Grazia Daniela Femminella

The emerging role of microRNAs in Alzheimer's disease

MicroRNAs (miRNAs) are small non-coding RNA which have been shown to regulate gene expression. The alteration ofmiRNAs expression has been associated with several pathological processes, including neurodegeneration. In the search for easily accessible and non-invasive biomarkers for Alzheimers disease (AD) diagnosis and prognosis, circulating miRNAs are among the most promising candidates. Some of them have been consistently identified as AD-specific miRNAs and their targets also seem implicated in pathophysiological processes underlying AD. Here, we review the emerging role for miRNA in AD, giving an overview on general miRNAs biology, their implications in AD pathophysiology and their potential role as future biomarkers.

β-adrenergic receptor responsiveness in aging heart and clinical implications.

Elderly healthy individuals have a reduced exercise tolerance and a decreased left ventricle inotropic reserve related to increased vascular afterload, arterial-ventricular load mismatching, physical deconditioning and impaired autonomic regulation (the so called “β-adrenergic desensitization”). Adrenergic responsiveness is altered with aging and the age-related changes are limited to the β-adrenergic receptor density reduction and to the β-adrenoceptor-G-protein(s)-adenylyl cyclase system abnormalities, while the type and level of abnormalities change with species and tissues. Epidemiological studies have shown an high incidence and prevalence of heart failure in the elderly and a great body of evidence correlate the changes of β-adrenergic system with heart failure pathogenesis. In particular it is well known that: (a) levels of cathecolamines are directly correlated with mortality and functional status in heart failure, (b) β1-adrenergic receptor subtype is down-regulated in heart failure, (c) heart failure-dependent cardiac adrenergic responsiveness reduction is related to changes in G proteins activity. In this review we focus on the cardiovascular β-adrenergic changes involvement in the aging process and on similarities and differences between aging heart and heart failure.

Impact of Diabetes on Cardiac Sympathetic Innervation in Patients With Heart Failure: A 123I meta-iodobenzylguanidine (123I MIBG) scintigraphic study

OBJECTIVE Impaired parasympathetic and sympathetic nervous system activity have been demonstrated in patients with diabetes mellitus (DM) and correlated with worse prognosis. Few data are available on the effect of DM on cardiac neuropathy in heart failure (HF). The aim of the current study was to assess cardiac sympathetic activity in HF patients with and without DM. RESEARCH DESIGN AND METHODS Patients with severe HF (n = 75), with (n = 37) and without DM (n = 38), and 14 diabetic patients with normal cardiac function underwent 123I meta-iodobenzylguanidine scintigraphy from which early and late heart-to-mediastinum (H/M) ratios were calculated. Clinical, echocardiographic, and biochemical data were measured. RESULTS DM compared with non-DM patients showed significantly lower early (1.65 ± 0.21 vs. 1.75 ± 0.21; P < 0.05) and late H/M ratios (1.46 ± 0.22 vs. 1.58 ± 0.24; P < 0.03). Early and late H/M were significantly higher in DM patients without HF (2.22 ± 0.35 and 1.99 ± 0.24, respectively) than HF patients with (P < 0.0001) and without (P < 0.0001) DM. In HF patients, an inverse correlation between early or late H/M ratio and hemoglobin A1c (HbA1c) (Pearson = −0.473, P = 0.001; Pearson = −0.382, P = 0.001, respectively) was observed. In DM, in multivariate analysis, HbA1c and ejection fraction remained significant predictors of early H/M; HbA1c remained the only significant predictor of late H/M. No correlation between early or late H/M and HbA1c was found in non-DM patients. CONCLUSIONS Diabetic patients with HF show lower cardiac sympathetic activity than HF patients not having DM or than DM patients with a similar degree of autonomic dysfunction not having HF. HbA1c correlated with the degree of reduction in cardiac sympathetic activity.

Targeting the β-Adrenergic Receptor System Through G-Protein–Coupled Receptor Kinase 2: A New Paradigm for Therapy and Prognostic Evaluation in Heart Failure From Bench to Bedside

G-protein–coupled receptors (GPCRs) are a superfamily of more than 1000 membrane proteins that respond to a wide spectrum of extracellular signals, modulating various physiopathological processes.1,2 Several GPCRs, such as adrenergic, angiotensin, endothelin, and adenosine receptors, are expressed in cardiovascular (CV) tissues to maintain CV homeostasis. Importantly, GPCR-mediated adrenergic deregulation has been shown to both cause and contribute to the onset and progression of major CV diseases ultimately leading to heart failure (HF). Thus, GPCRs have become salient targets of current pharmacotherapy in CV disorders, and in past decades, many efforts have been made to better clarify their role in the pathophysiology of cardiac disease, focusing not only on receptor functions but also on postreceptor components that mediate or regulate their responses. Among the latter, a relevant role has been attributed to G-protein–coupled receptor kinases (GRKs). In this review, we focus on GRK2, the most abundant and versatile GRK expressed on CV system, tracing the way from initial experimental evidence to more recent data suggesting a potential role for this kinase in the clinical management of HF.1,2 ### GPCR Signaling and GRK Functions: Pathophysiological Background On stimulation, GPCRs interact with heterotrimeric G proteins, which in turn dissociate into 2 functional monomers, namely Gα and Gβγ, both of which modulate different effector systems. Agonist binding to GPCR promotes the activation of complex regulatory mechanisms to protect the receptor from both acute and chronic stimulation, a process termed desensitization. As extensively described, GPCR desensitization involves 3 main events in chronological order: receptor phosphorylation and uncoupling from G proteins, internalization of membrane-bound receptors, and downregulation through reduced mRNA and protein synthesis or increased degradation of internalized receptors.1,2 The desensitization process is mediated by 3 families of proteins: second-messenger–dependent protein kinases, GRKs and arrestins. The defining feature of GRKs is that …

Blockade of β-adrenoceptors restores the GRK2-mediated adrenal α2-adrenoceptor–catecholamine production axis in heart failure

BACKGROUND AND PURPOSE Sympathetic nervous system (SNS) hyperactivity is characteristic of chronic heart failure (HF) and significantly worsens prognosis. The success of β‐adrenoceptor antagonist (β‐blockers) therapy in HF is primarily attributed to protection of the heart from the noxious effects of augmented catecholamine levels. β‐Blockers have been shown to reduce SNS hyperactivity in HF, but the underlying molecular mechanisms are not understood. The GPCR kinase‐2 (GRK2)–α2adrenoceptor–catecholamine production axis is up‐regulated in the adrenal medulla during HF causing α2‐adrenoceptor dysfunction and elevated catecholamine levels. Here, we sought to investigate if β‐blocker treatment in HF could lower SNS activation by directly altering adrenal GRK2 levels.

Myocardial β2-adrenoceptor gene delivery promotes coordinated cardiac adaptive remodelling and angiogenesis in heart failure

BACKGROUND AND PURPOSE We investigated whether β2‐adrenoceptor overexpression could promote angiogenesis and improve blood perfusion and left ventricular (LV) remodeling of the failing heart.

Cholinesterase inhibitors for Parkinson's disease: a systematic review and meta-analysis

Background Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder frequently associated with a wide variety of non-motor symptoms related to non-dopaminergic pathways. Although the depletion of dopamine is the key neurochemical impairment in PD and anticholinergic medications are used for symptomatic treatment, significant deficits in cholinergic transmission are also present and have been associated with cognitive decline and gait dysfunction. Therefore, use of a cholinesterase inhibitor (ChI) might improve cognitive function and reduce the risk of falls in patients with PD, although it could plausibly worsen motor features. Our objective was to conduct a systematic review of prospective, randomised controlled trials, in order to assess the efficacy and safety of ChIs compared with placebo in patients with PD. Methods and results MEDLINE, Web of Science, CENTRAL and Scopus databases were searched to identify studies published before 5 May 2014 and including patients with PD treated with ChIs. From 945 references identified and screened, 19 were assessed for eligibility and 4 trials were included for a total of 941 patients with PD. ChIs significantly slowed Mini-Mental State Examination decline without effect on risk of falls. Tremor rates and adverse drug reactions favoured the placebo group. Alzheimer Disease Assessment Scale-cognitive subscale, global assessment and behavioural disturbance improved in the ChI group without effect on disability. There was no significant difference between the groups for Unified Parkinson Disease Rating Scale III. A significantly reduced death rate was observed in the treated cohort as compared with placebo. Conclusions ChIs are effective in the treatment of cognitive impairment in patients with PD, but do not affect risk of falls. The choice of treatment has to be balanced considering the increased tremor and adverse drug reactions.

Oral Anticoagulation Therapy in Heart Failure Patients in Sinus Rhythm: A Systematic Review and Meta-Analysis

Background Heart failure (HF) patients show high morbidity and mortality rate with increased risk of malignant arrhythmia and thromboembolism. Anticoagulation reduces embolic event and death rates in HF patients with atrial fibrillation, but if antithrombotic therapy is beneficial in patients with HF in sinus rhythm is still debated. Methodology and Principal Findings We conducted a systematic review of prospective, randomized controlled trials (RCTs) to assess the efficacy and safety of oral anticoagulant therapies (OATs) compared to antiplatelet treatment in HF patients in sinus rhythm. MEDLINE, Web of Science, CENTRAL and Scopus databases were searched up to May 2012. Four RCTs were identified and a total of 3663 patients were included in the meta-analysis. Patients with both ischemic and non-ischemic HF were included. There was no significant difference in mortality (odds ratio (OR) 1.01, 95% confidence interval (CI) 0.86 to 1.19) between OATs group and antiplatelet drug group. OATs have reduced ischemic stroke risk (OR 0.49, 95% CI 0.32 to 0.74), but have increased major bleeding risk (OR 2.01, 95% CI 1.40 to 2.88) compared to antiplatelet treatment. Conclusion In HF patients in sinus rhythm OATs do not show a better risk-benefit profile compared to antiplatelet treatment in cardioembolism prevention. Warfarin and aspirin seem to be similar in reducing mortality. Warfarin reduces the incidence of ischemic stroke, but increases major bleedings. Thus, it is possible to speculate that aspirin prescription be indicated in patients with high risk of bleeding, whereas warfarin could be preferred in patients with high thromboembolic risk.

Autonomic dysfunction in Alzheimer's disease: tools for assessment and review of the literature.

Autonomic dysfunction is very common in patients with dementia, and its presence might also help in differential diagnosis among dementia subtypes. Various central nervous system structures affected in Alzheimers disease are also implicated in autonomic nervous system regulation, and it has been hypothesized that the deficit in central cholinergic function observed in Alzheimers disease could likely lead to autonomic dysfunction. Several feasible tests can be used in clinical practice for the assessment of parasympathetic and sympathetic functions, especially in terms of cardiovascular autonomic modulation. In this review, we describe the different tests available and the evidence from the literature which indicate a definite presence of autonomic dysfunction in dementia at various degrees. Importantly, the recognition of dysautonomia, besides possibly being an early marker of dementia, would help prevent the disabling complications which increase the risk of morbidity, institutionalization, and mortality in these individuals.

Effects of exercise training on cardiovascular adrenergic system

In heart failure (HF), exercise has been shown to modulate cardiac sympathetic hyperactivation which is one of the earliest features of neurohormonal derangement in this syndrome and correlates with adverse outcome. An important molecular alteration related to chronic sympathetic overstimulation in HF is represented by cardiac β-adrenergic receptor (β-AR) dysfunction. It has been demonstrated that exercise reverses β-AR dysfunction by restoring cardiac receptor membrane density and G-protein-dependent adenylyl cyclase activation. In particular, several evidence indicate that exercise reduces levels of cardiac G-protein coupled receptor kinase-2 (GRK2) which is known to be involved in both β1-AR and β2-AR dysregulation in HF. Similar alterations of β-AR system have been described also in the senescent heart. It has also been demonstrated that exercise training restores adrenal GRK2/α-2AR/catecholamine (CA) production axis. At vascular level, exercise shows a therapeutic effect on age-related impairment of vascular reactivity to adrenergic stimulation and restores β-AR-dependent vasodilatation by increasing vascular β-AR responsiveness and reducing endothelial GRK2 activity. Sympathetic nervous system overdrive is thought to account for >50% of all cases of hypertension and a lack of balance between parasympathetic and sympathetic modulation has been observed in hypertensive subjects. Non-pharmacological, lifestyle interventions have been associated with reductions in SNS overactivity and blood pressure in hypertension. Several evidence have highlighted the blood pressure lowering effects of aerobic endurance exercise in patients with hypertension and the significant reduction in sympathetic neural activity has been reported as one of the main mechanisms explaining the favorable effects of exercise on blood pressure control.