Rationale: In diabetic patients, heart failure with predominant left ventricular (LV) diastolic dysfunction is a common complication for which there is no effective treatment. Oxidation of the nitric oxide synthase (NOS) co-factor tetrahydrobiopterin (BH4) and dysfunctional NOS activity have been implicated in the pathogenesis of the diabetic vascular and cardiomyopathic phenotype. Objective: Using mice models and human myocardial samples, we evaluated whether and by which mechanism increasing myocardial BH4 availability prevented or reversed LV dysfunction induced by diabetes. Methods and Results: In contrast to the vascular endothelium, BH4 levels, superoxide production and NOS activity (by liquid chromatography) did not differ in the LV myocardium of diabetic mice or in atrial tissue from diabetic patients. Nevertheless, the impairment in both cardiomyocyte relaxation and [Ca2+]i decay and in vivo LV function (echocardiography and tissue Doppler) that developed in wild type mice (WT) 12 weeks post-DM induction (streptozotocin, 42-45mg/kg) was prevented in mice with elevated myocardial BH4 content secondary to overexpression of GTP-cyclohydrolase 1 (mGCH1-Tg) and reversed in WT mice receiving oral BH4 supplementation from the 12th to the 18th week after DM induction. The protective effect of BH4 was abolished by CRISPR/Cas9-mediated knockout of neuronal NOS (nNOS) in mGCH1-Tg. In HEK cells, S-nitrosoglutathione led to a PKG-dependent increase in plasmalemmal density of the insulin-independent glucose transporter, GLUT-1. In cardiomyocytes, mGCH1 overexpression induced a NO/sGC/PKG-dependent increase in glucose uptake via GLUT-1, which was instrumental in preserving mitochondrial creatine kinase activity, oxygen consumption rate, LV energetics (by 31P MRS) and myocardial function. Conclusions: We uncovered a novel mechanism whereby myocardial BH4 prevents and reverses LV diastolic and systolic dysfunction associated with diabetes via a nNOS-mediated increase in non-insulin dependent myocardial glucose uptake and utilization. These findings highlight the potential of GCH1/BH4-based therapeutics in human diabetic cardiomyopathy.

Ensuring multiple sclerosis (MS) patients’ adherence to therapy is often challenging, but it is crucial to their survival and health-related quality of life (HRQoL). The aim of the present study was to outline connections between adherence, physical and mental HRQoL, levels of psychological readiness to engage in a treatment, levels of social support, anthropometric, socio-demographic and clinical factors in patients suffering from MS. This cross-sectional study involved a sample of 237 Italian MS patients. A survey was conducted with a structured self-administered online questionnaire using validated measures of quality of life, adherence to therapy and anthropometric, socio-demographic, psychological and clinical variables. A path analysis was used to test the overall structure of the associations between the variables. The pathway indicates a positive association between mental health index and a stronger degree of engagement and being or having been in a long-term relationship. Physical health index was positively associated with age, having an occupation, and having a specific form of MS. Having had relapses in the previous year raised the odds of better adherence to therapy, while an increase in Body Mass Index (BMI) reduced them. Our findings could help in the management of MS patients, promoting behavioral interventions that take the psychological and socio-demographic peculiarities of each patient into account with a view to improving their adherence to therapy.

Current guidelines suggest the use of low doses of acetylsalicylic acid (ASA) for patients with diabetes mellitus (DM) in primary prevention. However, the evidences demonstrating the beneficial effect of ASA in primary prevention are conflicting. In this pilot study, we evaluated in a group of diabetic patients, in primary prevention, the impact of ASA treatment on oxidative stress and vascular function. We enrolled 22 newly diagnosed diabetic patients, without any previous clinical evidence of cardiovascular disease, to receive, in primary prevention, ASA (100 mg/daily). We tested, in basal condition, after 4 weeks of ASA administration and after 4 weeks of pharmacological washout, the impact of ASA treatment on endothelial function, assessed by a semipletysmographic method, measuring the main oxidative stress parameters related to it. As expected, after 4 weeks of treatment, ASA induced a significant reduction of plasma thromboxane-A2, as a consequence of cyclooxygenase-1 inhibition. By contrast, ASA significantly increased the plasma and urine 8-iso-PGF2α, a well-known prothrombotic molecule, parallel to an increase of plasma NOX2 levels. The enhancement of this oxidative pathway is associated with a significant impairment of endothelial vasodilation, assessed by reactive hyperemia index (RHI). The pharmacological washout reverted all parameters to basal condition. Our findings suggest that ASA utilization for primary prevention in diabetic patients causes a significant increase of oxidative stress burden impairing the vascular function. Present data, if confirmed on a larger population, could permanently discourage the use of the ASA for the primary prevention in patients with DM.

Background The worldwide prevalence of obstructive lung disease (OLD) is increasing, especially among people >65 years old, and nearly three in four adults with OLD have two or more comorbid conditions. This study describes the impact of such comorbidities on the healthcare service usage and related costs in a country with universal health coverage, basing on a large cohort of elderly patients with OLD and employing real-world data. Methods We carried out a retrospective cohort study on a large population of elderly (age >64 years) patients with OLD served by a Local Health Unit in northern Italy. Their comorbidities were assessed using the clinical diagnoses assigned by the Adjusted Clinical Group (ACG) system to individual patients by combining different information flows. Correlations between number of comorbidities and total annual healthcare service usage and costs were examined with Spearman’s test. Regression models were applied to analyze the associations between the above-mentioned variables, adjusting for age and sex. Results All types of healthcare service usage (access to emergency care; number of outpatient visits; number of hospital admissions) and pharmacy costs increased significantly with the number of comorbidities. Average total annual costs increased steadily with the number of comorbidities, ranging from € 1158.84 with no comorbidities up to € 9666.60 with 6 comorbidities or more. Poisson regression analyses showed an independent association between the number of comorbidities and the use of every type of healthcare service. Conclusion These results based on real-world data provide evidence that the burden of care for OLD patients related to their comorbidities is independent of and in addition to the burden related to OLD alone and is strongly dependent on the number of comorbidities, suggesting a holistic approach to multimorbid patients with OLD is the most sound public health strategy.

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