lower rate of all-cause mortality, cardiac death and readmission for ACS at 12 months. In patients with type 2 diabetes and NOCS-NSTEMI, we observed a higher incidence of 1-year mortality and adverse cardiovascular outcomes, as compared with patients without diabetes with NOCS-NSTEMI. In people with diabetes, non-users of incretins had a worse prognosis than current incretin users.

Detection of Borrelia burgdorferi sensu lato species in host-seeking Ixodes species ticks in the United States.

Lyme disease is the most commonly reported vector-borne disease in the United States and is transmitted by Ixodes scapularis in the eastern US and I. pacificus in the west. The causative agents, Borrelia burgdorferi sensu stricto (Bbss) and B. mayonii belong to the B. burgdorferi sensu lato (Bbsl) species complex. An additional eight species of Bbsl have been identified in Ixodes species ticks in the US, but their geographic distribution, vector associations, human encounter rates and pathogenicity in humans are poorly defined. To better understand the geographic distribution and vector associations of Bbsl spirochetes in frequent and infrequent human-biting Ixodes species ticks in the US, we previously screened 29,517 host-seeking I. scapularis or I. pacificus ticks and 692 ticks belonging to eight other Ixodes species for Borrelia spirochetes using a previously described tick testing algorithm that utilizes a combination of real-time PCR and Sanger sequencing for Borrelia species identification. The assay was designed to detect known human pathogens spread by Ixodes species ticks, but it was not optimized to detect Bbsl co-infections. To determine if such co-infections were overlooked particularly in ticks infected with Bbss, we retested and analyzed a subsample of 845 Borrelia infected ticks using a next generation sequencing multiplex PCR amplicon sequencing (MPAS) assay that can identify Borrelia species and Bbsl co-infections. The assay also includes targets that can molecularly confirm identifications of Ixodes species ticks to better inform pathogen-vector associations. We show that Bbss is the most prevalent species in I. scapularis and I. pacificus; other Bbsl species were rarely detected in I. scapularis and the only Bbsl co-infections identified in I. scapularis were with Bbss and B. mayonii. We detected B. andersonii in I. dentatus in the Mid-Atlantic and Upper Midwest regions, B. kurtenbachii in I. scapularis in the Upper Midwest, B. bissettiae in I. pacificus and I. spinipalpis in the Northwest, and B. carolinensis in I. affinis in the Mid-Atlantic and Southeast, and B. lanei in I. spinipalpis in the Northwest. Twelve of 62 (19.4%) Borrelia-infected I. affinis from the Mid-Atlantic region were co-infected with Bbss and B. carolinensis. Our data support the notion that Bbsl species are maintained in largely independent enzootic cycles, with occasional spill-over resulting in multiple Bbsl species detected in Ixodes species ticks.

Arterial stiffness and cognition in elderly persons with impaired glucose tolerance and microalbuminuria.

BACKGROUND: Cognitive decline that occurs frequently in impaired glucose tolerance (IGT) may be largely due to endothelial dysfunction. We assessed: (i) the relationships between impact of urinary albumin excretion rate (UAER), as marker of generalized endothelial dysfunction, and cognition; (ii) if cognitive decline could be explained by arterial stiffening using pulse wave velocity (PWV). METHODS: One hundred forty older patients (age range 70-85 years) with IGT and no dementia were selected. Patients were classified according to 24-hour UAER: normoalbuminuric (NA) (UAER<20 microg/min) or microalbuminuric (MA) (UAER between 20 and 199 microg/min). Cognitive abilities were assessed by the Mini-Mental State Examination (MMSE) and a composite score of executive and attention functioning (CCS) at baseline and after 12 months of follow-up. RESULTS: In MA patients (n=80), increased UAERs correlated with intimal media thickness (IMT) (r=0.268; p=02) and PWV (r=0.310; p=004). In the same group, increased UAERs were correlated with MMSE and CCS even after adjusting for age and mean arterial blood pressure (MABP). After adding PWV, the associations among UAERs, MMSE, and CCS were no longer significant. In MA patients, PWV correlated with IMT, MMSE, and CCS. In NA patients, no significant correlations were found among UAERs, MMSE, and CCS. At follow-up, baseline UAERs predicted an approximately 20% risk of poor cognition (according to MMSE and CCS) after adjusting for confounders. After adding PWV, UAERs no longer predicted cognitive performance. CONCLUSIONS: MA older persons with IGT showed a decline in cognition performance that may be partially explained by arterial stiffness.

Stretch, Injury and Inflammation Markers Evaluation to Predict Clinical Outcomes After Implantable Cardioverter Defibrillator Therapy in Heart Failure Patients With Metabolic Syndrome.

Background: Internal cardioverter defibrillator (ICD) therapy reduced all-cause mortality. Conversely, few studies reported that ICDs' shocks may reduce survival. Recently authors suggested that, multiple inflammatory and molecular pathways were related to worse prognosis in metabolic syndrome (MS) patients treated by ICDs. Therefore, it may be relevant to find new biomarkers to predict ICDs' shock and worse prognosis in treated patients. Methods: In 99 MS vs. 107 no MS patients treated by ICD for primary prevention, we evaluated all-cause mortality, cardiac deaths, hospitalization for heart failure, appropriate and inappropriate therapy, and survival after appropriate ICD therapy. Results: MS vs. no MS patients had higher levels of failing heart stress biomarkers. The highest values of ST2 were related to worse prognosis. Patients who had better survival after appropriate ICD therapy were those associated with lowest ST2 values. At multivariate Cox regression analysis, C reactive protein (CRP) (0.110 [0.027-0.446], p-value 0.002), troponine I (TnI) protein (0.010 [0.001-0.051], p-value 0.010), and B type natriuretic peptide (BNP) (1.151 [1.010-1.510], p-value 0.001), predicted all cause of deaths. BNP predicted cardiac deaths (1.010 [1.001-1.206], p-value 0.033). MS, and BNP predicted hospitalization for heart failure events (2.902 [1.345-4.795], p-value 0.001; 1.005 [1.000-1.016], p-value 0.007). ST2 predicted appropriate therapy (1.012 [1.007-1.260], p-value 0.001), as BNP (1.005 [1.001-1.160], p-value 0.028), LVEF (1.902 [1.857-1.950], p-value 0.001), and CRP (1.833 [1.878-1.993], p-value 0.028). ST2, and BNP predicted survival after ICD appropriate therapy (4.297 [1.985-9.302], p-value 0.001; 1.210 [1.072-1.685], p-value 0.024). Conclusions: ST2 values may differentiate MS patients with a higher risk of ICDs' therapy, and worse prognosis. Therefore, ST2 protein may be used as valid monitoring biomarker, and as a predictive biomarker in failing heart ICDs' patients affected by MS.

Inflammatory Cytokines and SIRT1 Levels in Subcutaneous Abdominal Fat: Relationship With Cardiac Performance in Overweight Pre-diabetics Patients.

Objectives: In obese patients the superficial adipose tissue expresses cytokines, and sirtuins, that may affect myocardial function. In this study, we investigated the effect of metformin therapy added to a hypocaloric diet on the inflammatory pattern and cardiac performance (MPI) in obese patients with pre-diabetic condition. Materials and Methods: Fifty-eight obese patients that were enrolled for abdominoplastic surgery were divided into patients with pre-diabetic condition (n 40) and normo-glycemic patients (n18). Patients with pre-diabetic condition were randomly assigned to metformin therapy added to a hypocaloric diet (group 1, n 20) or to a hypocaloric diet therapy alone (group 2, n20). Patients with normo-glycemic condition were assigned to a hypocaloric diet therapy. Results: During enrollment, obese patients with a pre-diabetic condition (group 1 and 2) presented higher glucose values, lower values of insulin, and higher values of the homeostasis model for the assessment of insulin resistance (HOMA-IR) than obese patients with normo-glycemic condition(group 3). In addition, they had higher values of C Reactive protein (CRP), interleukin 6 (IL6), and lower values of sirtuin 1(SIRT1). In the 12th month of the follow-up, metformin therapy induced in patients with pre-diabetic condition (group 1) a significant reduction of glucose values, HOMA-IR, and inflammatory markers such as CRP (1.04 ± 0.48 vs. 0.49 ± 0.02 mmol/L, p < 0.05), IL6 (4.22 ± 0.45 vs. 3.33 ± 0.34 pg/ml, p < 0.05), TNFα (6.95 ± 0.59 vs. 5.15 ± 0.44 pg/ml, p < 0.05), and Nitrotyrosine (5,214 ± 0,702 vs. 2,151 ± 0,351 nmol/l, p < 0.05). This was associated with a significant reduction of Intima-media thickness (1.01 ± 0.15 vs. 0.86 ± 0.15 mm, p < 0.05), Septum (14 ± 2.5 vs. 10.5 ± 2 mm, p < 0.05), Posterior wall (11 ± 1.5 vs. 8 ± 1 mm, p < 0.05), LV mass (192.5 ± 49.5 vs. 133.2 ± 37.6 g, p < 0.05) and of MPI (0.58 ± 0.03 vs. 0.38 ± 0.02, p < 0.05). At 12 months of follow-up, group 2 experienced only a reduction of cholesterol (4.15 ± 0.94 vs. 4.51 ± 0.88 mmol/L, p < 0.05) and triglycerides (1.71 ± 1.18 vs. 1.83 ± 0.54 mmol/L, p < 0.05). At 12 months of follow-up, group 3 experienced a significant reduction of inflammatory markers, and also of echographic parameters, associated with amelioration of myocardial performance. To date, IL6 expression was related to higher values of left ventricle mass (R-value 0.272, p-value 0.039), and to higher IMT (R-value 0.272, p-value 0.039), such as those observed for CRP (R-value 0.308, p-value 0.021), for glucose blood values (R-value 0.449, p-value 0.001), and for HOMA-IR (R-value 0.366, p-value 0.005). An inverse correlation was found between subcutaneous fat expression of SIRT1 and myocardial performance index (R-value-0.236, p-value 0.002). Conclusion: In obese patients with pre-diabetic condition a metformin therapy may reduce inflammation and oxidative stress, and this may be associated with the amelioration of the cardiac performance. Clinical research trial number: NCT03439592.

Cryptogenic stroke and diabetes: a probable link between silent atrial fibrillation episodes and cerebrovascular disease.

Diabetes mellitus is a risk factor for cardiovascular and cerebrovascular events independently of other factors such as age, sex, BMI and blood pressure. Diabetes plays an important role in the pathogenesis of atrial fibrillation because it causes alterations to the autonomic nervous system. It may also be associated with an increased prevalence of asymptomatic episodes of atrial fibrillation, which cause cerebrovascular disease more often than chronic atrial fibrillation. The presence of silent cerebral ischemia doubles the risk of stroke in the general population independently of other cardiovascular risk factors; therefore, early detection of these episodes is important to determine preventive measures against the first cerebrovascular disease.