Impact of renal denervation on patients with coronary microvascular dysfunction: study rationale and design.

AIMS: Long-standing hypertension may cause an impairment in microvascular coronary circulation, which is involved in many different cardiac conditions. Renal sympathetic denervation (RDN) has been successfully proven as a valuable therapeutic choice for patients with resistant hypertension; moreover, the procedure looks promising in other settings, such as heart failure and atrial fibrillation, given its ability to downregulate the sympathetic nervous system, which is a recognized driver in these conditions as well as in microvascular dysfunction progression. The aim of this study is to explore the effect of RDN on coronary physiology in patients with ascertained coronary microvascular dysfunction and resistant hypertension. METHODS: This is a multicenter, prospective, nonrandomized, open-label, interventional study. Consecutive patients with resistant hypertension, nonobstructive coronary artery disease (NOCAD) and documented microvascular dysfunction will be enrolled. Patients will undergo RDN by Spyral Symplicity 3 (Medtronic Inc, Minneapolis, Minnesota, USA) and reassessment of coronary microvascular function 6 months after the procedure. Primary endpoint will be the difference in the index of microcirculatory resistance. CONCLUSION: The IMPRESSION study seeks to evaluate if there is any pleiotropic effect of the RDN procedure that results in modulation of microvascular function; if observed, this would be the first evidence showing RDN as a valuable therapy to revert hypertension-related microvascular dysfunction.

Current Use of Oral Anticoagulation Therapy in Elderly Patients with Atrial Fibrillation: Results from an Italian Multicenter Prospective Study-The ISNEP Study.

Background: Atrial fibrillation (AF) is the most common heart arrhythmia, and its prevalence increases with age. Oral Anticoagulant Therapy (OAT) with non-vitamin K antagonist oral anticoagulants (NOACs) or vitamin K antagonists (VKAs) is essential to avoid thromboembolic events in AF. However, this treatment is associated with a high risk of bleeding and low adherence in elderly patients. Aim: The aim was to evaluate the real-world use of OAT in a population of patients aged ≥80 years in twenty-three Italian centers and to investigate the tolerance of and patient satisfaction with this therapy. Methods: The ISNEP Study is a multicenter cross-sectional study enrolling patients with AF and aged ≥80 years and treated with either NOACs or VKAs. A written questionnaire was administered to each patient to evaluate the adherence to and patient satisfaction with this therapy. Results: The study included 641 patients with a mean age of 85 (82−87) years. The use of NOACs was reported in 93.0% of cases, with the remaining 7.0% treated with VKAs. A history of stroke events was reported in five (11.1%) and one (0.2%) patients in the VKA and NOAC groups, respectively. The rate of referred ecchymosis/epistaxis was significantly higher in the VKA group compared to the NOAC group (p < 0.001). Patients receiving NOACs reported a substantial improvement in their quality of life compared to the VKA group. Conclusions: A small, but not negligible, proportion of elderly AF patients is still treated with VKAs. Patients treated with NOAC have a higher level of satisfaction with the therapy and complete adherence.

Structural Determinants of Constitutive Activation of Gα Proteins: Transducin as a Paradigm.

Heterotrimeric guanine nucleotide-binding proteins (Gα proteins) are intracellular nanomachines deputed to signal transduction. The switch-on process requires the release of bound GDP from a site at the interface between GTPase and helical domains. Nucleotide release is catalyzed by G protein Coupled Receptors (GPCRs). Here we investigate the functional dynamics of wild type (WT) and six constitutively active mutants (CAMs) of the Gα protein transducin (Gt) by combining atomistic molecular dynamics (MD) simulations with Maxwell-Demod discrete MD (MDdMD) simulations of the receptor-catalyzed transition between GDP-bound and nucleotide-free states. Compared to the WT, Gt CAMs increase the overall fluctuations of nucleotide and its binding site. This is accompanied by weakening of native links involving GDP, α1, the G boxes, ß1-ß3, and α5. Collectively, constitutive activation by the considered mutants seems to associate with weakening of the interfaces between α5 and the surrounding portions and the interface between GTPase (G) and helical (H) domains. These mutational effects associate with increases in the overall fluctuations of the G and H domains, which reflect on the collective motions of the protein. Gt CAMs, with prominence to G56P, T325A, and F332A, prioritize collective motions of the H domain overlapping with the collective motions associated with receptor-catalyzed nucleotide release. In spite of different local perturbations, the mechanisms of nucleotide exchange catalyzed by activating mutations and by receptor are expected to employ similar molecular switches in the nucleotide binding site and to share the detachment of the H domain from the G domain.

Rheumatic Heart Disease Predisposing to Embolic Myocardial Infarction: A Multimodality Imaging Approach.

We report a clinical case of a 45-year-old male with a diagnosis of inferior myocardial infarction and previous history of rheumatic fever during his childhood. Coronary angiography demonstrated normal coronary arteries. Transthoracic echocardiogram showed hypokinetic left ventricular inferolateral wall and mitral stenosis; furthermore, speckle tracking analysis revealed reduction of global longitudinal strain involving the inferior wall. A three-dimensional transesophaegeal echocardiography, performed to better characterize the anatomy of the valve and to find possible source of embolic infarct in an enlarged left atrium, showed rheumatic valvular involvement. Cardiac magnetic resonance confirmed the ischemic damage and also provided prognostic information. A multimodality imaging approach should be mandatory in patients with acute myocardial infarction and normal coronary angiography, to define possible sources of embolic infarction and to quantify myocardial damage.

WebPSN: a web server for high-throughput investigation of structural communication in biomacromolecules.

UNLABELLED: We developed a mixed Protein Structure Network (PSN) and Elastic Network Model-Normal Mode Analysis (ENM-NMA)-based strategy (i.e. PSN-ENM) to investigate structural communication in biomacromolecules. The approach starts from a Protein Structure Graph and searches for all shortest communication pathways between user-specified residues. The graph is computed on a single preferably high-resolution structure. Information on system's dynamics is supplied by ENM-NMA. The PSN-ENM methodology is made of multiple steps both in the setup and analysis stages, which may discourage inexperienced users. To facilitate its usage, we implemented WebPSN, a freely available web server that allows the user to easily setup the calculation, perform post-processing analyses and both visualize and download numerical and 3D representations of the output. Speed and accuracy make this server suitable to investigate structural communication, including allosterism, in large sets of bio-macromolecular systems. AVAILABILITY AND IMPLEMENTATION: The WebPSN server is freely available at http://webpsn.hpc.unimore.it.

Network and atomistic simulations unveil the structural determinants of mutations linked to retinal diseases.

A number of incurable retinal diseases causing vision impairments derive from alterations in visual phototransduction. Unraveling the structural determinants of even monogenic retinal diseases would require network-centered approaches combined with atomistic simulations. The transducin G38D mutant associated with the Nougaret Congenital Night Blindness (NCNB) was thoroughly investigated by both mathematical modeling of visual phototransduction and atomistic simulations on the major targets of the mutational effect. Mathematical modeling, in line with electrophysiological recordings, indicates reduction of phosphodiesterase 6 (PDE) recognition and activation as the main determinants of the pathological phenotype. Sub-microsecond molecular dynamics (MD) simulations coupled with Functional Mode Analysis improve the resolution of information, showing that such impairment is likely due to disruption of the PDEγ binding cavity in transducin. Protein Structure Network analyses additionally suggest that the observed slight reduction of theRGS9-catalyzed GTPase activity of transducin depends on perturbed communication between RGS9 and GTP binding site. These findings provide insights into the structural fundamentals of abnormal functioning of visual phototransduction caused by a missense mutation in one component of the signaling network. This combination of network-centered modeling with atomistic simulations represents a paradigm for future studies aimed at thoroughly deciphering the structural determinants of genetic retinal diseases. Analogous approaches are suitable to unveil the mechanism of information transfer in any signaling network either in physiological or pathological conditions.

A Mixed Protein Structure Network and Elastic Network Model Approach to Predict the Structural Communication in Biomolecular Systems: The PDZ2 Domain from Tyrosine Phosphatase 1E As a Case Study.

Graph theory is being increasingly used to study the structural communication in biomolecular systems. This requires incorporating information on the system's dynamics, which is time-consuming and not suitable for high-throughput investigations. We propose a mixed Protein Structure Network (PSN) and Elastic Network Model (ENM)-based strategy, i.e., PSN-ENM, for fast investigation of allosterism in biological systems. PSN analysis and ENM-Normal Mode Analysis (ENM-NMA) are implemented in the structural analysis software Wordom, freely available at http://wordom.sourceforge.net/ . The method performs a systematic search of the shortest communication pathways that traverse a protein structure. A number of strategies to compare the structure networks of a protein in different functional states and to get a global picture of communication pathways are presented as well. The approach was validated on the PDZ2 domain from tyrosine phosphatase 1E (PTP1E) in its free (APO) and peptide-bound states. PDZ domains are, indeed, the systems whose structural communication and allosteric features are best characterized both in vitro and in silico. The agreement between predictions by the PSN-ENM method and in vitro evidence is remarkable and comparable to or higher than that reached by more time-consuming computational approaches tested on the same biological system. Finally, the PSN-ENM method was able to reproduce the salient communication features of unbound and bound PTP1E inferred from molecular dynamics simulations. High speed makes this method suitable for high throughput investigation of the communication pathways in large sets of biomolecular systems in different functional states.

Prevalence estimates of alcohol related problems in an area of northern Italy using the capture-recapture method.

BACKGROUND: The alcohol-related problems (ARPs) are a relevant issue in public health and contribute to premature deaths and avoidable disease burden. The capture-recapture (C-R) method can be a useful tool to provide reliable estimates for populations with hidden nature such as subjects with ARP. METHODS: C-R method was used to estimate the 'true count' of individuals with ARP using three independent health-related current databases in an area of northern Italy during 2007. To predict the frequency of unascertained cases, we constructed log linear models. The goodness-of-fit of a model was measured by the likelihood ratio test and the final model was selected using Akaike's Information Criterion. Confidence intervals (CIs) were calculated according to Hook and Regal. RESULTS: Altogether 1014 subjects with ARP were directly identified from the three sources using the C-R method the estimated unknown population was 2729 subjects, giving a total of 3743 subjects with ARP (95% CI 3148-4504) and a prevalence of 8.24 (95% CI 7.97-8.50) per 1000 inhabitants aged >15 years. The analyses stratified for gender estimated 12.31/1000 (95% CI 11.85-12.77) men and 4.86/1000 (95% CI 4.58-5.14) women with ARP. Besides, the analysis calculated a prevalence of 14.99 per 1000 (95% CI 14.29-15.69) for males <50 years (1731), corresponding to the majority of subjects with ARP. CONCLUSION: The C-R technique is useful to provide a more realistic picture of the size of ARP population. This has important implications both for future planning of service provision and for the way in which the impact of ARP interventions are evaluated.

Network-level analysis of light adaptation in rod cells under normal and altered conditions.

Photoreceptor cells finely adjust their sensitivity and electrical response according to changes in light stimuli as a direct consequence of the feedback and regulation mechanisms in the phototransduction cascade. In this study, we employed a systems biology approach to develop a dynamic model of vertebrate rod phototransduction that accounts for the details of the underlying biochemistry. Following a bottom-up strategy, we first reproduced the results of a robust model developed by Hamer et al. (Vis. Neurosci., 2005, 22(4), 417), and then added a number of additional cascade reactions including: (a) explicit reactions to simulate the interaction between the activated effector and the regulator of G-protein signalling (RGS); (b) a reaction for the reformation of the G-protein from separate subunits; (c) a reaction for rhodopsin (R) reconstitution from the association of the opsin apoprotein with the 11-cis-retinal chromophore; (d) reactions for the slow activation of the cascade by opsin. The extended network structure successfully reproduced a number of experimental conditions that were inaccessible to prior models. With a single set of parameters the model was able to predict qualitative and quantitative features of rod photoresponses to light stimuli ranging over five orders of magnitude, in normal and altered conditions, including genetic manipulations of the cascade components. In particular, the model reproduced the salient dynamic features of the rod from Rpe65(-/-) animals, a well established model for Leber congenital amaurosis and vitamin A deficiency. The results of this study suggest that a systems-level approach can help to unravel the adaptation mechanisms in normal and in disease-associated conditions on a molecular basis.

Transnasal transesophageal echocardiography: a new approach for the PFO occlusion in awake patients.

OBJECTIVES: To reduce risks, discomfort, cost, and operative time for percutaneous patent foramen ovale (PFO) closure, we propose to perform this procedure under transesophageal echo-guidance using a 10 Fr. catheter introduced through nasal way (TEENW). BACKGROUND: Transesophageal or intracardiac echocardiography is commonly used to guide percutaneous PFO closure. Sedation needed quite frequently during transesophageal echocardiography, increased patients' discomfort, procedure prolongation, costs, use of both femoral veins, and additional intracardiac manipulations are the main limitations of standard techniques. METHODS: We enrolled 20 consecutive patients with a history of cerebral ischemia and PFO with right-to-left shunt. In 15 patients Amplatzer PFO occluder was used, whereas in five patients with longer PFO tunnel (>10 mm) Cardia Intrasept was selected. Without sedation, a multifrequency monoplane probe, developed for intracardiac echocardiography, was introduced into the nostril and advanced forward the esophagus. Then under echo guidance, the closing device was presented, opened and released. RESULTS: Procedure lasted for an average of 33.3 min, and no complications were seen. At procedure's completion, six patients showed persistence of reduced shunt during Valsalva manoeuvre. At six-month follow-up, shunts disappeared in all patients. CONCLUSION: TEENW is safe and well tolerated, and images' quality is high enough to deserve widespread adoption of this technique for PFO closure.

Nociceptive contribution to the evoked potentials after painful intramuscular electrical stimulation.

Our study aimed at investigating the nociceptive contribution to the somatosensory evoked potentials after electrical intramuscular stimulation (mSEPs) at painful intensity. Scalp mSEPs were recorded in 10 healthy subjects after electrical stimulation of the left brachioradialis muscle at three intensities: non-painful (I2), slightly painful (I4) and moderately painful (I6). For each intensity, mSEPs were recorded in a neutral condition (NC) in which subjects did not have any task, and in an attention condition (AC) in which subjects were asked to count the number of stimuli. In both NC and AC, the N120 and P220 amplitudes were significantly higher at I6 than at I2. While the N120 amplitude did not vary between NC and AC, the P220 amplitude was significantly higher in AC than in NC at all stimulus intensities. Our results suggest that nociceptive inputs contribute to the N120 amplitude increase at painful stimulus intensity, while the P220 amplitude is more sensitive to changes of subjects' attention level. Therefore, the N120 amplitude increase to moderately painful stimuli, as compared to non-painful stimuli, may represent a marker of the activation of the muscular thin myelinated afferents.

Tako-tsubo syndrome: a potential role for cytomegalovirus infection.

The tako-tsubo syndrome is a transient cardiomyopathy of unknown origin, which mimics acute ST-elevation myocardial infarction in the absence of obstructive epicardial coronary artery disease. This novel syndrome is characterized by chest pain, ST-segment changes, minimal enzymatic release, and balloon-like asynergy of the apical region. We report a case of tako-tsubo syndrome associated with acute cytomegalovirus infection and discuss the possible role of a viral aetiology in the onset of this syndrome.