Publications by authors named "Elisabetta Cerbai"

104 Publications

Of hits, players, and goalkeepers: the case of arrhythmias in diabetes.

Cardiovasc Res 2021 Mar 21. Epub 2021 Mar 21.

Department of Neurosciences, Psychology, Drugs and Child Health, University of Florence, Italy.

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http://dx.doi.org/10.1093/cvr/cvab101DOI Listing
March 2021

Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies.

Genet Med 2021 Jan 26. Epub 2021 Jan 26.

Amsterdam UMC, University of Amsterdam, Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam, Netherlands.

Purpose: To characterize the genetic architecture of left ventricular noncompaction (LVNC) and investigate the extent to which it may represent a distinct pathology or a secondary phenotype associated with other cardiac diseases.

Methods: We performed rare variant association analysis with 840 LVNC cases and 125,748 gnomAD population controls, and compared results to similar analyses on dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM).

Results: We observed substantial genetic overlap indicating that LVNC often represents a phenotypic variation of DCM or HCM. In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were uniquely associated with LVNC and may reflect a distinct LVNC etiology. In particular, MYH7 truncating variants (MYH7tv), generally considered nonpathogenic for cardiomyopathies, were 20-fold enriched in LVNC cases over controls. MYH7tv heterozygotes identified in the UK Biobank and healthy volunteer cohorts also displayed significantly greater noncompaction compared with matched controls. RYR2 exon deletions and HCN4 transmembrane variants were also enriched in LVNC, supporting prior reports of association with arrhythmogenic LVNC phenotypes.

Conclusion: LVNC is characterized by substantial genetic overlap with DCM/HCM but is also associated with distinct noncompaction and arrhythmia etiologies. These results will enable enhanced application of LVNC genetic testing and help to distinguish pathological from physiological noncompaction.
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http://dx.doi.org/10.1038/s41436-020-01049-xDOI Listing
January 2021

Dual Carbonic Anhydrase IX/XII Inhibitors and Carbon Monoxide Releasing Molecules Modulate LPS-Mediated Inflammation in Mouse Macrophages.

Antioxidants (Basel) 2021 Jan 5;10(1). Epub 2021 Jan 5.

Department of Pharmacy, "G. d'Annunzio" University of Chieti-Pescara, via dei Vestini 31, 66100 Chieti, Italy.

Low concentrations of carbon monoxide (CO) were reported to exhibit anti-inflammatory effects when administered in cells by suitable chemotypes such as CO releasing molecules (CO-RMs). In addition, the pH-modulating abilities of specific carbonic anhydrase isoforms played a crucial role in different models of inflammation and neuropathic pain. Herein, we report a series of chemical hybrids consisting of a Carbonic Anhydrase (CA) inhibitor linked to a CO-RM tail (CAI/CO-RMs). All compounds and their precursors were first tested in vitro for their inhibition activity against the human CA I, II, IX, and XII isoforms as well their CO releasing properties, aiming at corroborating the data by means of molecular modelling techniques. Then, their impact on metabolic activity modulation of RAW 264.7 mouse macrophages for 24 and 48 h was assessed with or without lipopolysaccharide (LPS) stimulation. The compounds were shown to counteract the inflammatory stimulus as also indicated by the reduced tumor necrosis factor alpha (TNF-α) release after treatment. All the biological results were compared to those of -acetylcysteine (NAC) as a reference antioxidant compound. Within the series, two CAI/CO-RM hybrids ( and ), bearing both the well-known scaffold able to inhibit CAs (acesulfame) and the cobalt-based CO releasing portion, induced a higher anti-inflammatory effect up to 48 h at concentrations lower than NAC.
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http://dx.doi.org/10.3390/antiox10010056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824903PMC
January 2021

Targeting Cyclic Guanosine Monophosphate to Treat Heart Failure: JACC Review Topic of the Week.

J Am Coll Cardiol 2020 10;76(15):1795-1807

Cardiovascular Department and Cardiology Unit, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.

The significant morbidity and mortality associated with heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF) justify the search for novel therapeutic agents. Reduced cyclic guanosine monophosphate levels contribute to HF progression. Among molecules modulating the nitric oxide (NO)-GMP-phosphodiesterase (PDE) pathway, the evaluation of nitrates, synthetic natriuretic peptides (NP), and NP analogs has yielded mixed results. Conversely, sacubitril/valsartan, combining NP degradation inhibition through neprilysin and angiotensin receptor blockade, has led to groundbreaking findings in HFrEF. Other strategies to increase tissue cyclic guanosine monophosphate have been attempted, such as PDE-3 or PDE-5 inhibition (with negative or neutral results), NO-independent soluble guanylate cyclase (sGC) activation, or enhancement of sGC sensitivity to endogenous NO. Following the positive results of the phase 3 VICTORIA (A Study of Vericiguat in Participants With Heart Failure With Reduced Ejection Fraction) trial on the sGC stimulator vericiguat in HFrEF, the main open questions are the efficacy of the sacubitril/valsartan-vericiguat combination in HFrEF and of vericiguat in HFpEF.
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http://dx.doi.org/10.1016/j.jacc.2020.08.031DOI Listing
October 2020

Modelling genetic diseases for drug development: Hypertrophic cardiomyopathy.

Pharmacol Res 2020 10 29;160:105176. Epub 2020 Aug 29.

Department of Neuroscience, Psychology, Drug Sciences and Child Health (NeuroFarBa), University of Florence, Italy. Electronic address:

Hypertrophic cardiomyopathy (HCM) is the commonest genetic cardiac disease, with a prevalence of 1/500. It is caused by over 1400 different mutations, mainly involving the genes coding for sarcomere proteins. The main pathological features of HCM are left ventricular hypertrophy, diastolic dysfunction and the increased ventricular arrhythmogenesis. Predicting the risk of heart failure and lethal arrhythmias is the most challenging clinical task for HCM patient management. Moreover, there are no disease-modifying therapies that can prevent disease progression or sudden arrhythmic death in HCM patients. In this review, we will illustrate the most advanced research models and methods that have been employed for HCM studies, including preclinical tests of novel or existing drugs, along with visionary future development based on gene editing approaches. Acknowledging the advantages and limitations of the different models, and a critical consideration of the different, often conflicting result obtained using different approaches is essential for a deep understanding of HCM pathophysiology and for obtaining meaningful information on novel treatments, in order to improve patient risk stratification and therapeutic management.
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http://dx.doi.org/10.1016/j.phrs.2020.105176DOI Listing
October 2020

Abnormalities in sodium current and calcium homoeostasis as drivers of arrhythmogenesis in hypertrophic cardiomyopathy.

Cardiovasc Res 2020 Jul;116(9):1585-1599

Department of Neurosciences, Psychiatry, Drug Research and Child Health (NeuroFarBa), University of Florence, Florence, Italy.

Hypertrophic cardiomyopathy (HCM) is a common inherited monogenic disease with a prevalence of 1/500 in the general population, representing an important cause of arrhythmic sudden cardiac death (SCD), heart failure, and atrial fibrillation in the young. HCM is a global condition, diagnosed in >50 countries and in all continents. HCM affects people of both sexes and various ethnic and racial origins, with similar clinical course and phenotypic expression. The most unpredictable and devastating consequence of HCM is represented by arrhythmic SCD, most commonly caused by sustained ventricular tachycardia or ventricular fibrillation. Indeed, HCM represents one of the main causes of arrhythmic SCD in the young, with a marked preference for children and adults <30 years. SCD is most prevalent in patients with paediatric onset of HCM but may occur at any age. However, risk is substantially lower after 60 years, suggesting that the potential for ventricular tachyarrhythmias is mitigated by ageing. SCD had been linked originally to sports and vigorous activity in HCM patients. However, it is increasingly clear that the majority of events occurs at rest or during routine daily occupations, suggesting that triggers are far from consistent. In general, the pathophysiology of SCD in HCM remains unresolved. While the pathologic and physiologic substrates abound and have been described in detail, specific factors precipitating ventricular tachyarrhythmias are still unknown. SCD is a rare phenomenon in HCM cohorts (<1%/year) and attempts to identify patients at risk, while generating clinically useful algorithms for primary prevention, remain very inaccurate on an individual basis. One of the reasons for our limited understanding of these phenomena is that limited translational research exists in the field, while most efforts have focused on clinical markers of risk derived from pathology, instrumental patient evaluation, and imaging. Specifically, few studies conducted in animal models and human samples have focused on targeting the cellular mechanisms of arrhythmogenesis in HCM, despite potential implications for therapeutic innovation and SCD prevention. These studies found that altered intracellular Ca2+ homoeostasis and increased late Na+ current, leading to an increased likelihood of early and delayed after-depolarizations, contribute to generate arrhythmic events in diseased cardiomyocytes. As an array of novel experimental opportunities have emerged to investigate these mechanisms, including novel 'disease-in-the-dish' cellular models with patient-specific induced pluripotent stem cell-derived cardiomyocytes, important gaps in knowledge remain. Accordingly, the aim of the present review is to provide a contemporary reappraisal of the cellular basis of SCD-predisposing arrhythmias in patients with HCM and discuss the implications for risk stratification and management.
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http://dx.doi.org/10.1093/cvr/cvaa124DOI Listing
July 2020

The hyperpolarization-activated cyclic nucleotide-gated 4 channel as a potential anti-seizure drug target.

Br J Pharmacol 2020 08 17;177(16):3712-3729. Epub 2020 Jun 17.

Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia.

Background And Purpose: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are encoded by four genes (HCN1-4) with distinct biophysical properties and functions within the brain. HCN4 channels activate slowly at robust hyperpolarizing potentials, making them more likely to be engaged during hyperexcitable neuronal network activity seen during seizures. HCN4 channels are also highly expressed in thalamic nuclei, a brain region implicated in seizure generalization. Here, we assessed the utility of targeting the HCN4 channel as an anti-seizure strategy using pharmacological and genetic approaches.

Experimental Approach: The impact of reducing HCN4 channel function on seizure susceptibility and neuronal network excitability was studied using an HCN4 channel preferring blocker (EC18) and a conditional brain specific HCN4 knockout mouse model.

Key Results: EC18 (10 mg·kg ) and brain-specific HCN4 channel knockout reduced seizure susceptibility and proconvulsant-mediated cortical spiking recorded using electrocorticography, with minimal effects on other mouse behaviours. EC18 (10 μM) decreased neuronal network bursting in mouse cortical cultures. Importantly, EC18 was not protective against proconvulsant-mediated seizures in the conditional HCN4 channel knockout mouse and did not reduce bursting behaviour in AAV-HCN4 shRNA infected mouse cortical cultures.

Conclusions And Implications: These data suggest the HCN4 channel as a potential pharmacologically relevant target for anti-seizure drugs that is likely to have a low side-effect liability in the CNS.
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http://dx.doi.org/10.1111/bph.15088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393203PMC
August 2020

Pirfenidone is a cardioprotective drug: Mechanisms of action and preclinical evidence.

Pharmacol Res 2020 05 19;155:104694. Epub 2020 Feb 19.

Institute of Life Sciences, Scuola Superiore Sant'Anna, Italy; Fondazione Toscana Gabriele Monasterio, Pisa, Italy.

Myocardial fibrosis is an endogenous response to different cardiac insults that may become maladaptive over time and contribute to the onset and progression of heart failure (HF). Fibrosis is a direct and indirect target of established HF therapies, namely inhibitors of the renin-angiotensin-aldosterone system, but its resilience to therapy warrants a search for novel, more targeted approaches to myocardial fibrosis. Pirfenidone is a drug approved for idiopathic pulmonary fibrosis, a severe form of idiopathic interstitial pneumonias. Pirfenidone is a small synthetic molecule with high oral bioavailability, exerting an antifibrotic activity, but also anti-oxidant and anti-inflammatory effects. These effects have been attributed to the inhibition of several growth factors (in particular transforming growth factor-β, but also platelet-derived growth factor and beta fibroblast growth factor), matrix metalloproteinases, and pro-inflammatory mediators (such as interleukin-1β and tumour necrosis factor-α), and possibly also an improvement of mitochondrial function and modulation of lymphocyte activation. Given the activation of similar profibrotic pathways in lung and heart disease, the crucial role of fibrosis in several cardiac disorders, and the wide spectrum of activity of pirfenidone, this drug has been evaluated with interest as a potential treatment for cardiac disorders. In animal studies, pirfenidone has shown cardioprotective effects across different species and in a variety of models of cardiomyopathy. In the present review we summarize the pharmacological characteristics of pirfenidone and the data from animal studies supporting its cardioprotective effects.
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http://dx.doi.org/10.1016/j.phrs.2020.104694DOI Listing
May 2020

Electrophysiological and Contractile Effects of Disopyramide in Patients With Obstructive Hypertrophic Cardiomyopathy: A Translational Study.

JACC Basic Transl Sci 2019 Nov 9;4(7):795-813. Epub 2019 Oct 9.

Hypertrophic Cardiomyopathy Program, New York University Langone Health, New York, New York.

Disopyramide is effective and safe in patients with obstructive hypertrophic cardiomyopathy. However, its cellular and molecular mechanisms of action are unknown. We tested disopyramide in cardiomyocytes from the septum of surgical myectomy patients: disopyramide inhibits multiple ion channels, leading to lower Ca transients and force, and shortens action potentials, thus reducing cellular arrhythmias. The electrophysiological profile of disopyramide explains the efficient reduction of outflow gradients but also the limited prolongation of the QT interval and the absence of arrhythmic side effects observed in 39 disopyramide-treated patients. In conclusion, our results support the idea that disopyramide is safe for outpatient use in obstructive patients.
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http://dx.doi.org/10.1016/j.jacbts.2019.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978554PMC
November 2019

Pharmacological Inhibition of Serine Proteases to Reduce Cardiac Inflammation and Fibrosis in Atrial Fibrillation.

Front Pharmacol 2019 20;10:1420. Epub 2019 Dec 20.

Section of Pharmacology, Department of Neurology, Psychology, Drug Sciences and Child Health, University of Florence, Florence, Italy.

Systemic inflammation correlates with an increased risk of atrial fibrillation (AF) and thrombogenesis. Systemic inflammation alters vessel permeability, allowing inflammatory and immune cell migration toward target organs, including the heart. Among inflammatory cells infiltrating the atria, macrophages and mast cell have recently attracted the interest of basic researchers due to the pathogenic mechanisms triggered by their activation. This chemotactic invasion is likely implicated in short- and long-term changes in cardiac cell-to-cell communication and in triggering fibrous tissue accumulation in the atrial myocardium and electrophysiological re-arrangements of atrial cardiomyocytes, thus favoring the onset and progression of AF. Serine proteases are a large and heterogeneous class of proteases involved in several processes that are important for cardiac function and are involved in cardiac diseases, such as (i) coagulation, (ii) fibrinolysis, (iii) extracellular matrix degradation, (iv) activation of receptors (i.e., protease-activated receptors [PPARs]), and (v) modulation of the activity of endogenous signals. The recognition of serine proteases substrates and their involvement in inflammatory/profibrotic mechanisms allowed the identification of novel cardio-protective mechanisms for commonly used drugs that inhibit serine proteases. The aim of this review is to summarize knowledge on the role of inflammation and fibrosis as determinants of AF. Moreover, we will recapitulate current findings on the role of serine proteases in the pathogenesis of AF and the possible beneficial effects of drugs inhibiting serine proteases in reducing the risk of AF through decrease of cardiac inflammation and fibrosis. These drugs include thrombin and factor Xa inhibitors (used as oral anticoagulants), dipeptidyl-peptidase 4 (DPP4) inhibitors, used for type-2 diabetes, as well as novel experimental inhibitors of mast cell chymases.
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http://dx.doi.org/10.3389/fphar.2019.01420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951407PMC
December 2019

Angiotensin-II Drives Human Satellite Cells Toward Hypertrophy and Myofibroblast Trans-Differentiation by Two Independent Pathways.

Int J Mol Sci 2019 Oct 3;20(19). Epub 2019 Oct 3.

Department of NEUROFARBA, Center of Molecular Medicine, University of Firenze, 50139 Firenze, Italy.

Skeletal muscle regeneration is ensured by satellite cells (SC), which upon activation undergo self-renewal and myogenesis. The correct sequence of healing events may be offset by inflammatory and/or fibrotic factors able to promote fibrosis and consequent muscle wasting. Angiotensin-II (Ang) is an effector peptide of the renin angiotensin system (RAS), of which the direct role in human SCs (hSCs) is still controversial. Based on the hypertrophic and fibrogenic effects of Ang via transient receptor potential canonical (TRPC) channels in cardiac and renal tissues, we hypothesized a similar axis in hSCs. Toward this aim, we demonstrated that hSCs respond to acute Ang stimulation, dose-dependently enhancing p-mTOR, p-AKT, p-ERK1/2 and p-P38. Additionally, sub-acute Ang conditioning increased cell size and promoted trans-differentiation into myofibroblasts. To provide a mechanistic hypothesis on TRPC channel involvement in the processes, we proved that TRPC channels mediate a basal calcium entry into hSCs that is stimulated by acute Ang and strongly amplified by sub-chronic Ang conditioning. Altogether, these findings demonstrate that Ang induces a fate shift of hSCs into myofibroblasts and provide a basis to support a benefit of RAS and TRPC channel blockade to oppose muscle fibrosis.
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http://dx.doi.org/10.3390/ijms20194912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801484PMC
October 2019

Optical Investigation of Action Potential and Calcium Handling Maturation of hiPSC-Cardiomyocytes on Biomimetic Substrates.

Int J Mol Sci 2019 Aug 3;20(15). Epub 2019 Aug 3.

Department NeuroFarBa, University of Florence, 50134 Florence, Italy.

Cardiomyocytes from human induced pluripotent stem cells (hiPSC-CMs) are the most promising human source with preserved genetic background of healthy individuals or patients. This study aimed to establish a systematic procedure for exploring development of hiPSC-CM functional output to predict genetic cardiomyopathy outcomes and identify molecular targets for therapy. Biomimetic substrates with microtopography and physiological stiffness can overcome the immaturity of hiPSC-CM function. We have developed a custom-made apparatus for simultaneous optical measurements of hiPSC-CM action potential and calcium transients to correlate these parameters at specific time points (day 60, 75 and 90 post differentiation) and under inotropic interventions. In later-stages, single hiPSC-CMs revealed prolonged action potential duration, increased calcium transient amplitude and shorter duration that closely resembled those of human adult cardiomyocytes from fresh ventricular tissue of patients. Thus, the major contribution of sarcoplasmic reticulum and positive inotropic response to β-adrenergic stimulation are time-dependent events underlying excitation contraction coupling (ECC) maturation of hiPSC-CM; biomimetic substrates can promote calcium-handling regulation towards adult-like kinetics. Simultaneous optical recordings of long-term cultured hiPSC-CMs on biomimetic substrates favor high-throughput electrophysiological analysis aimed at testing (mechanistic hypothesis on) disease progression and pharmacological interventions in patient-derived hiPSC-CMs.
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http://dx.doi.org/10.3390/ijms20153799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695920PMC
August 2019

EC18 as a Tool To Understand the Role of HCN4 Channels in Mediating Hyperpolarization-Activated Current in Tissues.

ACS Med Chem Lett 2019 Apr 6;10(4):584-589. Epub 2019 Feb 6.

Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), University of Florence, Florence 50139, Italy.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are membrane proteins encoded by four genes (HCN1-4) and widely distributed in the central and peripheral nervous system and in the heart. HCN channels are involved in several physiological functions, including the generation of rhythmic activity, and are considered important drug targets if compounds with isoform selectivity are developed. At present, however, few compounds are known, which are able to discriminate among HCN channel isoforms. The inclusion of the three-methylene chain of zatebradine into a cyclohexane ring gave a compound () showing a 5-fold preference for HCN4 channels, and ability to selectively modulate I in different tissues. Compound has been tested for its ability to reduce I and to interact with other ion channels in the heart and the central nervous system. Its preference for HCN4 channels makes this compound useful to elucidate the contribution of this isoform in the physiological and pathological processes involving hyperpolarization-activated current.
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http://dx.doi.org/10.1021/acsmedchemlett.8b00587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466822PMC
April 2019

Development of Light-Responsive Liquid Crystalline Elastomers to Assist Cardiac Contraction.

Circ Res 2019 04;124(8):e44-e54

Department of Chemistry "Ugo Schiff" (D.M., C.Pa.), University of Florence, Italy.

Rationale: Despite major advances in cardiovascular medicine, heart disease remains a leading cause of death worldwide. However, the field of tissue engineering has been growing exponentially in the last decade and restoring heart functionality is now an affordable target; yet, new materials are still needed for effectively provide rapid and long-lasting interventions. Liquid crystalline elastomers (LCEs) are biocompatible polymers able to reversibly change shape in response to a given stimulus and generate movement. Once stimulated, LCEs can produce tension or movement like a muscle. However, so far their application in biology was limited by slow response times and a modest possibility to modulate tension levels during activation.

Objective: To develop suitable LCE-based materials to assist cardiac contraction.

Methods And Results: Thanks to a quick, simple, and versatile synthetic approach, a palette of biocompatible acrylate-based light-responsive LCEs with different molecular composition was prepared and mechanically characterized. Out of this, the more compliant one was selected. This material was able to contract for some weeks when activated with very low light intensity within a physiological environment. Its contraction was modulated in terms of light intensity, stimulation frequency, and t/t ratio to fit different contraction amplitude/time courses, including those of the human heart. Finally, LCE strips were mounted in parallel with cardiac trabeculae, and we demonstrated their ability to improve muscular systolic function, with no impact on diastolic properties.

Conclusions: Our results indicated LCEs are promising in assisting cardiac mechanical function and developing a new generation of contraction assist devices.
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http://dx.doi.org/10.1161/CIRCRESAHA.118.313889DOI Listing
April 2019

Editorial: The Role of Calcium Handling in Heart Failure and Heart Failure Associated Arrhythmias.

Front Physiol 2019 22;10. Epub 2019 Jan 22.

Department of Neuroscience, Psychology, Drug Research and Child Health (NeuroFarBa), University of Florence, Florence, Italy.

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http://dx.doi.org/10.3389/fphys.2019.00001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349775PMC
January 2019

Selective Blockade of HCN1/HCN2 Channels as a Potential Pharmacological Strategy Against Pain.

Front Pharmacol 2018 8;9:1252. Epub 2018 Nov 8.

Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), University of Florence, Florence, Italy.

A prominent role of hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels has been suggested based on their expression and (dys)function in dorsal root ganglion (DRG) neurons, being likely involved in peripheral nociception. Using HCN blockers as antinociceptive drugs is prevented by the widespread distribution of these channels. However, tissue-specific expression of HCN isoforms varies significantly, HCN1 and HCN2 being considered as major players in DRG excitability. We characterized the pharmacological effect of a novel compound, MEL55A, able to block selectively HCN1/HCN2 isoforms, on DRG neuron excitability and for its antiallodynic properties . HEK293 cells expressing HCN1, HCN2, or HCN4 isoforms were used to verify drug selectivity. The pharmacological profile of MEL55A was tested on mouse DRG neurons by patch-clamp recordings, and in oxaliplatin-induced neuropathy by means of thermal hypersensitivity. Results were compared to the non-isoform-selective drug, ivabradine. MEL55A showed a marked preference toward HCN1 and HCN2 isoforms expressed in HEK293, with respect to HCN4. In cultured DRG, MEL55A reduced amplitude, both in basic conditions and after stimulation by forskolin, and cell excitability, its effect being quantitatively similar to that observed with ivabradine. MEL55A was able to relieve chemotherapy-induced neuropathic pain. In conclusion, selective blockade of HCN1/HCN2 channels, over HCN4 isoform, was able to modulate electrophysiological properties of DRG neurons similarly to that reported for classical blockers, ivabradine, resulting in a pain-relieving activity. The availability of small molecules with selectivity toward HCN channel isoforms involved in nociception might represent a safe and effective strategy against chronic pain.
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http://dx.doi.org/10.3389/fphar.2018.01252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237106PMC
November 2018

Altered Ca and Na Homeostasis in Human Hypertrophic Cardiomyopathy: Implications for Arrhythmogenesis.

Front Physiol 2018 16;9:1391. Epub 2018 Oct 16.

Department of Neuroscience, Psychology, Drug Sciences and Child Health (NEUROFARBA), University of Florence, Florence, Italy.

Hypertrophic cardiomyopathy (HCM) is the most common mendelian heart disease, with a prevalence of 1/500. HCM is a primary cause of sudden death, due to an heightened risk of ventricular tachyarrhythmias that often occur in young asymptomatic patients. HCM can slowly progress toward heart failure, either with preserved or reduced ejection fraction, due to worsening of diastolic function. Accumulation of intra-myocardial fibrosis and replacement scars underlies heart failure progression and represents a substrate for sustained arrhythmias in end-stage patients. However, arrhythmias and mechanical abnormalities may occur in hearts with little or no fibrosis, prompting toward functional pathomechanisms. By studying viable cardiomyocytes and trabeculae isolated from inter-ventricular septum samples of non-failing HCM patients with symptomatic obstruction who underwent myectomy operations, we identified that specific abnormalities of intracellular Ca handling are associated with increased cellular arrhytmogenesis and diastolic dysfunction. In HCM cardiomyocytes, diastolic Ca concentration is increased both in the cytosol and in the sarcoplasmic reticulum and the rate of Ca transient decay is slower, while the amplitude of Ca-release is preserved. Ca overload is the consequence of an increased Ca entry via L-type Ca-current [due to prolongation the action potential (AP) plateau], combined with a reduced rate of Ca-extrusion through the Na/Ca exchanger [due to increased cytosolic (Na)] and a lower expression of SERCA. Increased late Na current (I) plays a major role, as it causes both AP prolongation and Na overload. Intracellular Ca overload determines an higher frequency of Ca waves leading to delayed-afterdepolarizations (DADs) and premature contractions, but is also linked with the increased diastolic tension and slower relaxation of HCM myocardium. Sustained increase of intracellular [Ca] goes hand-in-hand with the increased activation of Ca/calmodulin-dependent protein-kinase-II (CaMKII) and augmented phosphorylation of its targets, including Ca handling proteins. In transgenic HCM mouse models, we found that Ca overload, CaMKII and increased I drive myocardial remodeling since the earliest stages of disease and underlie the development of hypertrophy, diastolic dysfunction and the arrhythmogenic substrate. In conclusion, diastolic dysfunction and arrhythmogenesis in human HCM myocardium are driven by functional alterations at cellular and molecular level that may be targets of innovative therapies.
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http://dx.doi.org/10.3389/fphys.2018.01391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215954PMC
October 2018

Synthesis of novel benzenesulfamide derivatives with inhibitory activity against human cytosolic carbonic anhydrase I and II and Vibrio cholerae α- and β-class enzymes.

J Enzyme Inhib Med Chem 2018 Dec;33(1):1125-1136

a NEUROFARBA Department, Sezione di Scienze Farmaceutiche e Nutraceutiche , Università degli Studi di Firenze , Sesto Fiorentino (Florence) , Italy.

The synthesis of a new series of sulfamides incorporating ortho-, meta, and para-benzenesulfamide moieties is reported, which were investigated for the inhibition of two human (h) isoforms of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1), hCA I and II, and two Vibrio cholerae enzymes, belonging to the α- and β-CA classes (VchCAα, VchCAβ). The compounds were prepared by using the "tail approach", aiming to overcome the scarcity of selective inhibition profiles associated to CA inhibitors belonging to the zinc binders. The built structure-activity relationship showed that the incorporation of benzhydryl piperazine tails on a phenyl sulfamide scaffold determines rather good efficacies against hCA I and VchCAα, with several compounds showing Ks < 100 nM. The activity was lower against hCA II and VchCAβ, probably due to the fact that the incorporated tails are quite bulky. The obtained evidences allow us to continue the investigations of different tails/zinc binding groups, with the purpose to increase the effectiveness/selectivity of such inhibitors against bacterial CAs from pathogens, affording thus potential new anti-infectives.
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http://dx.doi.org/10.1080/14756366.2018.1467901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041819PMC
December 2018

Hyperpolarization-activated cyclic-nucleotide-gated channels: pathophysiological, developmental, and pharmacological insights into their function in cellular excitability.

Can J Physiol Pharmacol 2018 Oct 3;96(10):977-984. Epub 2018 Jul 3.

Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), University of Florence, Florence, Italy.

The hyperpolarization-activated cyclic-nucleotide-gated (HCN) proteins are voltage-dependent ion channels, conducting both Na and K, blocked by millimolar concentrations of extracellular Cs and modulated by cyclic nucleotides (mainly cAMP) that contribute crucially to the pacemaker activity in cardiac nodal cells and subsidiary pacemakers. Over the last decades, much attention has focused on HCN current, I, in non-pacemaker cardiac cells and its potential role in triggering arrhythmias. In fact, in addition to pacemakers, HCN current is constitutively present in the human atria and has long been proposed to sustain atrial arrhythmias associated to different cardiac pathologies or triggered by various modulatory signals (catecholamines, serotonin, natriuretic peptides). An atypical I occurs in diseased ventricular cardiomyocytes, its amplitude being linearly related to the severity of cardiac hypertrophy. The properties of atrial and ventricular I and its modulation by pharmacological interventions has been object of intense study, including the synthesis and characterization of new compounds able to block preferentially HCN1, HCN2, or HCN4 isoforms. Altogether, clues emerge for opportunities of future pharmacological strategies exploiting the unique properties of this channel family: the prevalence of different HCN subtypes in organs and tissues, the possibility to target HCN gain- or loss-of-function associated with disease, the feasibility of novel isoform-selective drugs, as well as the discovery of HCN-mediated effects for old medicines.
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http://dx.doi.org/10.1139/cjpp-2018-0115DOI Listing
October 2018

Defining the diagnostic effectiveness of genes for inclusion in panels: the experience of two decades of genetic testing for hypertrophic cardiomyopathy at a single center.

Genet Med 2019 02 6;21(2):284-292. Epub 2018 Jun 6.

Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy.

Purpose: Genetic testing in hypertrophic cardiomyopathy (HCM) has long relied on Sanger sequencing of sarcomeric genes. The advent of next-generation sequencing (NGS) has catalyzed routine testing of additional genes of dubious HCM-causing potential. We used 19 years of genetic testing results to define a reliable set of genes implicated in Mendelian HCM and assess the value of expanded NGS panels.

Methods: We dissected genetic testing results from 1,198 single-center HCM probands and devised a widely applicable score to identify which genes yield effective results in the diagnostic setting.

Results: Compared with early panels targeting only fully validated sarcomeric HCM genes, expanded NGS panels allow the prompt recognition of probands with HCM-mimicking diseases. Scoring by "diagnostic effectiveness" highlighted that PLN should also be routinely screened besides historically validated genes for HCM and its mimics.

Conclusion: The additive value of expanded panels in HCM genetic testing lies in the systematic screening of genes associated with HCM mimics, requiring different patient management. Only variants in a limited set of genes are highly actionable and interpretable in the clinic, suggesting that larger panels offer limited additional sensitivity. A score estimating the relative effectiveness of a given gene's inclusion in diagnostic panels is proposed.
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http://dx.doi.org/10.1038/s41436-018-0046-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752309PMC
February 2019

Late sodium current inhibitors to treat exercise-induced obstruction in hypertrophic cardiomyopathy: an in vitro study in human myocardium.

Br J Pharmacol 2018 07 3;175(13):2635-2652. Epub 2018 May 3.

Department NeuroFarBa, University of Florence, Florence, Italy.

Background And Purpose: In 30-40% of hypertrophic cardiomyopathy (HCM) patients, symptomatic left ventricular (LV) outflow gradients develop only during exercise due to catecholamine-induced LV hypercontractility (inducible obstruction). Negative inotropic pharmacological options are limited to β-blockers or disopyramide, with low efficacy and tolerability. We assessed the potential of late sodium current (I )-inhibitors to treat inducible obstruction in HCM.

Experimental Approach: The electrophysiological and mechanical responses to β-adrenoceptor stimulation were studied in human myocardium from HCM and control patients. Effects of I -inhibitors (ranolazine and GS-967) in HCM samples were investigated under conditions simulating rest and exercise.

Key Results: In cardiomyocytes and trabeculae from 18 surgical septal samples of patients with obstruction, the selective I -inhibitor GS-967 (0.5 μM) hastened twitch kinetics, decreased diastolic [Ca ] and shortened action potentials, matching the effects of ranolazine (10μM). Mechanical responses to isoprenaline (inotropic and lusitropic) were comparable in HCM and control myocardium. However, isoprenaline prolonged action potentials in HCM myocardium, while it shortened them in controls. Unlike disopyramide, neither GS-967 nor ranolazine reduced force at rest. However, in the presence of isoprenaline, they reduced Ca -transient amplitude and twitch tension, while the acceleration of relaxation was maintained. I -inhibitors were more effective than disopyramide in reducing contractility during exercise. Finally, I -inhibitors abolished arrhythmias induced by isoprenaline.

Conclusions And Implications: Ranolazine and GS-967 reduced septal myocardium tension during simulated exercise in vitro and therefore have the potential to ameliorate symptoms caused by inducible obstruction in HCM patients, with some advantages over disopyramide and β-blockers.
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http://dx.doi.org/10.1111/bph.14223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6003658PMC
July 2018

Sex-related differences in chronic heart failure.

Int J Cardiol 2018 Mar;255:145-151

Scuola Superiore Sant'Anna, Pisa, Italy; Fondazione Toscana Gabriele Monasterio, Pisa, Italy.

The prevalence of chronic heart failure (CHF) is steadily increasing. Both sexes are affected, with significant differences in etiology, epidemiology and clinical presentation, prognosis, comorbidities, and response to treatment. Women tend to develop CHF at a more advanced age, present more often with HF with preserved ejection fraction, are more symptomatic, and have a worse quality of life than men, but also a better prognosis. In women, CHF has more frequently a non-ischemic etiology, and arterial hypertension and diabetes mellitus are leading comorbidities. Furthermore, many sex-related differences have been detected in the response to treatment, for example a greater prognostic benefit from angiotensin-receptor blockers in women, a higher incidence of complications after defibrillator implantation, and a greater response to cardiac resynchronization therapy. Furthermore, women are less likely to receive defibrillator therapy or heart transplantation. The significant underrepresentation of women in clinical trials limits our capacity to evaluate the extent of sex-related differences in CHF, although their characterization seems crucial in order to achieve the ultimate goal of a tailored therapy for this condition.
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http://dx.doi.org/10.1016/j.ijcard.2017.10.068DOI Listing
March 2018

The importance of integrated left atrial evaluation: From hypertension to heart failure with preserved ejection fraction.

Int J Clin Pract 2018 Feb 28;72(2). Epub 2017 Dec 28.

Division of Cardiology, University of Perugia School of Medicine, Perugia, Italy.

Aim: Functional analysis and measurement of left atrium are an integral part of cardiac evaluation, and they represent a key element during non-invasive analysis of diastolic function in patients with hypertension (HT) and/or heart failure with preserved ejection fraction (HFpEF). However, diastolic dysfunction remains quite elusive regarding classification, and atrial size and function are two key factors for left ventricular (LV) filling evaluation. Chronic left atrial (LA) remodelling is the final step of chronic intra-cavitary pressure overload, and it accompanies increased neurohormonal, proarrhythmic and prothrombotic activities. In this systematic review, we aim to purpose a multi-modality approach for LA geometry and function analysis, which integrates diastolic flow with LA characteristics and remodelling through application of both traditional and new diagnostic tools.

Methods: The most important studies published in the literature on LA size, function and diastolic dysfunction in patients with HFpEF, HT and/or atrial fibrillation (AF) are considered and discussed.

Results: In HFpEF and HT, pulsed and tissue Doppler assessments are useful tools to estimate LV filling pressure, atrio-ventricular coupling and LV relaxation but they need to be enriched with LA evaluation in terms of morphology and function. An integrated evaluation should be also applied to patients with a high arrhythmic risk, in whom eccentric LA remodelling and higher LA stiffness are associated with a greater AF risk.

Conclusion: Evaluation of LA size, volume, function and structure are mandatory in the management of patients with HT, HFpEF and AF. A multi-modality approach could provide additional information, identifying subjects with more severe LA remodelling. Left atrium assessment deserves an accurate study inside the cardiac imaging approach and optimised measurement with established cut-offs need to be better recognised through multicenter studies.
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http://dx.doi.org/10.1111/ijcp.13050DOI Listing
February 2018

Arterial hypertension and atrial fibrillation: standard and advanced echocardiography from diagnosis to prognostication.

J Cardiovasc Med (Hagerstown) 2018 Feb;19(2):51-61

Dipartimento di Patologia Chirurgica, Medica, Molecolare e dell'Area Critica, Università di Pisa, Pisa.

: Structural changes in left and right cardiac chambers that occur in arterial hypertension (AH) may lead to an increased risk of atrial fibrillation. Considering that AH is currently the most common cardiovascular disease in the general population, it represents a major risk factor for atrial fibrillation development. This review explores the complex relationship between atrial fibrillation and AH, starting from its pathophysiological basis. It focuses on the role of echocardiography in the management of hypertensive and atrial fibrillation patients, with emphasis on what should be evaluated about left ventricular remodeling, diastolic and systolic function, left atrial (LA) size and function and right ventricular deformation in patients with AH.
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http://dx.doi.org/10.2459/JCM.0000000000000607DOI Listing
February 2018

Content of mitochondrial calcium uniporter (MCU) in cardiomyocytes is regulated by microRNA-1 in physiologic and pathologic hypertrophy.

Proc Natl Acad Sci U S A 2017 10 9;114(43):E9006-E9015. Epub 2017 Oct 9.

Department of Biomedical Sciences, University of Padua, 35131 Padua, Italy;

The mitochondrial Ca uniporter complex (MCUC) is a multimeric ion channel which, by tuning Ca influx into the mitochondrial matrix, finely regulates metabolic energy production. In the heart, this dynamic control of mitochondrial Ca uptake is fundamental for cardiomyocytes to adapt to either physiologic or pathologic stresses. Mitochondrial calcium uniporter (MCU), which is the core channel subunit of MCUC, has been shown to play a critical role in the response to β-adrenoreceptor stimulation occurring during acute exercise. The molecular mechanisms underlying the regulation of MCU, in conditions requiring chronic increase in energy production, such as physiologic or pathologic cardiac growth, remain elusive. Here, we show that microRNA-1 (miR-1), a member of the muscle-specific microRNA (myomiR) family, is responsible for direct and selective targeting of MCU and inhibition of its translation, thereby affecting the capacity of the mitochondrial Ca uptake machinery. Consistent with the role of miR-1 in heart development and cardiomyocyte hypertrophic remodeling, we additionally found that MCU levels are inversely related with the myomiR content, in murine and, remarkably, human hearts from both physiologic (i.e., postnatal development and exercise) and pathologic (i.e., pressure overload) myocardial hypertrophy. Interestingly, the persistent activation of β-adrenoreceptors is likely one of the upstream repressors of miR-1 as treatment with β-blockers in pressure-overloaded mouse hearts prevented its down-regulation and the consequent increase in MCU content. Altogether, these findings identify the miR-1/MCU axis as a factor in the dynamic adaptation of cardiac cells to hypertrophy.
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http://dx.doi.org/10.1073/pnas.1708772114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664523PMC
October 2017

Liquid Crystalline Networks toward Regenerative Medicine and Tissue Repair.

Small 2017 12 17;13(46). Epub 2017 Oct 17.

European Laboratory for Non-Linear Spectroscopy, via N. Carrara 1, Sesto F. No., 50019, Italy.

The communication reports the use of liquid crystalline networks (LCNs) for engineering tissue cultures with human cells. Their ability as cell scaffolds for different cell lines is demonstrated. Preliminary assessments of the material biocompatibility are performed on human dermal fibroblasts and murine muscle cells (C2C12), demonstrating that coatings or other treatments are not needed to use the acrylate-based materials as support. Moreover, it is found that adherent C2C12 cells undergo differentiation, forming multinucleated myotubes, which show the typical elongated shape, and contain bundles of stress fibers. Once biocompatibility is demonstrated, the same LCN films are used as a substrate for culturing human induced pluripotent stem cell-derived cardiomyocites (hiPSC-CMs) proving that LCNs are capable to develop adult-like dimensions and a more mature cell function in a short period of culture in respect to standard supports. The demonstrated biocompatibility together with the extraordinary features of LCNs opens to preparation of complex cell scaffolds, both patterned and stimulated, for dynamic cell culturing. The ability of these materials to improve cell maturation and differentiation will be developed toward engineered heart and skeletal muscular tissues exploring regenerative medicine toward bioartificial muscles for injured sites replacement.
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http://dx.doi.org/10.1002/smll.201702677DOI Listing
December 2017

Resistant hypertension: an overview.

Minerva Cardioangiol 2018 Jun 5;66(3):337-348. Epub 2017 Sep 5.

Section of Cardiology and Cardiovascular Pathophysiology, Department of Medicine, University of Perugia, Perugia, Italy.

Despite the availability of anti-hypertensive medications with proven efficacy and good tolerability, many hypertensive patients have blood pressure (BP) levels not at the goals set by international societies. Some of these patients are either non-adherent to the prescribed drugs or not optimally treated. However, a proportion has resistant hypertension (RH) defined as office BP above goal despite the use of ≥3 antihypertensive medications at maximally tolerated doses (one ideally being a diuretic). Diagnosis of RH based upon office measurements, however, needs confirmation through 24-h BP monitoring to exclude "white coat" RH since cardiovascular events and mortality rates follow mean ambulatory BPs. Standardized combination therapy based upon angiotensin converting enzyme inhibitors or angiotensin receptor blockers, amlodipine or other dihydropiridine calcium channel blockers and thiazide or thiazide-like diuretics has been advocated to treat RH with spironolactone as preferred fourth add-on drug. Interventional procedures such as renal denervation have been devised to treat RH and tested with insofar not positive results in series of patients not responding to medical treatment. It is unclear whether RH constitutes a specific phenotype of EH or should rather be considered a more serious form of uncontrolled hypertension. Whatever the case, its presence associates with an increased cardio- and cerebrovascular risk and deserves, therefore, particular care.
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http://dx.doi.org/10.23736/S0026-4725.17.04495-4DOI Listing
June 2018

The Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: from Biophysics to Pharmacology of a Unique Family of Ion Channels.

Pharmacol Rev 2017 10;69(4):354-395

Department of Neurosciences, Psychology, Drug Research, and Child Health, University of Florence, Firenze, Italy

Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels are important members of the voltage-gated pore loop channels family. They show unique features: they open at hyperpolarizing potential, carry a mixed Na/K current, and are regulated by cyclic nucleotides. Four different isoforms have been cloned (HCN1-4) that can assemble to form homo- or heterotetramers, characterized by different biophysical properties. These proteins are widely distributed throughout the body and involved in different physiologic processes, the most important being the generation of spontaneous electrical activity in the heart and the regulation of synaptic transmission in the brain. Their role in heart rate, neuronal pacemaking, dendritic integration, learning and memory, and visual and pain perceptions has been extensively studied; these channels have been found also in some peripheral tissues, where their functions still need to be fully elucidated. Genetic defects and altered expression of HCN channels are linked to several pathologies, which makes these proteins attractive targets for translational research; at the moment only one drug (ivabradine), which specifically blocks the hyperpolarization-activated current, is clinically available. This review discusses current knowledge about HCN channels, starting from their biophysical properties, origin, and developmental features, to (patho)physiologic role in different tissues and pharmacological modulation, ending with their present and future relevance as drug targets.
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http://dx.doi.org/10.1124/pr.117.014035DOI Listing
October 2017

Myocardial I-metaiodobenzylguanidine imaging in hypertension and left ventricular hypertrophy.

J Nucl Cardiol 2018 Apr 10;25(2):461-470. Epub 2017 Aug 10.

Dipartimento di Patologia Chirurgica, Molecolare e dell'Area Critica, Università di Pisa Medica, 56100, Pisa, Italy.

Sympathetic nervous system plays a pivotal role in essential hypertension and in the development of left ventricular hypertrophy. Moreover, cardiac sympathetic dys-regulation has been demonstrated as a key con-causal factor in the genesis and progression of pathologic conditions such as congestive heart failure and ischemic heart disease to which hypertension predisposes as a risk factor. However, despite its fundamental role in cardiac pathophysiology, the evaluation of cardiac sympathetic nervous system has never gained a wide clinical application, remaining mostly a research tool. In this context, nuclear imaging techniques are the only modalities to allow the direct evaluation of cardiac sympathetic nervous integrity, giving the chance to obtain objective measures of the sympathetic tone. This review, while summarizing the general profile of currently available tests for autonomic evaluation, focuses on I-metaiodobenzylguanidine nuclear imaging as a preferential tool to assess cardiac sympathetic status. Specifically, the review discusses the available evidence on cardiac I-metaiodobenzylguanidine scintigraphy in arterial hypertension and left ventricular hypertrophy and its diagnostic and prognostic potential in congestive heart failure and ischemic heart disease.
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http://dx.doi.org/10.1007/s12350-017-1029-2DOI Listing
April 2018

Pathogenesis of Hypertrophic Cardiomyopathy is Mutation Rather Than Disease Specific: A Comparison of the Cardiac Troponin T E163R and R92Q Mouse Models.

J Am Heart Assoc 2017 Jul 22;6(7). Epub 2017 Jul 22.

Department of Experimental and Clinical Medicine, University of Florence, Italy.

Background: In cardiomyocytes from patients with hypertrophic cardiomyopathy, mechanical dysfunction and arrhythmogenicity are caused by mutation-driven changes in myofilament function combined with excitation-contraction (E-C) coupling abnormalities related to adverse remodeling. Whether myofilament or E-C coupling alterations are more relevant in disease development is unknown. Here, we aim to investigate whether the relative roles of myofilament dysfunction and E-C coupling remodeling in determining the hypertrophic cardiomyopathy phenotype are mutation specific.

Methods And Results: Two hypertrophic cardiomyopathy mouse models carrying the R92Q and the E163R mutations were investigated. Echocardiography showed left ventricular hypertrophy, enhanced contractility, and diastolic dysfunction in both models; however, these phenotypes were more pronounced in the R92Q mice. Both E163R and R92Q trabeculae showed prolonged twitch relaxation and increased occurrence of premature beats. In E163R ventricular myofibrils or skinned trabeculae, relaxation following Ca removal was prolonged; resting tension and resting ATPase were higher; and isometric ATPase at maximal Ca activation, the energy cost of tension generation, and myofilament Ca sensitivity were increased compared with that in wild-type mice. No sarcomeric changes were observed in R92Q versus wild-type mice, except for a large increase in myofilament Ca sensitivity. In R92Q myocardium, we found a blunted response to inotropic interventions, slower decay of Ca transients, reduced SERCA function, and increased Ca/calmodulin kinase II activity. Contrarily, secondary alterations of E-C coupling and signaling were minimal in E163R myocardium.

Conclusions: In E163R models, mutation-driven myofilament abnormalities directly cause myocardial dysfunction. In R92Q, diastolic dysfunction and arrhythmogenicity are mediated by profound cardiomyocyte signaling and E-C coupling changes. Similar hypertrophic cardiomyopathy phenotypes can be generated through different pathways, implying different strategies for a precision medicine approach to treatment.
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http://dx.doi.org/10.1161/JAHA.116.005407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5586279PMC
July 2017