Silvia G Priori
(Head of Laboratory)
Marco Denegri, PhD
Rossana Bongianino, PhD
Alessandro Vollero, PhD
Silvia Fasciano, PhD
Serena Barbaro, MSc
Damiano Mangione, MSc
Mirella Memmi, MSc
Patrick Gambelli, MSc
Carlo Napolitano, MD, PhD
Andrea Mazzanti, MD
Nicola Monteforte, MD
Raffaella Bloise, MD
Our laboratories are located at the ICS Maugeri in Pavia. Inherited arrhythmias are disorders caused by mutations in genes encoding for cardiac ion channels that lead to life threatening arrhythmias in young individuals. Our research is focused on the study of the mechanisms that promote arrhythmogenesis in these disorders and on the development of targeted therapies that may reduce mortality in affected individuals. The laboratory coordinates a major EU-funded project (EU-Rhythmy) aimed at finding new ways to treat genetic cardiac arrhythmias.
In the last 15 years we investigated the arrhythmogenic substrate of the dominant and recessive forms of catecholaminergic ventricular tachycardia (CPVT) a disease with high penetrance and high lethality. In 2000 we discovered that the RyR2 gene, encoding for the tetrameric Calcium channel that bears the same name, is responsible for the dominant form of CPVT. In the following years we developed and extensively characterized a knock-in animal model that recapitulates the arrhythmic phenotype seen in CPVT patients. We have also studied the recessive variant of CPVT caused by loss of function mutations in the CASQ2 gene that encodes for Calsequestrin: a protein that polymerizes to form a mesh that binds calcium with high affinity. We have also developed knock out and a knock in animal models of the disease.
Our projects focus on the characterization of electrophysiological mechanisms and calcium handling abnormalities in animal models and cellular models to identify novel therapeutic targets for curing diseases. Among the approaches that we are following is the development of small molecules, gene therapy and drug-repurposing.
The group is also involved in clinical and genetic research with the focus to identify risk factor for life-threatening in patients with inherited arrhythmias. To pursue these translational studies we have established an integrated activity with a laboratory for genetic screening and a large clinical service where patients with inherited arrhythmias are followed. Having access to clinical and molecular data we have created large disease-specific registries that have allowed to define genotype-phenotype correlations and risk stratification schemes now adopted in clinical guidelines for the management of patients with inherited arrhythmias.
The research group has developed 1-2-3-LQTS Risk Calculator: an independently validated risk calculator for patients with Long QT Syndrome.
Selected PapersAllele-Specific Silencing of Mutant mRNA Rescues Ultrastructural and Arrhythmic Phenotype in Mice Carriers of the R4496C Mutation in the Ryanodine Receptor Gene (RYR2). Bongianino R, Denegri M, Mazzanti A, Lodola F, Vollero A, Boncompagni S, Fasciano S, Rizzo G, Mangione D, Barbaro S, Di Fonso A, Napolitano C, Auricchio A, Protasi F, Priori SG. Circ Res. 2017;121(5):525-536.
Arrhythmogenic Right Ventricular Cardiomyopathy: Clinical Course and Predictors of Arrhythmic Risk. Mazzanti A, Ng K, Faragli A, Maragna R, Chiodaroli E, Orphanou N, Monteforte N, Memmi M, Gambelli P, Novelli V, Bloise R, Catalano O, Moro G, Tibollo V, Morini M, Bellazzi R, Napolitano C, Bagnardi V, Priori SG. J Am Coll Cardiol. 2016;68(23):2540-2550.
Single delivery of an adeno-associated viral construct to transfer the CASQ2 gene to knock-in mice affected by catecholaminergic polymorphic ventricular tachycardia is able to cure the disease from birth to advanced age. Denegri M, Bongianino R, Lodola F, Boncompagni S, De Giusti VC, Avelino-Cruz JE, Liu N, Persampieri S, Curcio A, Esposito F, Pietrangelo L, Marty I, Villani L, Moyaho A, Baiardi P, Auricchio A, Protasi F, Napolitano C, Priori SG. Circulation. 2014;129(25):2673-81.
Gene-Specific Therapy with Mexiletine Reduces Arrhythmic Events in Patients with Long QT Syndrome Type 3. Mazzanti A, Maragna R, Faragli A, Monteforte N, Bloise R, Memmi M, Novelli V, Baiardi P, Bagnardi V, Etheridge SP, Napolitano C, Priori SG. J Am Coll Cardiol 2016;67(9):1053-8.
Abnormal propagation of calcium waves and ultrastructural remodeling in recessive catecholaminergic polymorphic ventricular tachycardia. Liu N, Denegri M, Dun W, Boncompagni S, Lodola F, Protasi F, Napolitano C, Boyden PA, Priori SG. Circ Res. 2013;113(2):142-52.