Energy condensation and dipole alignment in protein dynamics.

The possibility that distant biomolecules in a cell interact via electromagnetic (e.m.) radiation was proposed many years ago to explain the high rate of encounters of partners in some enzymatic reactions. The results of two recent experiments designed to test the propensity of protein bovine serum albumin (BSA) to interact via e.m. radiation with other proteins were interpreted in a theoretical framework based on three main assumptions: (i) in order to experience this kind of interaction the protein must be in an out-of-equilibrium state; (ii) in this state there is a condensation of energy in low-frequency vibrational modes; and (iii) the hydration layers of water around the protein sustain the energy condensation. In the present paper we present the results of molecular dynamics simulations of BSA in four states: at equilibrium and out-of-equilibrium in water, and at room and high temperature in vacuum. By comparing physical properties of the system in the four states, our simulations provide a qualitative and quantitative assessment of the three assumptions on which the theoretical framework is based. Our results confirm the assumptions of the theoretical model showing energy condensation at low frequency and electretlike alignment between the protein's and the water's dipoles; they also allow a quantitative estimate of the contribution of the out-of-equilibrium state and of the water to the observed behavior of the protein. In particular, it has been found that in the out-of-equilibrium state the amplitude of the oscillation of the protein's dipole moment greatly increases, thereby enhancing a possible absorption or emission of e.m. radiation. The analysis of BSA's dynamics outlined in the present paper provides a procedure for checking the propensity of a biomolecule to interact via e.m. radiation with its biochemical partners.

Revascularization outcomes in diabetic patients presenting with acute coronary syndrome with non-ST elevation.

BACKGROUND: To compare the outcomes of diabetic patients hospitalized with non-ST elevation myocardial infarction (NSTEMI) or unstable angina (UA) referred for revascularization by either coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) in a real-life setting. METHODS: The study included 1987 patients with diabetes mellitus enrolled from the biennial Acute Coronary Syndrome Israeli Survey between 2000 and 2016, who were hospitalized for NSTEMI or UA, and underwent either PCI (N = 1652, 83%) or CABG (N = 335, 17%). Propensity score-matching analysis compared all-cause mortality in 200 pairs (1:1) who underwent revascularization by either PCI or CABG. RESULTS: Independent predictors for CABG referral included 3-vessel coronary artery disease (OR 4.9, 95% CI 3.6-6.8, p < 0.001), absence of on-site cardiac surgery (OR 1.4, 95% CI 1.1-1.9, p = 0.013), no previous PCI (OR 1.5, 95% CI 1.1-2.2, p = 0.024) or MI (OR 1.7, 95% CI 1.2-2.6, p = 0.002). While at 2 years of follow-up, survival analysis revealed no differences in mortality risk between the surgical and percutaneous revascularization groups (log-rank p = 0.996), after 2 years CABG was associated with a significant survival benefit (HR 1.53, 95% CI 1.07-2.21; p = 0.021). Comparison of the propensity score matching pairs also revealed a consistent long-term advantage toward CABG (log-rank p = 0.031). CONCLUSIONS: In a real-life setting, revascularization by CABG of diabetic patients hospitalized with NSTEMI/UA is associated with better long-term outcomes. Prospective randomized studies are warranted in order to provide more effective recommendations in future guidelines.

The dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist tirzepatide: a novel cardiometabolic therapeutic prospect.

Incretin hormones are peptides released in the intestine in response to the presence of nutrients in its lumen. The main incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 stimulates insulin secretion, inhibits glucagon secretion at pancreatic α cells and has also extrapancreatic influences as slowing of gastric emptying which increases the feeling of satiety. GIP is the main incretin hormone in healthy people, causative of most the incretin effects, but the insulin response after GIP secretion in type 2 diabetes mellitus (T2DM) is strongly reduced. Therefore, in the past GIP has been considered an unappealing therapeutic target for T2DM. This conception has been changing during recent years, since it has been reported that resistance to GIP can be reversed and its effectiveness restored by improving glycemic control. This fact paved the way for the development of a GIP receptor agonist-based therapy for T2DM, looking also for the possibility of finding a combined GLP-1/GIP receptor agonist. In this framework, the novel dual GIP and GLP-1 receptor agonist tirzepatide seems to be not just a new antidiabetic medication. Administered as a subcutaneous weekly injection, it is a manifold single pharmacological agent that has the ability to significantly lower glucose levels, as well as improve insulin sensitivity, reduce weight and amend dyslipidemia favorably modifying the lipid profile. Tirzepatide and additional dual GLP-1/GIP receptor agonists that could eventually be developed in the future seem to be a promising furthest advance for the management of several cardiometabolic settings. Obviously, it is too early to be overly hopeful since it is still necessary to determine the long-term effects of these compounds and properly verify the potential cardiovascular benefits. Anyway, we are currently facing a novel and very appealing therapeutic option.

Kinetic coherence underlies the dynamics of disordered proteins.

The dynamics of two proteins of similar size, the globular lysozyme and the intrinsically disordered Huntingtin interacting protein, has been simulated in three states resembling a globule, a pre-molten globule, and a molten globule. A coherence time τ has been defined, measuring the delay in the display of a stochastic behaviour after a perturbation of the system. This time has been computed for two sets of collective variables: the projection of the phase point onto the positions and momenta subspaces (τ r and τ p ), and the principal components (PCs) of positions q and momenta π produced by a covariance analysis in these subspaces (τ q and τ π ). In all states τ p ≈ 3.5τ r , and τ π ≈ 3.5τ q . The coherence times of individual PCs, τ (l) q and τ (l) π, have also been computed, and τ (l) π > τ (l) q in all states. The prevalence of τ p over τ r , or of τ π over τ q , drives the dynamics of the protein over a time range of ≈1-2 ps; moreover, a hidden synchronism appears to raise the momenta subspace's coherence above that of its individual PCs. In the transition of lysozyme to the molten globule the τ (l) q decrease but, unexpectedly, the τ (l) π increase; after this transition τ p ≈ 5τ r and τ π ≈ 5τ q . A gain of kinetic coherence accompanies thus the loss of structural coherence caused by the denaturation of the protein in the transition from globule to molten globule. The increase of the τ (l) π does not take place in the analogous transition of the Huntingtin protein. These results are compared with those of a similar analysis performed on three pseudo-proteins designed by scrambling the primary sequence of the Huntingtin interacting protein, and on two oligopeptides. The hidden synchronism appears to be a generic property of these polypeptides. The τ (l) π spectrum is similar in denaturated and in intrinsically disordered biomolecules; but the gain of kinetic coherence as a result of denaturation seems to be a specific property of the biologically functional lysozyme.

Type 2 diabetes mellitus increases the mortality risk after acute coronary syndrome treated with coronary artery bypass surgery.

BACKGROUND: Type 2 diabetes mellitus (DM) is a risk factor for cardiovascular diseases and is common among patients undergoing coronary artery bypass grafting (CABG) surgery. The main objective of our study was to investigate the impact of DM type 2, and its treatment subgroups, on short- and long-term mortality in patients with acute coronary syndrome (ACS) who undergo CABG. METHODS: The study included 1307 patients enrolled from the biennial Acute Coronary Syndrome Israeli Survey between 2000 and 2016, who were hospitalized for ACS and underwent CABG. Of them, 527 (40%) patients were with and 780 (60%) were without DM. RESULTS: Compared with the non-diabetic group, the diabetic group of patients comprised more women and had more comorbidities such as hypertension, dyslipidemia, renal impairment, peripheral vascular disease and prior ischemic heart disease. Overall 30-day mortality rate was similar between DM and non-DM patients (4.2% vs. 4%, p = 0.976). Ten-year mortality rate was higher in DM compared with non-diabetic patients (26.6% vs. 17.7%, log-rank p < 0.001), and higher in the subgroup of insulin-treated patients compared to non-insulin treated patients (31.5% vs. 25.6%, log-rank p = 0.019). Multivariable analysis showed that DM increased the mortality hazard by 1.61-fold, and insulin treatment among the diabetic patients increased the mortality hazard by 1.57-fold. CONCLUSIONS: While type 2 DM did not influence the in-hospital mortality hazard, we showed that the presence of DM among patients with ACS referred to CABG, is a powerful risk factor for long-term mortality, especially when insulin was included in the diabetic treatment strategy.

Hypomagnesemia is associated with new-onset diabetes mellitus following heart transplantation.

BACKGROUND: Diabetes mellitus (DM) is a major cause of morbidity and mortality following heart transplantation (HT), with 21% and 35% of survivors being affected within 1 and 5 years following HT, respectively. Magnesium deficiency is common among HT patients treated with calcineurin inhibitors and is a known risk factor for DM in non-HT patients. We therefore investigated the association between serum Mg (s-Mg) levels and new-onset diabetes after transplantation (NODAT). METHODS: Between 2002 and 2017, 102 non-DM HT patients were assessed. In accordance with the mean value of all s-Mg levels recorded during the first year post-HT, patients were divided into high s-Mg (≥ 1.8 mg/dL) and low s-Mg (< 1.8 mg/dL) groups. The endpoint was NODAT, defined according to the diagnostic criteria of the American Diabetes Association. RESULTS: Baseline clinical and demographic characteristics for the high (n = 45) and low s-Mg (n = 57) groups were similar. Kaplan-Meier survival analysis showed that 15-year freedom from NODAT was significantly higher among patients with high vs low s-Mg (85% vs 46% log-rank test, p < 0.001). Consistently, multivariate analysis adjusted for age, gender, immunosuppression therapies, BMI and mean creatinine values in the first year post-HT, showed that low s-Mg was independently associated with a significant > 8-fold increased risk for NODAT (95% CI 2.15-32.63, p = 0.003). Stroke rate was significantly higher in patients with low s-Mg levels vs high s-Mg (14% vs 0, p = 0.025), as well as long term mortality (HR 2.6, 95% CI 1.02-6.77, p = 0.05). CONCLUSIONS: Low s-Mg level post-HT is an independent risk factor for NODAT in HT patients. The implications of interventions, focusing on preventing or correcting low s-Mg, for the risk of NODAT and for clinical outcomes should be evaluated.

Metformin therapy in patients with diabetes mellitus is associated with a reduced risk of vasculopathy and cardiovascular mortality after heart transplantation.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a major cause of morbidity and mortality following heart transplantation (HT). Reduced cardiovascular mortality and morbidity have been reported in non-HT patients treated with metformin. Given the high prevalence of type 2 diabetes mellitus (T2DM) in HT patients, we investigated the association between metformin therapy and cardiovascular outcomes after HT. METHODS: The study population comprised 103 DM patients who had undergone HT between 1994 and 2018 and were prospectively followed-up. We excluded from the study patients with type 1 diabetes mellitus. Fifty-five HT patients (53%) in the cohort were treated with metformin. Clinical data were recorded on prospectively designed forms. The primary outcomes included CAV, survival, and the combined end-point of CAV or cardiovascular mortality. RESULTS: Kaplan-Meier survival analysis showed that the CAV rate at 20 years of follow-up was lower in DM patients treated with metformin than in those who were not (30 vs. 65%; log-rank p = 0.044). Similarly, the combined risk of CAV or cardiovascular mortality was lower in the metformin-treated patients than in those not receiving metformin (32 vs. 68%; log rank p = 0.01). Consistently, multivariate analysis adjusted for age and comorbidities showed that metformin therapy was independently associated with a significant 90% reduction (95% confidence interval 0.02-0.46, p = 0.003) in the risk for the development of CAV, and a 91% reduction (95% confidence interval 0.02-0.42; p = 0.003) in the risk for CAV or cardiovascular mortality. CONCLUSIONS: In diabetic HT patients, metformin therapy is independently associated with a significant reduction in the long-term risk for CAV and the combined end-point of CAV or cardiovascular mortality after HT.

Renal glucosuria is associated with lower body weight and lower rates of elevated systolic blood pressure: results of a nationwide cross-sectional study of 2.5 million adolescents.

BACKGROUND: Gene coding mutations found in sodium glucose co-transporters (SGLTs) are known to cause renal glucosuria. SGLT2 inhibitors have recently been shown to be effective hypoglycemic agents as well as possessing cardiovascular and renal protective properties. These beneficial effects have to some extent, been attributed to weight loss and reduced blood pressure. The aim of the current study was to evaluate the prevalence of renal glucosuria amongst a large cohort of Israeli adolescents and to investigate whether renal glucosuria is associated with lower body weight and lower blood pressure values. METHODS: Medical and socio-demographic data were collected from the Israeli Defense Force's conscription center's database. A cross-sectional study to evaluate the association between conscripts diagnosed as overweight [BMI percentiles of ≥ 85 and < 95 and obesity (≥ 95 BMI percentile)] and afflicted with renal glucosuria was conducted. In addition, we assessed the association of renal glucosuria with elevated diastolic and systolic blood pressure. Multinomial regression models were used. RESULTS: The final study cohort comprised 2,506,830 conscripts of whom 1108 (0.044%) were diagnosed with renal glucosuria, unrelated to diabetes mellitus, with males twice as affected compared to females. The adjusted odds ratio for overweight and obesity was 0.66 (95% CI 0.50-0.87) and 0.62 (95% CI 0.43-0.88), respectively. Adolescents afflicted with renal glucosuria were also less likely to have an elevated systolic blood pressure of 130-139 mmHg with an adjusted odds ratio of 0.74 (95% CI 0.60-0.90). CONCLUSIONS: Renal glucosuria is associated with lower body weight and obesity as well as with lower rates of elevated systolic blood pressure.

The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential : A consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation.

In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARMα agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARMα agonist safely reduces residual cardiovascular risk.

The association between fasting plasma glucose and glycated hemoglobin in the prediabetes range and future development of hypertension.

BACKGROUND: Prediabetes is a well-established risk factor for progression to overt diabetes mellitus (DM), which is in turn associated with development of hypertension (HTN) and vice versa. However, the role of prediabetes and HbA1c in particular as an independent risk factor for the development of hypertension is unclear. AIM: In this current study, we aimed to evaluate the association between both fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) levels in the prediabetes range and development of HTN among a large cohort of normotensive subjects. DESIGN AND METHODS: We investigated 5016 normotensive participants without DM and other cardiovascular risk factors who were annually screened in a tertiary medical center. Subjects were divided into normoglycemic and prediabetic groups. Normoglycemia was defined as HbA1c < 5.7% and FPG < 100 mg/dl. Prediabetes was defined according to the ADA criteria, i.e., 6.5% > HbA1c ≥ 5.7% or impaired fasting glucose (IFG):126 mg/dl > FPG ≥ 100 mg/dl. Subgroup analysis was made by dividing participants into four groups according to FPG and HbA1C levels, i.e., normoglycemia, impaired HbA1c only, IFG only, and both parameters impaired. RESULTS: During a follow-up of 3.7 ± 2.9 years, 318 (6.3%) subjects developed HTN. A cumulative hazard function for the development of hypertension showed a 2.89-fold ([95% CI 2.19-3.83], p < .0001) increased risk for HTN in the prediabetic population. In a multivariable Cox proportional hazard regression model adjusted to common confounding risk factors for HTN, prediabetes was found to be independently associated with a 1.95-fold ([95%, CI 1.43-2.52] p < .0001) increased risk for hypertension. Impaired HbA1C only was not found to be independently associated with HTN, while IFG only showed a 2.13-fold (95%, [CI 1.46-3.11] p < .0001) increased risk for HTN compared to normoglycemic, and a 2.55-fold ([95% CI 1.85-3.51] p < .0001) increased risk for HTN when both parameters impaired. CONCLUSION: Our study demonstrates that FPG in the prediabetes range, albeit not glycated hemoglobin, is independently and significantly associated with future development of HTN. Therefore, our findings further highlight the pivotal predictive role of IFG for HTN development as opposed to the limited independent role of abnormal HbA1c levels.

Type 2 diabetes mellitus increases long-term mortality risk after isolated surgical aortic valve replacement.

BACKGROUND: Diabetes mellitus (DM) adversely affects morbidity and mortality for major atherosclerosis-related cardiovascular diseases and is associated with increased risk for the development of aortic stenosis. Clinical data regarding the impact of DM on outcomes of patients undergoing aortic valve replacement (AVR) have revealed inconsistent results. The aim of the current study was to investigate and compare the impact of type 2 DM on short-, intermediate- and long-term mortality between DM and non-DM patients who undergo isolated AVR. METHODS: We performed an observational study in a large tertiary medical center over a 14-year period (2004-2018), which included all patients who had undergone isolated AVR surgery for the first time. Of the 1053 study patients, 346 patients (33%) had type 2 DM (DM group) and were compared with non-DM (non-DM group) patients (67%). Short-term (in-hospital), intermediate (1- and 3-years), and late (5- and 10-years) mortality were evaluated. Mean follow-up of was 69 ± 43 months. RESULTS: Short-term (in-hospital) mortality was similar between the DM compared with the non-DM group: 3.5% and 2.5% (p = 0.517). Intermediate-term mortality (1- and 3-year) was higher in the DM group compared with the non-DM group, but did not reach statistical significance: 8.1% vs. 5.7% (p = 0.169) and 12.1% vs. 8.3% (p = 0.064) respectively. Long-term (5- and 10-year) mortality was significantly higher in the DM group, compared to the non-DM group: 19.4% vs. 12.9% (p = 0.007) and 30.3% vs. 23.5% (p = 0.020) respectively. Among the 346 DM patients, 55 (16%) were treated with insulin and 291 (84%) with oral antiglycemic medication only. Overall in-hospital mortality among insulin-treated DM patients was 7.3% compared with 2.7% among non insulin-treated DM patients (p = 0.201). Long-term mortality was higher in the subgroup of insulin-treated DM patients compared with the subgroup of non-insulin treated DM patients with an overall mortality rate of 36.4% vs. 29.2% (p = 0.039). Furthermore, predictors for late mortality included DM (HR 1.39 CI 1.03-1.86, p = 0.031) and insulin treatment (HR 1.76 CI 1.05-2.94, p = 0.033), as demonstrated after adjustment for confounders by multivariable analysis. CONCLUSIONS: Type 2 DM is an independent predictor for long-term mortality after isolated AVR surgery.

Impact of type 2 diabetes mellitus on short- and long-term mortality after coronary artery bypass surgery.

BACKGROUND: Type 2 diabetes mellitus (DM) is a frequent co-morbidity among patients undergoing coronary artery bypass grafting (CABG) surgery. The aim of this study was to evaluate the impact of DM on the early- and long-term outcomes of patients who underwent isolated CABG. METHODS: We performed an observational cohort study in a large tertiary medical center over a period of 11 years. All data from patients who had undergone isolated CABG surgery between 2004 and 2014 were obtained from our departmental database. The study population included 2766 patients who were divided into two groups: Group I (1553 non-diabetic patients), and Group II (1213 patients suffering from type 2 DM). Group II patients were then divided into two subgroups: subgroup IIA (981 patients treated with oral antihyperglycemic medications) and subgroup IIB (232 insulin-treated patients with or without additional oral antihyperglycemic drugs). In-hospital, 1-, 3-, 5- and 10-year mortality outcome variables were evaluated. Mean follow-up was 97 ± 41 months. RESULTS: In-hospital mortality was similar between Group I and Group II patients (1.87% vs. 2.31%, p = 0.422) and between the subgroups IIA and IIB (2.14% vs. 3.02%, p = 0.464). Long-term mortality (1, 3, 5 and 10 years) was higher in Group II (DM type 2) compared with Group I (non-diabetic patients) (5.3% vs. 3.6%, p = 0.038; 9.3% vs. 5.6%, p < 0.001; 15.3% vs. 9.3%, p < 0.001 and 47.3% vs. 29.6% p < 0.001). Kaplan-Meier analysis demonstrated that all-cause mortality was higher in Group II compared with Group I (p < 0.001) and in subgroup IIB compared with subgroup IIA (p = 0.001). Multivariable analysis showed that DM increased the mortality hazard by twofold, and among diabetic patients, insulin treatment increased the mortality hazard by twofold. CONCLUSIONS: Diabetic and non-diabetic patients have similar in-hospital mortality rates. Survival rates of diabetic patients start to deteriorate 3 year after surgery. Type 2 DM is an independent predictor for long-term mortality after isolated CABG surgery. Mortality is even higher when the diabetes treatment strategy included insulin.

Omega-3 polyunsaturated fatty acids supplementation in patients with diabetes and cardiovascular disease risk: does dose really matter?

There is a vast disagreement in relation to the possible beneficial effects of omega-3 polyunsaturated fatty acids (omega-3 PUFA) supplementation in patients with diabetes and cardiovascular disease. The conflicting results between the various original studies and meta-analyses could be partially explained as a result of variable supplementation dosage and duration, either of which may modify the effects of omega-3 PUFA on cardio-metabolic biomarkers. Meta-analyses are limited usually by the inability to draw inferences regarding dosage, duration and the interaction of dosage and duration of omega-3 PUFA intake. Even so, almost all endpoints in the so-called "negative" meta-analyses leaned toward a trend for benefit with a near 10% reduction in cardiovascular outcomes and a borderline statistical significance. Many trials included in these meta-analyses tested an insufficient daily dose of omega-3 PUFA of less than 1000 mg. Probably, the consistent cardiovascular effects of omega-3 PUFA supplements could be expected only with daily doses above 2000 mg.

Admission blood glucose and 10-year mortality among patients with or without pre-existing diabetes mellitus hospitalized with heart failure.

BACKGROUND: High admission blood glucose (ABG) level has been associated with a poor short-term outcome among non-diabetic patients with heart failure (HF). We aimed to investigate the association between ABG levels and long-term (10 years) mortality in patients with or without pre-existing diabetes mellitus (DM) admitted with HF. METHODS: We analyzed data on 1811 patients with DM and 2182 patients without pre-existing DM who were hospitalized with HF during a prospective national survey. The relationship between ABG and 10-year mortality was assessed using the Cox proportional hazard model adjusting for multiple variables. ABG was analyzed both as a categorical (<110, 110-140, 140-200, and >200 mg/dL) and as a continuous variable. RESULTS: At 10 years of follow-up the cumulative probability of mortality was 85 and 78% among patients with DM and patients with no pre-existing DM (p < 0.001), respectively. Among patients with no pre-existing DM, glucose levels of 110-140, 140-200 and ≥200 mg/dL were associated with 9% (p = 0.140), 16% (p = 0.031) and 53% (p < 0.001) increased mortality risk compared to ABG < 110 mg/dL. Each 18-mg/dL (1-mmol/L) increase in glucose level was associated with a 5% increased risk of mortality (p < 0.001) among patients with no-pre-existing DM. In contrast, among patients with DM, only those with glucose levels >200 mg/dL had an increased mortality risk (>200 mg/dL versus <110 mg/dL; HR = 1.20, p = 0.032). CONCLUSION: Among hospitalized HF patients with no pre-existing DM there is a linear relationship between ABG level and long-term mortality, whereas among patients with DM only ABG level >200 mg/dL is associated with increased mortality risk.

The addition of vildagliptin to metformin prevents the elevation of interleukin 1ß in patients with type 2 diabetes and coronary artery disease: a prospective, randomized, open-label study.

BACKGROUND: Patients with type 2 diabetes present with an accelerated atherosclerotic process. Animal evidence indicates that dipeptidyl peptidase-4 inhibitors (gliptins) have anti-inflammatory and anti-atherosclerotic effects, yet clinical data are scarcely available. DESIGN AND METHODS: A prospective, randomized, open-label study was performed in 60 patients with coronary artery disease (CAD) and type 2 diabetes, who participated in a cardiac rehabilitation program. After a washout period of 3 weeks, patients were randomized in a 2:1 ratio to receive combined vildagliptin/metformin therapy (intervention group: n = 40) vs. metformin alone (control group: n = 20) for a total of 12 weeks. Blinded assessment of interleukin-1ß (IL-1ß, the primary endpoint), hemoglobin A1c (HbA1c), and high sensitivity C reactive protein (hsCRP), were performed at baseline and after 12 weeks. RESULTS: Mean age of study patients was 67 ± 9 years, 75% were males, and baseline HbA1c and inflammatory markers levels were similar between the two groups. At 12 weeks of follow up, levels of IL-1ß, hsCRP, and HbA1c were significantly lower in the intervention group as compared with the control group. There was a continuous elevation of IL-1ß among the control group, which was not observed in the intervention group (49 vs. 4%, respectively; p < 0.001). The hsCRP was lowered by 60% in the vildagliptin/metformin group vs. 23% in the metformin group (p < 0.01). Moreover, a significant relative reduction of the HbA1c was seen in the intervention group (7% reduction, p < 0.03). CONCLUSION: The addition of vildagliptin to metformin treatment in patients with type 2 diabetes and CAD led to a significant suppression of the IL-1ß elevation during follow up. A significant relative reduction of hsCRP and HbA1c in the intervention group was also observed. Trial registration NCT01604213.

Thermal compaction of the intrinsically disordered protein tau: entropic, structural, and hydrophobic factors.

Globular denatured proteins have structural properties similar to those of random coils. Experiments on denatured proteins have shown that when the temperature is increased thermal compaction may take place, resulting in a reduction of their radius of gyration Rg to range between 5% and 35% of its initial value. This phenomenon has been attributed to various causes, namely entropic, hydrophobic, and structural factors. The intrinsically disordered protein tau, which helps in nucleating and stabilizing microtubules in the axons of the neurons, also undergoes a relevant compaction process: when its temperature is increased from 293 K to 333 K its gyration radius decreases by 18%. We have performed an atomistic simulation of this molecule, at the lowest and highest temperatures of the mentioned interval, using both standard molecular dynamics and metadynamics, in parallel with small-angle X-ray scattering experiments. Using the fit of the experimental data and a genetic algorithm to select the most probable configurations among those produced in both atomistic simulations (standard MD and metadynamics), we were able to compute relevant changes, related to the temperature increase, in the average angles between residues, in the transient secondary structures, in the solvent accessible surface area, and in the number of intramolecular H-bonds. The analysis of the data showed how to decompose the compaction phenomenon into three contributions. An estimate of the entropic contribution to the compaction was obtained using the changes in the mean values of the angles between contiguous residues. The computation of the solvent accessible surface at the two temperatures allowed an estimation of the second factor contributing to the compaction, namely the increase in the hydrophobic interaction. We also measured the change in the average number of residues temporarily being in α-helices, 3-helices, PP II helices, ß-sheets and ß-turns. Those changes in the secondary structure population produce a reduction in the contour length of the protein, yielding a structural contribution to the reduction of Rg. This analysis shows that in tau the entropic factor accounts for about 60% of the compaction, the hydrophobic factor for about 25%, and the change in the secondary structure for about 15%.

Characteristics and outcomes of diabetic patients with an implantable cardioverter defibrillator in a real world setting: results from the Israeli ICD registry.

AIMS: There are limited data regarding the effect of diabetes mellitus (DM) on the risks of both appropriate and inappropriate implantable cardioverter defibrillator (ICD) therapy. The present study was designed to compare the outcome of appropriate and inappropriate ICD therapy in patients with or without DM. METHODS AND RESULTS: The risk of a first appropriate ICD therapy for ventricular tachyarrhythmias (including anti tachycardia pacing and shock) was compared between 764 DM and 1346 non-DM patients enrolled in the national Israeli ICD registry. We also compared the risks of inappropriate ICD therapy, and death or cardiac hospitalization between diabetic and non-diabetic patients. Diabetic patients were older, were more likely to have ischemic cardiomyopathy, lower ejection fraction, atrial fibrillation, and other co-morbidities. The 3-year cumulative incidence of appropriate ICD therapy was similar in the DM and non-DM groups (12 and 13%, respectively, p = 0.983). Multivariate analysis showed that DM did not affect the risk of appropriate ICD therapy (HR = 1.07, 95% CI 0.78-1.47, p = 0.694) or inappropriate therapy (HR = 0.72, 95% CI 0.42-1.23, p = 0.232). However, DM was associated with a 31% increased risk for death or cardiac hospitalization (p = 0.005). Results were similar in subgroup analyses including ICD and defibrillators with cardiac resynchronization therapy function recipients, primary or secondary prevention indication for an ICD. CONCLUSIONS: Despite a significant excess of cardiac hospitalizations and mortality in the diabetic population, there was no difference in the rate of ICD treatments, suggesting that the outcome difference is not related to arrhythmias.

Metabolic syndrome is independently associated with increased 20-year mortality in patients with stable coronary artery disease.

BACKGROUND: Data regarding long-term association of metabolic syndrome (MetS) with adverse outcomes are conflicting. We aim to determine the independent association of MetS (based on its different definitions) with 20 year all-cause mortality among patients with stable coronary artery disease (CAD). METHODS: Our study comprised 15,524 patients who were enrolled in the Bezafibrate Infarction Prevention registry between February 1, 1990, and October 31, 1992, and subsequently followed-up for the long-term mortality through December 31, 2014. MetS was defined according to two definitions: The International Diabetes Federation (IDF); and the National Cholesterol Education Program-Third Adult Treatment Panel (NCEP). RESULTS: According to the IDF criteria 2122 (14%) patients had MetS, whereas according to the NCEP definition 7446 (48%) patients had MetS. Kaplan-Meier survival analysis showed that all-cause mortality was significantly higher among patients with MetS defined by both the IDF (67 vs. 61%; log rank-p < 0.001) as well as NCEP (67 vs. 54%; log rank-p < 0.001) criteria. Multivariate adjusted mortality risk was 17% greater [Hazard Ratio (HR) 1.17; 95% Confidence Interval (CI) 1.07-1.28] in patients with MetS according to IDF and 21% (HR 1.21; 95% CI 1.13-1.29) using the NCEP definition. Subgroup analysis demonstrated that long-term increased mortality risk associated with MetS was consistent among most clinical subgroups excepted patients with renal failure (p value for interaction < 0.05). CONCLUSIONS: Metabolic syndrome is independently associated with an increased 20-year all-cause mortality risk among patients with stable CAD. This association was consistent when either the IDF or NCEP definitions were used. Trial registration retrospective registered.