Publications by authors named "Andrea Mazzanti"

200 Publications

Optical tuning of dielectric nanoantennas for thermo-optically reconfigurable nonlinear metasurfaces.

Opt Lett 2021 May;46(10):2453-2456

We demonstrate optically tunable control of second-harmonic generation in all-dielectric nanoantennas: by using a control beam that is absorbed by the nanoresonator, we thermo-optically change the refractive index of the radiating element to modulate the amplitude of the second-harmonic signal. For a moderate temperature increase of roughly 40 K, modulation of the efficiency up to 60% is demonstrated; this large tunability of the single meta-atom response paves the way to exciting avenues for reconfigurable homogeneous and heterogeneous metasurfaces.
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http://dx.doi.org/10.1364/OL.420790DOI Listing
May 2021

Outcomes of manual versus remote magnetic navigation for catheter ablation of ventricular tachycardia: a systematic review and updated meta-analysis.

Pacing Clin Electrophysiol 2021 Apr 6. Epub 2021 Apr 6.

Division of Cardiology, Mauriziano Umberto I Hospital, Turin, Italy.

Purpose: Ventricular tachycardia (VT) ablation is a complex procedure that requires remarkable catheter manipulation skill, great mapping accuracy and catheter stability, and can expose patients to serious complications. Magnetic navigation system (RMN)-guided ablation and contact force-sensing (CFS) catheters have the potential to overcome these obstacles. We performed a systematic review and updated meta-analysis of all available studies evaluating the outcomes of VT ablation by using RMN-guided compared to manual navigation (MAN)-guided, with and without CFS catheters.

Methods: MEDLINE/PubMed, Cochrane, and Google Scholar were searched for randomized controlled trials (RCT) or observational studies with multivariate adjustment comparing RMN-guided versus MAN-guided VT ablation.

Results: Thirteen studies enrolling 1348 patients (656 RMN-guided vs. 692 MAN-guided) were included. CFS catheter were used in 14% of MAN-guided patients. In comparison to MAN-guided and CFS-guided, RMN-guided VT ablation was associated with a significant higher acute ablation success (OR 2.32, 1.66-3.23 and OR 2.91, 1.29-6.53, respectively) but similar results in term of long-term VT recurrence (OR 0.75, 0.56-1.01 and OR 0.79, 0.27-2.36, respectively). RMN-guided showed a better safety profile (for all complications, OR 0.52, 0.34-0.81) and allowed a significant x-ray reduction compared to MAN-guided (OR 0.21, 0.14-0.32) and CFS-guided VT ablation (OR 0.23, 0.11-0.52, all 95% CI).

Conclusions: RMN-guided was superior to MAN-guided and CFS-guided VT ablation in term of acute ablation success, all complications endpoint, and reduction of fluoroscopy exposure, but did not reduce long-term VT recurrence. Large prospective multicenter randomized trials are needed to confirm these findings.
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http://dx.doi.org/10.1111/pace.14231DOI Listing
April 2021

Arrhythmic Mitral Valve Prolapse: Introducing an Era of Multimodality Imaging-Based Diagnosis and Risk Stratification.

Diagnostics (Basel) 2021 Mar 8;11(3). Epub 2021 Mar 8.

Department of Cardiovascular Imaging, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy.

Mitral valve prolapse is a common cardiac condition, with an estimated prevalence between 1% and 3%. Most patients have a benign course, but ever since its initial description mitral valve prolapse has been associated to sudden cardiac death. Although the causal relationship between mitral valve prolapse and sudden cardiac death has never been clearly demonstrated, different factors have been implicated in arrhythmogenesis in patients with mitral valve prolapse. In this work, we offer a comprehensive overview of the etiology and the genetic background, epidemiology, pathophysiology, and we focus on the state-of-the-art imaging-based diagnosis of mitral valve prolapse. Going beyond the classical, well-described clinical factors, such as young age, female gender and auscultatory findings, we investigate multimodality imaging features, such as alterations of anatomy and function of the mitral valve and its leaflets, the structural and contractile anomalies of the myocardium, all of which have been associated to sudden cardiac death.
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http://dx.doi.org/10.3390/diagnostics11030467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999774PMC
March 2021

Broadband and Tunable Light Harvesting in Nanorippled MoS Ultrathin Films.

ACS Appl Mater Interfaces 2021 Mar 9;13(11):13508-13516. Epub 2021 Mar 9.

Dipartimento di Fisica, Università di Genova, Via Dodecaneso 33, 16146 Genova, Italy.

Nanofabrication of flat optic silica gratings conformally layered with two-dimensional (2D) MoS is demonstrated over large area (cm), achieving a strong amplification of the photon absorption in the active 2D layer. The anisotropic subwavelength silica gratings induce a highly ordered periodic modulation of the MoS layer, promoting the excitation of Guided Mode Anomalies (GMA) at the interfaces of the 2D layer. We show the capability to achieve a broadband tuning of these lattice modes from the visible (VIS) to the near-infrared (NIR) by simply tailoring the illumination conditions and/or the period of the lattice. Remarkably, we demonstrate the possibility to strongly confine resonant and nonresonant light into the 2D MoS layers via GMA excitation, leading to a strong absorption enhancement as high as 240% relative to a flat continuous MoS film. Due to their broadband and tunable photon harvesting capabilities, these large area 2D MoS metastructures represent an ideal scalable platform for new generation devices in nanophotonics, photo- detection and -conversion, and quantum technologies.
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http://dx.doi.org/10.1021/acsami.0c20387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041252PMC
March 2021

Ranolazine as an Alternative Therapy to Flecainide for SCN5A V411M Long QT Syndrome Type 3 Patients.

Front Pharmacol 2020 17;11:580481. Epub 2020 Dec 17.

Centro de Investigación e Innovación en Bioingeniería (CI2B), Universitat Politècnica de València, Valencia, España.

The prolongation of the QT interval represents the main feature of the long QT syndrome (LQTS), a life-threatening genetic disease. The heterozygous SCN5A V411M mutation of the human sodium channel leads to a LQTS type 3 with severe proarrhythmic effects due to an increase in the late component of the sodium current (INaL). The two sodium blockers flecainide and ranolazine are equally recommended by the current 2015 ESC guidelines to treat patients with LQTS type 3 and persistently prolonged QT intervals. However, awareness of pro-arrhythmic effects of flecainide in LQTS type 3 patients arose upon the study of the SCN5A E1784K mutation. Regarding SCN5A V411M individuals, flecainide showed good results albeit in a reduced number of patients and no evidence supporting the use of ranolazine has ever been released. Therefore, we ought to compare the effect of ranolazine and flecainide in a SCN5A V411M model using an in-silico modeling and simulation approach. We collected clinical data of four patients. Then, we fitted four Markovian models of the human sodium current (INa) to experimental and clinical data. Two of them correspond to the wild type and the heterozygous SCN5A V411M scenarios, and the other two mimic the effects of flecainide and ranolazine on INa. Next, we inserted them into three isolated cell action potential (AP) models for endocardial, midmyocardial and epicardial cells and in a one-dimensional tissue model. The SCN5A V411M mutation produced a 15.9% APD90 prolongation in the isolated endocardial cell model, which corresponded to a 14.3% of the QT interval prolongation in a one-dimensional strand model, in keeping with clinical observations. Although with different underlying mechanisms, flecainide and ranolazine partially countered this prolongation at the isolated endocardial model by reducing the APD90 by 8.7 and 4.3%, and the QT interval by 7.2 and 3.2%, respectively. While flecainide specifically targeted the mutation-induced increase in peak INaL, ranolazine reduced it during the entire AP. Our simulations also suggest that ranolazine could prevent early afterdepolarizations triggered by the SCN5A V411M mutation during bradycardia, as flecainide. We conclude that ranolazine could be used to treat SCN5A V411M patients, specifically when flecainide is contraindicated.
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http://dx.doi.org/10.3389/fphar.2020.580481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845660PMC
December 2020

All-Optically Reconfigurable Plasmonic Metagrating for Ultrafast Diffraction Management.

Nano Lett 2021 Feb 26;21(3):1345-1351. Epub 2021 Jan 26.

Dipartimento di Fisica, Politecnico di Milano, Piazza Leonardo da Vinci, 32, I-20133 Milano, Italy.

Hot-electron dynamics taking place in nanostructured materials upon irradiation with fs-laser pulses has been the subject of intensive research, leading to the emerging field of ultrafast nanophotonics. However, the most common description of nonlinear interaction with ultrashort laser pulses assumes a homogeneous spatial distribution for the photogenerated carriers. Here we theoretically show that the inhomogeneous evolution of the hot carriers at the nanoscale can disclose unprecedented opportunities for ultrafast diffraction management. In particular, we design a highly symmetric plasmonic metagrating capable of a transient symmetry breaking driven by hot electrons. The subsequent power imbalance between symmetrical diffraction orders is calculated to exceed 20% under moderate (∼2 mJ/cm) laser fluence. Our theoretical investigation also indicates that the recovery time of the symmetric configuration can be controlled by tuning the geometry of the metaatom, and can be as fast as 2 ps for electrically connected configurations.
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http://dx.doi.org/10.1021/acs.nanolett.0c04075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883391PMC
February 2021

Peptide-Based Targeting of the L-Type Calcium Channel Corrects the Loss-of-Function Phenotype of Two Novel Mutations of the Gene Associated With Brugada Syndrome.

Front Physiol 2020 8;11:616819. Epub 2021 Jan 8.

Institute of Genetic and Biomedical Research (IRGB), Milan Unit, National Research Council, Milan, Italy.

Brugada syndrome (BrS) is an inherited arrhythmogenic disease that may lead to sudden cardiac death in young adults with structurally normal hearts. No pharmacological therapy is available for BrS patients. This situation highlights the urgent need to overcome current difficulties by developing novel groundbreaking curative strategies. BrS has been associated with mutations in 18 different genes of which loss-of-function (LoF) mutations constitute the second most common cause. Here we tested the hypothesis that BrS associated with mutations in the gene encoding the L-type calcium channel (LTCC) pore-forming unit (Caα1.2) is functionally reverted by administration of a mimetic peptide (MP), which through binding to the LTCC chaperone beta subunit (Caβ2) restores the physiological life cycle of aberrant LTCCs. Two novel Caα1.2 mutations associated with BrS were identified in young individuals. Transient transfection in heterologous and cardiac cells showed LoF phenotypes with reduced Ca current (I). In HEK293 cells overexpressing the two novel Caα1.2 mutations, Western blot analysis and cell surface biotinylation assays revealed reduced Caα1.2 protein levels at the plasma membrane for both mutants. Nano-BRET, Nano-Luciferase assays, and confocal microscopy analyses showed (i) reduced affinity of Caα1.2 for its Caβ2 chaperone, (ii) shortened Caα1.2 half-life in the membrane, and (iii) impaired subcellular localization. Treatment of Caα1.2 mutant-transfected cells with a cell permeant MP restored channel trafficking and physiologic channel half-life, thereby resulting in I similar to wild type. These results represent the first step towards the development of a gene-specific treatment for BrS due to defective trafficking of mutant LTCC.
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http://dx.doi.org/10.3389/fphys.2020.616819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821386PMC
January 2021

Molecular Recognition of the HPLC Whelk-O1 Selector towards the Conformational Enantiomers of Nevirapine and Oxcarbazepine.

Int J Mol Sci 2020 Dec 25;22(1). Epub 2020 Dec 25.

Department of Chemistry and Technology of Drugs, "Department of Excellence 2018-2022", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.

The presence of stereogenic elements is a common feature in pharmaceutical compounds, and affording optically pure stereoisomers is a frequent issue in drug design. In this context, the study of the chiral molecular recognition mechanism fundamentally supports the understanding and optimization of chromatographic separations with chiral stationary phases. We investigated, with molecular docking, the interactions between the chiral HPLC selector Whelk-O1 and the stereoisomers of two bioactive compounds, the antiviral Nevirapine and the anticonvulsant Oxcarbazepine, both characterized by two stereolabile conformational enantiomers. The presence of fast-exchange enantiomers and the rate of the interconversion process were studied using low temperature enantioselective HPLC and VT-NMR with Whelk-O1 applied as chiral solvating agent. The values of the energetic barriers of interconversion indicate, for the single enantiomers of both compounds, half-lives sufficiently long enough to allow their separation only at critically sub-ambient temperatures. The chiral selector Whelk-O1 performed as a strongly selective discriminating agent both when applied as a chiral stationary phase (CSP) in HPLC and as CSA in NMR spectroscopy.
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http://dx.doi.org/10.3390/ijms22010144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796420PMC
December 2020

Ultra-broadband photon harvesting in large-area few-layer MoS nanostripe gratings.

Nanoscale 2020 Dec;12(48):24385-24393

Dipartimento di Fisica, Università di Genova, Via Dodecaneso 33, 16146 Genova, Italy.

Flat optics nanoarrays based on few-layer MoS2 are homogeneously fabricated over large-area (cm2) transparent templates, demonstrating effective tailoring of the photon absorption in two-dimensional (2D) transition-metal dichalcogenide (TMD) layers. The subwavelength subtractive re-shaping of the few-layer MoS2 film into a one-dimensional (1D) nanostripe array results in a pronounced photonic anomaly, tunable in a broadband spectral range by simply changing the illumination conditions (or the lattice periodicity). This scheme promotes efficient coupling of light to the 2D TMD layers via resonant interaction between the MoS2 excitons and the photonic lattice, with subsequent enhancement of absorption exceeding 400% relative to the flat layer. In parallel, an ultra-broadband absorption amplification in the whole visible spectrum is achieved, thanks to the non-resonant excitation of substrate guided modes promoted by MoS2 nanoarrays. These results highlight the potential of nanoscale re-shaped 2D TMD layers for large-area photon harvesting in layered nanophotonics, quantum technologies and new-generation photovoltaics.
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http://dx.doi.org/10.1039/d0nr06744jDOI Listing
December 2020

Iridium(III) Complexes with Fluorinated Phenyl-tetrazoles as Cyclometalating Ligands: Enhanced Excited-State Energy and Blue Emission.

Inorg Chem 2020 Nov 30;59(22):16238-16250. Epub 2020 Oct 30.

Istituto per la Sintesi Organica e la Fotoreattività, Consiglio Nazionale delle Ricerche, Via P. Gobetti 101, Bologna 40129, Italy.

Five cationic iridium(III) complexes with fluorinated cyclometalating tetrazole ligands [Ir(dfptrz)L], where Hdfptrz = 5-(2,4-difluorophenyl)-2-methyl-2-tetrazole and L = 2,2'-bypiridine (), 4,4'-di-butyl-2,2'-bipyridine (), 1,10-phenantroline (), 4,4'-bis(dimethylamino)-2,2'-bipyridine (), and -butyl isocyanide (), were prepared following a one-pot synthetic strategy based on a bis-cyclometalated solvato complex obtained via silver(I)-assisted cyclometalation, which was then reacted with the proper ancillary ligand to get the targeted complexes. The X-ray crystal structures of and were determined, showing that the tetrazole ligands are in a trans arrangement with respect to the iridium center. Electrochemical and photophysical properties, along with density functional theory calculations, allowed a full rationalization of the electronic properties of -. In acetonitrile solution at 298 K, complexes -, equipped with bipyridine and phenanthroline ligands, exhibit strong vibronically structured luminescence bands in the blue region with photoluminescence quantum yields (PLQYs) in the range 56-76%. This behavior is radically different from the nonfluorinated analogues reported previously, which emits in the green region from MLCT excited states. shows relatively strong emission (PLQY = 40%) of charge transfer character centered on the amino-bipyridine ancillary ligand, whereas the emission of is very weak (PLQY = 0.6%), further blue-shifted and attributed to the lowest ligand-centered (LC) triplet state of the tetrazolyl cyclometalated moiety. A similar photophysical behavior is observed in PMMA at 298 K, whereas in a 77 K matrix, all of the compounds are strong emitters. This novel fluorinated phenyl-tetrazole cyclometalating ligand provides the corresponding iridium(III) complexes with a combination of excited-state energy and redox potentials that make them very promising as photoredox catalysts.
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http://dx.doi.org/10.1021/acs.inorgchem.0c01995DOI Listing
November 2020

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

Genet Med 2021 Jan 7;23(1):47-58. Epub 2020 Sep 7.

Member of the European Reference Network for rare, low prevalence and/or complex diseases of the heart: ERN GUARD-Heart, Amsterdam, Netherlands.

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.

Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.

Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.

Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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http://dx.doi.org/10.1038/s41436-020-00946-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790744PMC
January 2021

Sudden death in lambda light chain AL cardiac amyloidosis: a review of literature and update for clinicians and pathologists.

Int J Clin Exp Pathol 2020 1;13(7):1474-1482. Epub 2020 Jul 1.

Department of Anatomic, Hystologic, Orthopedic and Forensic Science, Sapienza University of Rome Viale Regina Elena 336, Roma 00161, Italy.

Light chain (AL) amyloidosis is the most common type of systemic amyloidosis, affecting around 10 people per million per year. In Europe, approximately 5000 new diagnosis per year are reported. Deposition of amyloid fibrils derived from antibody light chains are key pathogenic agents in AL amyloidosis. They can be deposited in multiple organs but cardiac involvement carries a major risk of mortality. The prognosis is poor in cases associated with multiple myeloma. The average survival is around 1 year. Up to half of all patients with cardiac amyloidosis die suddenly; 75% ofthose deaths are due to heart failure. Ventricular arrhythmia is also associated with cardiac amyloidosis and unexpected death. It is crucial to make a diagnosis and start treatment at an early stage. Recent data suggest that cardiac amyloidosis has become a treatable and curable condition with a combination of agents targeting multiple steps of the amyloid cascade. ICD implantation may not be as effective for the therapy of light chain (AL) cardiac amyloidosis as supposed earlier. In cases of unexpected and sudden death, autopsy may show unknown conditions and is valuable to assess existing risks for family members. Even after careful autopsy, a proportion of sudden deaths, ranging from 2 to 54%, remain unexplained and this broad range of values is likely due to the heterogeneity of autopsy protocols. Post mortem diagnosis of cardiac amyloidosis still represents a challenge for forensic pathologists. Detailed morphologic study of the heart and a complete histopathologic study are mandatory. Immunohistochemistry is essential for amyloid subclassification. A review of existing literature is performed by the authors and a methodological approach in post mortem diagnosis of light chain AL cardiac amyloidosis is proposed. Both macroscopic and microscopic findings are discussed.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414507PMC
July 2020

An International Multicenter Evaluation of Inheritance Patterns, Arrhythmic Risks, and Underlying Mechanisms of -Catecholaminergic Polymorphic Ventricular Tachycardia.

Circulation 2020 Sep 22;142(10):932-947. Epub 2020 Jul 22.

Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (K.N., J.W., A.S.T., A.C.S., J.M., J.D.R.).

Background: Genetic variants in calsequestrin-2 () cause an autosomal recessive form of catecholaminergic polymorphic ventricular tachycardia (CPVT), although isolated reports have identified arrhythmic phenotypes among heterozygotes. Improved insight into the inheritance patterns, arrhythmic risks, and molecular mechanisms of -CPVT was sought through an international multicenter collaboration.

Methods: Genotype-phenotype segregation in -CPVT families was assessed, and the impact of genotype on arrhythmic risk was evaluated using Cox regression models. Putative dominant missense variants and the established recessive CASQ2-p.R33Q variant were evaluated using oligomerization assays and their locations mapped to a recent CASQ2 filament structure.

Results: A total of 112 individuals, including 36 CPVT probands (24 homozygotes/compound heterozygotes and 12 heterozygotes) and 76 family members possessing at least 1 presumed pathogenic variant, were identified. Among homozygotes and compound heterozygotes, clinical penetrance was 97.1% and 26 of 34 (76.5%) individuals had experienced a potentially fatal arrhythmic event with a median age of onset of 7 years (95% CI, 6-11). Fifty-one of 66 heterozygous family members had undergone clinical evaluation, and 17 of 51 (33.3%) met diagnostic criteria for CPVT. Relative to heterozygotes, homozygote/compound heterozygote genotype status in probands was associated with a 3.2-fold (95% CI, 1.3-8.0; =0.013) increased hazard of a composite of cardiac syncope, aborted cardiac arrest, and sudden cardiac death, but a 38.8-fold (95% CI, 5.6-269.1; <0.001) increased hazard in genotype-positive family members. In vitro turbidity assays revealed that p.R33Q and all 6 candidate dominant missense variants evaluated exhibited filamentation defects, but only p.R33Q convincingly failed to dimerize. Structural analysis revealed that 3 of these 6 putative dominant negative missense variants localized to an electronegative pocket considered critical for back-to-back binding of dimers.

Conclusions: This international multicenter study of -CPVT redefines its heritability and confirms that pathogenic heterozygous variants may manifest with a CPVT phenotype, indicating a need to clinically screen these individuals. A dominant mode of inheritance appears intrinsic to certain missense variants because of their location and function within the CASQ2 filament structure.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484339PMC
September 2020

Diagnosis of arrhythmogenic cardiomyopathy: The Padua criteria.

Int J Cardiol 2020 11 16;319:106-114. Epub 2020 Jun 16.

Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova, Italy.

The original designation of "Arrhythmogenic right ventricular (dysplasia/) cardiomyopathy"(ARVC) was used by the scientists who first discovered the disease, in the pre-genetic and pre-cardiac magnetic resonance era, to describe a new heart muscle disease predominantly affecting the right ventricle, whose cardinal clinical manifestation was the occurrence of malignant ventricular arrhythmias. Subsequently, autopsy investigations, genotype-phenotype correlations studies and the increasing use of contrast-enhancement cardiac magnetic resonance showed that the fibro-fatty replacement of the myocardium represents the distinctive phenotypic feature of the disease that affects the myocardium of both ventricles, with left ventricular involvement which may parallel or exceed the severity of right ventricular involvement. This has led to the new designation of "Arrhythmogenic Cardiomyopathy" (ACM), that represents the evolution of the original term of ARVC. The present International Expert Consensus document proposes an upgrade of the criteria for diagnosis of the entire spectrum of the phenotypic variants of ACM. The proposed "Padua criteria" derive from the diagnostic approach to ACM, which has been developed over 30 years by the multidisciplinary team of basic researchers and clinical cardiologists of the Medical School of the University of Padua. The Padua criteria are a working framework to improve the diagnosis of ACM by introducing new diagnostic criteria regarding tissue characterization findings by contrast-enhanced cardiac magnetic resonance, depolarization/repolarization ECG abnormalities and ventricular arrhythmia features for diagnosis of the left ventricular phenotype. The proposed diagnostic criteria need to be further validated by future clinical studies in large cohorts of patients.
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http://dx.doi.org/10.1016/j.ijcard.2020.06.005DOI Listing
November 2020

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.

Circulation 2020 Jul 20;142(4):324-338. Epub 2020 May 20.

Masonic Medical Research Institute, Utica, NY (R.P.).

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility.

Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score.

Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance (<5×10) near , , and , and 1 missense variant in (p.Asp85Asn) at the suggestive threshold (<10). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r=0.40; =3.2×10). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls (<10-13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive (<0.005).

Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045956DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382531PMC
July 2020

Color Routing via Cross-Polarized Detuned Plasmonic Nanoantennas in Large-Area Metasurfaces.

Nano Lett 2020 Jun 21;20(6):4121-4128. Epub 2020 May 21.

Dipartimento di Fisica, Università di Genova, Via Dodecaneso 33, I-16146 Genova, Italy.

Bidirectional nanoantennas are of key relevance for advanced functionalities to be implemented at the nanoscale and, in particular, for color routing in an ultracompact flat-optics configuration. Here we demonstrate a novel approach avoiding complex collective geometries and/or restrictive morphological parameters based on cross-polarized detuned plasmonic nanoantennas in a uniaxial (quasi-1D) bimetallic configuration. The nanofabrication of such a flat-optics system is controlled over a large area (cm) by a novel self-organized technique exploiting ion-induced nanoscale wrinkling instability on glass templates to engineer tilted bimetallic nanostrip dimers. These nanoantennas feature broadband color routing with superior light scattering directivity figures, which are well described by numerical simulations and turn out to be competitive with the response of lithographic nanoantennas. These results demonstrate that our large-area self-organized metasurfaces can be implemented in real-world applications of flat-optics color routing from telecom photonics to optical nanosensing.
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http://dx.doi.org/10.1021/acs.nanolett.9b05276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735747PMC
June 2020

Desmoplakin Cardiomyopathy, a Fibrotic and Inflammatory Form of Cardiomyopathy Distinct From Typical Dilated or Arrhythmogenic Right Ventricular Cardiomyopathy.

Circulation 2020 Jun 6;141(23):1872-1884. Epub 2020 May 6.

Department of Internal Medicine, Division of Cardiovascular Medicine (E.D.S., P.A., A.S.H.), University of Michigan, Ann Arbor.

Background: Mutations in desmoplakin (), the primary force transducer between cardiac desmosomes and intermediate filaments, cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy. Clinical correlates of cardiomyopathy have been limited to small case series.

Methods: Clinical and genetic data were collected on 107 patients with pathogenic mutations and 81 patients with pathogenic plakophilin 2 () mutations as a comparison cohort. A composite outcome of severe ventricular arrhythmia was assessed.

Results: and cohorts included similar proportions of probands (41% versus 42%) and patients with truncating mutations (98% versus 100%). Left ventricular (LV) predominant cardiomyopathy was exclusively present among patients with (55% versus 0% for , <0.001), whereas right ventricular cardiomyopathy was present in only 14% of patients with versus 40% for (<0.001). Arrhythmogenic right ventricular cardiomyopathy diagnostic criteria had poor sensitivity for cardiomyopathy. LV late gadolinium enhancement was present in a primarily subepicardial distribution in 40% of patients with (23/57 with magnetic resonance images). LV late gadolinium enhancement occurred with normal LV systolic function in 35% (8/23) of patients with . Episodes of acute myocardial injury (chest pain with troponin elevation and normal coronary angiography) occurred in 15% of patients with and were strongly associated with LV late gadolinium enhancement (90%), even in cases of acute myocardial injury with normal ventricular function (4/5, 80% with late gadolinium enhancement). In 4 cases with 18F-fluorodeoxyglucose positron emission tomography scans, acute LV myocardial injury was associated with myocardial inflammation misdiagnosed initially as cardiac sarcoidosis or myocarditis. Left ventricle ejection fraction <55% was strongly associated with severe ventricular arrhythmias for cases (<0.001, sensitivity 85%, specificity 53%). Right ventricular ejection fraction <45% was associated with severe arrhythmias for cases (<0.001) but was poorly associated for cases (=0.8). Frequent premature ventricular contractions were common among patients with severe arrhythmias for both (80%) and (91%) groups (=non-significant).

Conclusions: cardiomyopathy is a distinct form of arrhythmogenic cardiomyopathy characterized by episodic myocardial injury, left ventricular fibrosis that precedes systolic dysfunction, and a high incidence of ventricular arrhythmias. A genotype-specific approach for diagnosis and risk stratification should be used.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286080PMC
June 2020

Natural History and Risk Stratification in Andersen-Tawil Syndrome Type 1.

J Am Coll Cardiol 2020 04;75(15):1772-1784

Department of Cardiology and Electrotherapy, Medical University of Gdansk, Gdansk, Poland.

Background: Andersen-Tawil Syndrome type 1 (ATS1) is a rare arrhythmogenic disorder, caused by loss-of-function mutations in the KCNJ2 gene. We present here the largest cohort of patients with ATS1 with outcome data reported.

Objectives: This study sought to define the risk of life-threatening arrhythmic events (LAE), identify predictors of such events, and define the efficacy of antiarrhythmic therapy in patients with ATS1.

Methods: Clinical and genetic data from consecutive patients with ATS1 from 23 centers were entered in a database implemented at ICS Maugeri in Pavia, Italy, and pooled for analysis.

Results: We enrolled 118 patients with ATS1 from 57 families (age 23 ± 17 years at enrollment). Over a median follow-up of 6.2 years (interquartile range: 2.7 to 16.5 years), 17 patients experienced a first LAE, with a cumulative probability of 7.9% at 5 years. An increased risk of LAE was associated with a history of syncope (hazard ratio [HR]: 4.54; p = 0.02), with the documentation of sustained ventricular tachycardia (HR 9.34; p = 0.001) and with the administration of amiodarone (HR: 268; p < 0.001). The rate of LAE without therapy (1.24 per 100 person-years [py]) was not reduced by beta-blockers alone (1.37 per 100 py; p = 1.00), or in combination with Class Ic antiarrhythmic drugs (1.46 per 100 py, p = 1.00).

Conclusions: Our data demonstrate that the clinical course of patients with ATS1 is characterized by a high rate of LAE. A history of unexplained syncope or of documented sustained ventricular tachycardia is associated with a higher risk of LAE. Amiodarone is proarrhythmic and should be avoided in patients with ATS1.
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http://dx.doi.org/10.1016/j.jacc.2020.02.033DOI Listing
April 2020

Warning: not all carriers of pathogenic mutations in desmosomal genes should follow the same medical advices!

Cardiovasc Res 2020 05;116(6):1085-1088

Molecular Cardiology, ICS Maugeri, IRCCS, Via Maugeri, 10, 27100 Pavia, Italy.

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http://dx.doi.org/10.1093/cvr/cvaa049DOI Listing
May 2020

Light-Triggered Catalytic Asymmetric Allylic Benzylation with Photogenerated -Nucleophiles.

J Org Chem 2020 03 3;85(6):4463-4474. Epub 2020 Mar 3.

Department of Chemical Sciences, University of Padova, via Marzolo 1, 35131 Padova, Italy.

Herein is reported the asymmetric allylic benzylation of Morita-Baylis-Hillman (MBH) carbonates with 2-methylbenzophenone (MBP) derivatives as nonstabilized photogenerated -nucleophiles. The dual activation of both reaction partners, chiral Lewis-base activation of the electrophile and light activation of the nucleophile, enables the stereoselective installation of benzyl groups at the allylic position to forge tertiary and quaternary carbon centers.
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http://dx.doi.org/10.1021/acs.joc.0c00175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997570PMC
March 2020

An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.

Circulation 2020 02 16;141(6):429-439. Epub 2020 Jan 16.

European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (A.M., I.T., L.C., A.B., D.K., B.S., C.S., Y.D.W., S.D., A.A.M.W., E.R.B., J.T.-H., J.P.K., F.D., P.J.S., E.S.-B., S.G.P.).

Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare variants implicated in LQT5 was sought through an international multicenter collaboration.

Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death.

Results: A total of 32 distinct rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, <0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6-52.2]; =0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3-10.8], =0.590). The cumulative prevalence of the 32 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%).

Conclusions: The present study suggests that putative/confirmed loss-of-function variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035205PMC
February 2020

Outcomes and management of arrhythmogenic right ventricular cardiomyopathy in pregnancy: a case report.

Eur Heart J Case Rep 2019 Dec 26;3(4):1-5. Epub 2019 Nov 26.

Department of Cardiology, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Via F. Sforza, 35, 20122 Milan, Italy.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited disease with an estimated prevalence of up to 1:5000 in the general population. Few cases of ARVC during pregnancy are described in literature.

Case Summary: A 32-year-old primigravida was referred to our clinic during the 32nd gestational week. Arrhythmogenic right ventricular cardiomyopathy diagnosis with biventricular involvement was made according to Task Force criteria. Beta-blocker therapy was started and an elective caesarean section was planned, during the 37th gestational week; no complications occurred. Thirteen months after delivery, the patient was readmitted in our hospital due to an episode of pre-syncope and after team discussion, an implantable cardioverter-defibrillator (ICD) was implanted.

Discussion: This case suggests that the absence of signs and symptoms of heart failure (HF) at a first evaluation plays a major role to predict maternal and foetal outcome in ARVC. Our experience is consistent with the evidence that indicates a favourable outcome in asymptomatic patients treated with optimal medical therapy during pregnancy. In our case, despite no major HF or arrhythmic complications during pregnancy, delivery, and puerperium, we observed an arrhythmic disease progression more likely independent from pregnancy, leading to ICD implantation.
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http://dx.doi.org/10.1093/ehjcr/ytz208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939797PMC
December 2019

Central-to-Axial Chirality Conversion Approach Designed on Organocatalytic Enantioselective Povarov Cycloadditions: First Access to Configurationally Stable Indole-Quinoline Atropisomers.

Chemistry 2019 Dec 21;25(68):15694-15701. Epub 2019 Nov 21.

Department of Industrial Chemistry "Toso Montanari", Alma Mater Studiorum-University of Bologna, Viale Risorgimento 4, 40136, Bologna, Italy.

The first stereoselective synthesis of enantioenriched axially chiral indole-quinoline systems is presented. The strategy takes advantage of an organocatalytic enantioselective Povarov cycloaddition of 3-alkenylindoles and N-arylimines, followed by an oxidative central-to-axial chirality conversion process, allowing for access to previously unreported axially chiral indole-quinoline biaryls. The methodology is also implemented for the design and the preparation of challenging compounds exhibiting two stereogenic axes. DFT calculations shed light on the stereoselectivity of the central-to-axial chirality conversion, showing unconventional behavior.
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http://dx.doi.org/10.1002/chem.201904213DOI Listing
December 2019

Conformational and Stereodynamic Behavior of Five- to Seven-Membered 1-Aryl-2-iminoazacycloalkanes.

ACS Omega 2019 Mar 4;4(3):4712-4720. Epub 2019 Mar 4.

Department of Industrial Chemistry "Toso Montanari", University of Bologna, Viale Risorgimento 4, 40136 Bologna, Italy.

The stereodynamic behavior of 1-arylpyrrolidin-2-imines, having a C-N stereogenic axis, has been studied by means of dynamic nuclear magnetic resonance and density functional theory calculations, evaluating the steric effect of -aryl substituents. The rotational barrier due to / isomerism about the -C=N-H bond was also determined. The dynamic stereochemistry of homologous six- and seven-membered iminoazacycloalkane rings and their oxo-analogues was also comparatively investigated, evidencing a ring size effect. It was found that the seven-membered heterocycle shows additional dynamic features because of ring inversion.
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http://dx.doi.org/10.1021/acsomega.9b00192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6648013PMC
March 2019

Deuterium Incorporation Protects Cells from Oxidative Damage.

Oxid Med Cell Longev 2019 18;2019:6528106. Epub 2019 Jul 18.

Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Rimini, Italy.

In the cold environments of the interstellar medium, a variety of molecules in which a hydrogen (H) atom has been replaced by its heavier isotope deuterium (D) can be found. From its emergence, life had to counteract the toxic action of many agents, which posed a constant threat to its development and propagation. Oxygen-reactive species are archaic toxicants that lead to protein damage and genomic instability. Most of the oxidative lesions involve cleavage of C-H bonds and H abstraction. According to free radical chemistry principles, the substitution of D for H in oxidation-sensitive positions of cellular components should confer protection against the oxidative attack without compromising the chemical identity of the compounds. Here, we show that deuterated nucleosides and proteins protect from oxidative damage. Our data suggest a new, subtle but likely role of D in terrestrial life's evolution in that its inclusion in critical biomolecules might have facilitated their resistance during the infinite generations of life entities, cells, and organisms.
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http://dx.doi.org/10.1155/2019/6528106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668601PMC
January 2020

Axial Chirality at the Boron-Carbon Bond: Synthesis, Stereodynamic Analysis, and Atropisomeric Resolution of 6-Aryl-5,6-dihydrodibenzo[][1,2]azaborinines.

J Org Chem 2019 Oct 30;84(19):12253-12258. Epub 2019 Jul 30.

Department of Industrial Chemistry "Toso Montanari" , University of Bologna , Viale del Risorgimento 4 , Bologna 40136 , Italy.

6-Aryl-5,6-dihydrodibenzo[][1,2]azaborinines display restricted rotation at the boron-carbon aryl bond, yielding conformational isomers or atropisomers. The stereodynamic processes were monitored by variable-temperature NMR (D-NMR), dynamic enantioselective HPLC (D-HPLC), or kinetic racemization measurements. The absolute configuration of stable atropisomers (compound , Δ = 26.0 kcal·mol) was determined by TD-DFT simulation of the electronic circular dichroism (ECD) spectra. The racemization energy of is more than 12 kcal·mol smaller than its isostere 9-(2-methylnaphthalen-1-yl)phenanthrene.
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http://dx.doi.org/10.1021/acs.joc.9b01550DOI Listing
October 2019

Ethnic differences in patients with Brugada syndrome and arrhythmic events: New insights from Survey on Arrhythmic Events in Brugada Syndrome.

Heart Rhythm 2019 10 5;16(10):1468-1474. Epub 2019 Jul 5.

Quebec Heart and Lung Institute, Quebec City, Quebec, Canada.

Background: There is limited information on ethnic differences between patients with Brugada syndrome (BrS) and arrhythmic events (AEs).

Objective: The purpose of this study was to compare clinical, electrocardiographic (ECG), electrophysiological, and genetic characteristics between white and Asian patients with BrS and AEs.

Methods: The Survey on Arrhythmic Events in Brugada Syndrome is a multicenter survey from Western and Asian countries, gathering 678 patients with BrS and first documented AE. After excluding patients with other (n = 14 [2.1%]) or unknown (n = 30 [4.4%]) ethnicity, 364 (53.7%) whites and 270 (39.8%) Asians comprised the study group.

Results: There was no difference in AE age onset (41.3 ± 16.1 years in whites vs 43.3 ± 12.3 years in Asians; P = .285). Higher proportions of whites were observed in pediatric and elderly populations. Asians were predominantly men (98.1% vs 85.7% in whites; P < .001) and frequently presented with aborted cardiac arrest (71.1% vs 56%; P < .001). Asians tended to display more spontaneous type 1 BrS-ECG pattern (71.5% vs 64.3%; P = .068). A family history of sudden cardiac death was noted more in whites (29.1% vs 11.5%; P < .001), with a higher rate of SCN5A mutation carriers (40.1% vs 13.2% in Asians; P < .001), as well as more fever-related AEs (8.5% vs 2.9%; P = .011). No difference was observed between the 2 groups regarding history of syncope and ventricular arrhythmia inducibility.

Conclusion: There are important differences between Asian and white patients with BrS. Asian patients present almost exclusively as male adults, more often with aborted cardiac arrest and spontaneous type 1 BrS-ECG. However, they have less family history of sudden cardiac death and markedly lower SCN5A mutation rates. The striking difference in SCN5A mutation rates should be tested in future studies.
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http://dx.doi.org/10.1016/j.hrthm.2019.07.003DOI Listing
October 2019

Predictive chirality sensing via Schiff base formation.

Org Biomol Chem 2019 07 27;17(27):6699-6705. Epub 2019 Jun 27.

Department of Chemistry, Georgetown University, 37th and O Streets, Washington, DC 20057, USA.

Among the large number of chiroptical sensors that have been developed to date, few allow rational determination of the absolute configuration of chiral substrates together with quantitative ee analysis. We have prepared and tested stereodynamic N-aryl aminobenzaldehyde sensors that bind chiral amines via Schiff base formation. The covalent binding of the amine substrate generates a conformational bias in the chromophoric sensor moiety which results in characteristic CD signals. Computational analysis revealed that CD prediction of the sign of the Cotton effect and thus determination of the absolute configuration of the substrate becomes practical with a sterically crowded sensor design because the number of conformations to be considered is largely reduced and the chiroptical sensor response is less sensitive to conformational equilibria. The amplitude of the measured CD signal can be used for quantitative ee analysis of nonracemic amine samples with the help of a calibration curve.
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http://dx.doi.org/10.1039/c9ob01265fDOI Listing
July 2019