Serum proprotein convertase subtilisin/Kexin type 9 and vascular disease in type 2 diabetic patients

BackgroundProprotein Convertase Subtilisin/Kexin type 9 (PCSK9) levels have been suggested as novel atherosclerotic biomarker. PCSK9 plays important roles in the pathogenesis of atherosclerosis by regulating the degradation of low-density lipoprotein receptor as well as different inflammatory pathways. Considering the important prognostic role of arterial stiffness in cardiovascular disease (CVD), the aim of the study is to investigate the correlation between PCSK9 levels and arterial stiffness in a cohort of diabetic patients, without previous CV events. MethodsThis cross-sectional analysis enrolled 401 Caucasian patients with type II diabetes mellitus (T2DM). PCSK9 levels were measured by ELISA test, arterial stiffness was estimated by measuring carotid-femoral pulse wave velocity (PWV). ResultsPatients were divided in three tertiles according to increasing value of PCSK9. From the I to the III tertiles, there was a significant increase in high sensitivity C-reactive protein (hs-CRP), fibrinogen and white blood cells (WBC) and a reduction in estimated glomerular filtration rate (e-GFR). Patients with higher levels of PCSK9 presented increased systolic, diastolic blood pressure, pulse pressure and PWV. PWV was significantly and directly correlated with PCSK9, fibrinogen, age, BMI and PP, and indirectly correlated with diet, lifestyle and e-GFR. Serum PCSK9 was the major predictor of PWV, justifying a 16.9% of its variation. ConclusionOur study demonstrates a close association between circulating PCSK9 levels and PWV in T2DM subjects without previous CV events even after adjusting for well-known CV risk factor and pharmacological medications. Serum PCSK9 could be a useful biomarker for CV risk stratification in diabetic subjects

Short-term effect of sacubitril/valsartan on endothelial dysfunction and arterial stiffness in patients with chronic heart failure

Heart failure (HF) is associated to endothelial dysfunction that promotes the increase of arterial stiffness thus augmenting myocardial damage. Sacubitril/Valsartan is used in the treatment of HF reduced ejection fraction (HFrEF) and has been proven effective in reducing cardiovascular disease (CVD) progression and all-cause mortality. The aim of this study was to evaluate the effect of Sacubitril/Valsartan on endothelial dysfunction, arterial stiffness, oxidative stress levels and platelets activation in patients with HFrEF, at baseline and after 6 months of treatment. We enrolled 100 Caucasian patients. Endothelial function was evaluated by the reactive hyperemia index (RHI) and arterial stiffness (AS) by the measurement of carotid-femoral pulse wave velocity (PWV), augmentation pressure (AP) and augmentation index (AI). At baseline, among enrolled outpatients, 43% showed a NYHA class II and 57% a NYHA class III. At 6 months, there was a significant improvement of several hemodynamic, clinical and metabolic parameters with a significant reduction in oxidative stress indices such as 8-isoprostane (p < 0.0001) and Nox-2 (p < 0.0001), platelets activity biomarkers such as sP-selectin (p < 0.0001) and Glycoprotein-VI (p < 0.0001), and inflammatory indices. Moreover, we observed a significant improvement in arterial stiffness parameters and in endothelial function indices. Our study demonstrated that 6 months treatment with Sacubitril/Valsartan, in patients with HFrEF, improves endothelial dysfunction and arterial stiffness, by reducing oxidative stress, platelet activation and inflammation circulating biomarkers, without adverse effects

Prescription appropriateness of anti-diabetes drugs in elderly patients hospitalized in a clinical setting: evidence from the REPOSI Register

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P < 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria

Biological Therapy of Severe Asthma with Dupilumab, a Dual Receptor Antagonist of Interleukins 4 and 13

Interleukin-4 (IL-4) and interleukin-13 (IL-13) are key cytokines involved in the pathophysiology of both immune-inflammatory and structural changes underlying type 2 asthma. IL-4 plays a pivotal role in Th2 cell polarization, immunoglobulin E (IgE) synthesis and eosinophil recruitment into the airways. IL-13 synergizes with IL-4 in inducing IgE production and also promotes nitric oxide (NO) synthesis, eosinophil chemotaxis, bronchial hyperresponsiveness and mucus secretion, as well as the proliferation of airway resident cells such as fibroblasts and smooth muscle cells. The biological effects of IL-4 and IL-13 are mediated by complex signaling mechanisms activated by receptor dimerization triggered by cytokine binding to the α-subunit of the IL-4 receptor (IL-4Rα). The fully human IgG4 monoclonal antibody dupilumab binds to IL-4Rα, thereby preventing its interactions with both IL-4 and IL-13. This mechanism of action makes it possible for dupilumab to effectively inhibit type 2 inflammation, thus significantly reducing the exacerbation of severe asthma, the consumption of oral corticosteroids (OCS) and the levels of fractional exhaled NO (FeNO). Dupilumab has been approved not only for the add-on therapy of severe asthma, but also for the biological treatment of atopic dermatitis and nasal polyposis

Ranolazine Attenuates Brain Inflammation in a Rat Model of Type 2 Diabetes

Recent studies suggest a pathogenetic association between metabolic disturbances, including type 2 diabetes (T2DM), and cognitive decline and indicate that T2DM may represent a risk factor for Alzheimer’s disease (AD). There are a number of experimental studies presenting evidence that ranolazine, an antianginal drug, acts as a neuroprotective drug. The aim of the present study was to evaluate the effects of ranolazine on hippocampal neurodegeneration and astrocytes activation in a T2DM rat model. Diabetes was induced by a high fat diet (HFD) and streptozotocin (STZ) injection. Animals were divided into the following groups: HFD/STZ + Ranolazine, HFD/STZ + Metformin, HFD/STZ + Vehicle, NCD + Vehicle, NCD + Ranolazine and NCD + Metformin. The presence of neurodegeneration was evaluated in the hippocampal cornus ammonis 1 (CA1) region by cresyl violet staining histological methods, while astrocyte activation was assessed by western blot analysis. Staining with cresyl violet highlighted a decrease in neuronal density and cell volume in the hippocampal CA1 area in diabetic HFD/STZ + Vehicle rats, while ranolazine and metformin both improved T2DM-induced neuronal loss and neuronal damage. Moreover, there was an increased expression of GFAP in the HFD/STZ + Vehicle group compared to the treated diabetic groups. In conclusion, in the present study, we obtained additional evidence supporting the potential use of ranolazine to counteract T2DM-associated cognitive decline

Long Term Metabolic Effects of Sacubitril/Valsartan in Non-Diabetic and Diabetic Patients With Heart Failure Reduced Ejection Fraction. A Real Life Study

Sacubitril/Valsartan (sac/val) has improved clinical prognosis in patients affected by heart failure (HF) with reduced ejection fraction (HFrEF). HF and type 2 diabetes mellitus (T2DM) frequently coexist, with a prevalence of T2DM of 35%-40% in patients with HF. T2DM is the third co-morbidities in patients with HF and a strong independent risk factor for the progression of HF. In a post hoc analysis of PARADIGM-HF, improved glycemic control was shown in patients with T2DM and HFrEF receiving sac/val compared to enalapril at 12 months of follow-up. The aim of the present study was to evaluate, in a series of repeated observations in 90 HFrEF patients, the long term effect of sac/val treatment on renal function, glycometabolic state and insulin sensitivity parameters, according to diabetic status. We studied 90 patients (74 men and 16 women, mean age 68 ± 10 years, 60 diabetics and 30 non-diabetics) suffering from HFrEF and still symptomatic despite optimal pharmacological therapy. Patients with left ventricular ejection fraction (LVEF) <35% and II-III NYHA functional class were enrolled. All patients underwent clinical-instrumental and laboratory determinations and Minnesota Living with HF Questionnaire (MLHFQ) every 6 months until 30 months to evaluate benefits and adverse events. After 30 months follow-up, we observed a significant improvement in glycometabolic parameters including HbA1c, fasting glucose and insulin, insulin-like growth factor-1 (IGF-1), HOMA index, and LDL cholesterol. Moreover, renal function, NTpro-BNP levels and echocardiographic parameters significantly improved. In diabetic patients a significant reduction in use of oral antidiabetic drugs and insulin was observed after 30 months of sac/val treatment. In the whole population, multivariate analysis shows that the evolution of cardiac index (CI) was significantly associated to simultaneous changes in HOMA, IGF-1 and visit; per each visit and for 1 ng/ml increase in IGF-1 there was an increase in CI of 64.77 ml/min/m2 (p < 0.0001) and 0.98 ml/min/m2 (p = 0.003), respectively, whereas 1 point increase in HOMA was associated with a -7.33 ml/min/m2 (p = 0.003) reduction in CI. The present data confirm persistent metabolic improvement in patients with HFrEF after treatment with sac/val and highlights its potential therapeutical role in patients with metabolic comorbidities

Association between right ventricular dysfunction and adverse cardiac events in mild COPD patients

Background: Lung hyperinflation and systemic inflammation are currently believed to be the most important causes of right heart alterations in chronic obstructive pulmonary disease (COPD) patients. A multicentre observational study was performed to assess the morphological and functional parameters of right ventricle (RV) in COPD subjects, as well as to evaluate the potential prognostic impact on the development of major cardiovascular adverse events (MACEs). Methods: For this retrospective study, from 1 January 2010 to 31 December 2021, we enrolled COPD patients on the basis of their airflow limitation. In particular, we selected subjects spanning across GOLD 1 and 2 functional stages. Clinical, laboratory and functional parameters were collected at baseline. Echocardiography was routinely performed in all COPD patients. RV dysfunction was defined on the basis of tricuspid annular plane systolic excursion (TAPSE) values. MACE occurrence (non-fatal ischemic stroke, non-fatal myocardial infarction, cardiac revascularization or coronary bypass surgery and cardiovascular death) was evaluated during a median follow-up of 55 (36-72) months. Results: Among the 749 enrolled patients, 408 subjects had a TAPSE value ≥20 mm, while the remaining 341 had a TAPSE value <20 mm. In patients with TAPSE ≥20 mm the observed MACEs were 1.9 events/100 patient-year, while in the group with a worse right heart function there were 4.2 events/100 patient-year (p < .0001). The multivariate analysis model confirmed the association between RV dysfunction and MACE. Indeed, a 1-mm increase in TAPSE value and the intake of long-acting β2 -receptor agonists (LABA)/long-acting muscarinic antagonist (LAMA) inhaled therapy were protective factors for the onset of MACE, while the presence of diabetes mellitus and high values of both uric acid (UA) and systolic pulmonary arterial pressure (S-PAP) enhanced the risk of MACE in study participants. Conclusions: The results of this study showed that in patients with mild COPD there is an association between right heart dysfunction and the risk of MACE during follow-up

Oxidative Stress and Left Ventricular Performance in Patients with Different Glycometabolic Phenotypes

The aim of the present study was to evaluate the possible correlation between oxidative stress and subclinical myocardial damage, assessed with speckle tracking echocardiography (STE), in normal glucose tolerance (NGT) patients with one-hour plasma glucose values ≥ 155 mg/dL (NGT ≥ 155), comparing them to NGT p p p p p p p = 0.001), but similar to IGT patients. Our study demonstrated that NGT ≥ 155 subjects exhibit early functional impairment of myocardial contractile fibres, these alterations are correlated with increased oxidative stress

Role of vitamin D in cardiovascular diseases

Vitamin D represents a group of secosteroids involved in the calcium and phosphate metabolism. The active form of vitamin D, 1,25-dihydroxylcalciferol, exerts its biological mechanisms via the VDR (vitamin D receptor) which acts as a regulator of several target genes. Hypovitaminosis D is associated with many diseases, which are not only limited to the metabolism of the skeleton, but growing evidence links the deficit of vitamin D to cardiovascular, metabolic, immune, and neoplastic diseases. In regard to the cardiovascular system, current evidence shows the presence of VDR in endothelial cells. Moreover, both in vitro and animal experimental models demonstrated that the deficit of vitamin D can promote endothelial dysfunction and atherosclerosis development. Vitamin D can interfere with vascular functions also by affecting the production of vasodilator mediators. VDR is also expressed in left ventricle cardiomyocytes, and hypovitaminosis D can relate to cardiac hypertrophy and heart failure. Randomized clinical trials (RCT) designed to prove the therapeutic role of vitamin D supplementation have been inconclusive to date. The aim of this review is to highlight the main interactions between vitamin D metabolism and cardiovascular diseases; thus, focusing on pathogenic mechanisms and related clinical manifestations

Effects of Sacubitril-Valsartan on Clinical, Echocardiographic, and Polygraphic Parameters in patients affected by heart failure with reduced ejection fraction and sleep apnea

Background: Heart failure with reduced ejection fraction (HFrEF) is a clinical condition frequently diagnosed in clinical practice. In patients affected by HFrEF, sleep apnea (SA) can be detected among the most frequent comorbidities. Sacubitril-valsartan (sac/val) association has been proven to be effective in reducing disease progression and all-cause mortality in HFrEF patients. Sac/val treatment can potentially attenuate SA development via several pathophysiologic mechanisms, including improvement of global hemodynamics, reduction of extracellular fluid overload, and decrease of sympathetic neural activity. Methods: We recruited 132 patients affected by HFrEF and SA, already under treatment with continuous positive airway pressure (CPAP), which was discontinued 24 h before the scheduled study timepoints. Physical examination, echocardiography, nocturnal cardio-respiratory monitoring, and laboratory tests were performed in each patient at baseline and after a 6-month treatment with sac/val. Results: After 6 months, sac/val induced statistically significant changes in clinical, hemodynamic, biohumoral (NT-proBNP, serum electrolytes, creatinine, and uric acid), and echocardiographic parameters. In particular, cardiac index (CI), both atrial and ventricular volumes and global longitudinal strain (GLS) improved. Moreover, polysomnography, carried out during a temporary CPAP interruption, revealed a significant reduction in global apnea-hypopnea index (AHI) value (p < 0.0001), central AHI (p < 0.0001), obstructive AHI (p < 0.0001), oxygen desaturation index (ODI) (p < 0.0001), and percentage time of saturation below 90% (TC90) (p < 0.0001). The changes of CI, estimated glomerular filtration rate (eGFR), NT-proBNP, and tricuspid annular plane excursion (TAPSE) contributed to 23.6, 7.6, 7.3, and 4.8% of AHI variability, respectively, and the whole model accounted for a 43.3% of AHI variation. Conclusions: Our results suggest that treatment with sac/val is able to significantly improve the cardiorespiratory performance of patients with HFrEF and SA, integrating the positive impact of CPAP. Thus, both CPAP and sac/val therapy may synergistically contribute to lower the risks of both cardiac and pulmonary complications in HFrEF patients with SA