Matteo Pedrazzini | Università degli studi di Pavia (original) (raw)

Papers by Matteo Pedrazzini

Heart Rhythm, May 1, 2023

Heart Rhythm, Nov 1, 2009

Backgrounds: Control of recurrent ventricular tachycardia (VT) is an important determinant of qua... more Backgrounds: Control of recurrent ventricular tachycardia (VT) is an important determinant of quality of life in patients with implantable defibrillators. The role of invasive catheter ablation for this purpose in elderly patients with ischemic heart disease has not been defined. Methods: We conducted a retrospective review of acute and chronic outcomes of radiofrequency (RF) catheter ablation in 223 consecutive patients with post-infarct VT. Outcomes were compared for elderly patients-age Ն75 years (elderly group, nϭ59) and the younger group (aged Ͻ75, nϭ164). Results: The groups were similar in LV ejection fraction 28Ϯ10 vs 29Ϯ12%, and amiodarone use 64% vs 59%; there were more women in the elderly group 20% vs 7% (pϭ0.04) (Table). A similar number of VTs were inducible during the procedure (2.8Ϯ1.5 in the elderly and 2.5Ϯ1.6 in the younger group, respectively, pϭns). Ablation abolished inducible VTs or modified inducible VTs to different VTs in 88.3% in elderly and 92.7% in younger patients (pϭns). Major complications occurred in 8.5% (Cardiac tamponade: 2, cerebral infarction: 1 and other embolic event: 1) of elderly and 4.3% (Cardiogenic shock/severe hypotension: 4, complete atrioventricular block: 2 and pulmonary embolisim: 1) of younger patients (pϭ0.31). During a mean follow-up of 45Ϯ32 months, 49% of elderly and 32% of younger patients died (pϭ0.02). In 212 patients who were followed more than 6 months (mean follow-up period: 18Ϯ24 months, 6 to 121 months), 53% of elderly and 52% of younger patients were free from any VT. There was no significant difference in long-term VT recurrence between elderly and younger group (pϭns). Conclusions: RF catheter ablation of VT in selected elderly patients with ischemic heart disease can be performed with acceptable safety and effectiveness. Advanced age should not preclude ablation when recurrent VT is adversely affecting quality of life in elderly patients who otherwise have a reasonable expectation for survival.

European Heart Journal, Oct 1, 2022

Stem Cell Research, Jul 1, 2021

Circulation-arrhythmia and Electrophysiology, Dec 1, 2008

Background-Inherited cardiac arrhythmia susceptibility contributes to sudden death during infancy... more Background-Inherited cardiac arrhythmia susceptibility contributes to sudden death during infancy and may contribute to perinatal and neonatal mortality, but the molecular basis of this risk and the relationship to genetic disorders presenting later in life is unclear. We studied the functional and pharmacological properties of a novel de novo cardiac sodium channel gene (SCN5A) mutation associated with an extremely severe perinatal presentation of long-QT syndrome in unrelated probands of different ethnicity. Methods and Results-Two subjects exhibiting severe fetal and perinatal ventricular arrhythmias were screened for SCN5A mutations, and the functional properties of a novel missense mutation (G1631D) were determined by whole-cell patch clamp recording. In vitro electrophysiological studies revealed a profound defect in sodium channel function characterized by Ϸ10-fold slowing of inactivation, increased persistent current, slowing of recovery from inactivation, and depolarized voltage dependence of activation and inactivation. Single-channel recordings demonstrated increased frequency of late openings, prolonged mean open time, and increased latency to first opening for the mutant. Subjects carrying this mutation responded clinically to the combination of mexiletine with propranolol and survived. Pharmacologically, the mutant exhibited 2-fold greater tonic and use-dependent mexiletine block than wild-type channels. The mutant also exhibited enhanced tonic (2.4-fold) and use-dependent block (Ϸ5-fold) by propranolol, and we observed additive effects of the 2 drugs on the mutant. Conclusions-Our study demonstrates the molecular basis for a malignant perinatal presentation of long-QT syndrome, illustrates novel functional and pharmacological properties of SCN5A-G1631D, which caused the disorder, and reveals therapeutic benefits of propranolol block of mutant sodium channels in this setting. (Circ Arrhythmia Electrophysiol. 2008;1:370-378.) Key Words: antiarrhythmia agents Ⅲ arrhythmia Ⅲ death, sudden Ⅲ heart arrest Ⅲ ion channels S udden unexplained death attributable to cardiac arrhythmia may occur at any age. When death occurs during infancy for no apparent reason, a diagnosis of the sudden infant death syndrome (SIDS) may be appropriate. 1,2 Recent evidence suggests that 9% to 10% of SIDS victims carry germ line mutations in arrhythmia susceptibility genes such as those associated with the congenital long-QT syndrome (LQTS). 3 Anecdotally, ventricular arrhythmias occurring during the perinatal or neonatal periods are associated with a poor prognosis and a low survival rate. 4-7 Whether cardiac arrhythmia susceptibility presenting in early life represents a biologically distinct disease is an unanswered question.

Heart Rhythm, May 1, 2006

Journal of Molecular and Cellular Cardiology, Mar 1, 2008

Life-threatening arrhythmias have been suspected as one cause of the sudden infant death syndrome... more Life-threatening arrhythmias have been suspected as one cause of the sudden infant death syndrome (SIDS), and this hypothesis is supported by the observation that mutations in arrhythmia susceptibility genes occur in 5-10% of cases. However, the functional consequences of cardiac potassium channel gene mutations associated with SIDS and how these alleles might mechanistically predispose to sudden death are unknown. To address these questions, we studied four missense KCNH2 (encoding HERG) variants, one compound KCNH2 genotype, and a missense KCNQ1 mutation all previously identified in Norwegian SIDS cases. Three of the six variants exhibited functional impairments while three were biophysically similar to wild-type channels (KCNH2 variants V279M, R885C, S1040G). When coexpressed with WT-HERG, R273Q and K897T/R954C generated currents resembling the rapid component of the cardiac delayed rectifier current (I Kr) but with significantly diminished amplitude. Action potential modeling demonstrated that this level of functional impairment was sufficient to evoke increased action potential duration and pausedependent early afterdepolarizations. By contrast, KCNQ1-I274V causes a gain-of-function in I Ks characterized by increased current density, faster activation, and slower deactivation leading to accumulation of instantaneous current upon repeated stimulation. Action potential simulations using a Markov model of heterozygous I274V-I Ks incorporated into the Luo-Rudy (LRd) ventricular cell model demonstrated marked rate-dependent shortening of action potential duration predicting a short QT phenotype. Our results indicate that certain potassium channel mutations associated with SIDS confer overt functional defects consistent with either LQTS or SQTS, and further emphasize the role of congenital arrhythmia susceptibility in this syndrome.

Circulation, Aug 30, 2005

Background-Clinical heterogeneity among patients with long-QT syndrome (LQTS) sharing the same di... more Background-Clinical heterogeneity among patients with long-QT syndrome (LQTS) sharing the same disease-causing mutation is usually attributed to variable penetrance. One potential explanation for this phenomenon is the coexistence of modifier gene alleles, possibly common single nucleotide polymorphisms, altering arrhythmia susceptibility. We demonstrate this concept in a family segregating a novel, low-penetrant KCNH2 mutation along with a common single nucleotide polymorphism in the same gene. Methods and Results-The proband is a 44-year-old white woman with palpitations associated with presyncope since age 20, who presented with ventricular fibrillation and cardiac arrest. Intermittent QT prolongation was subsequently observed (max QTc, 530 ms), and LQT2 was diagnosed after the identification of a missense KCNH2 mutation (A1116V) altering a conserved residue in the distal carboxyl-terminus of the encoded HERG protein. The proband also carried the common KCNH2 polymorphism K897T on the nonmutant allele. Relatives who carried A1116V without K897T were asymptomatic, but some exhibited transient mild QTc prolongation, suggesting latent disease. Heterologous expression studies performed in cultured mammalian cells and using bicistronic vectors linked to different fluorescent proteins demonstrated that coexpression of A1116V with K897T together resulted in significantly reduced current amplitude as compared with coexpression of either allele with WT-HERG. Thus, the presence of KCNH2-K897T is predicted to exaggerate the I Kr reduction caused by the A1116V mutation. These data explain why symptomatic LQTS occurred only in the proband carrying both alleles. Conclusions-We have provided evidence that a common KCNH2 polymorphism may modify the clinical expression of a latent LQT2 mutation. A similar mechanism may contribute to the risk for sudden death in more prevalent cardiac diseases. (Circulation. 2005;112:1251-1258.) Key Words: death, sudden Ⅲ genetics Ⅲ ion channels Ⅲ long-QT syndrome Ⅲ molecular biology T he congenital long QT syndrome (LQTS) is an inherited disorder characterized by prolongation of the QT interval and an increased risk for life-threatening ventricular arrhythmias. 1,2 The disease is genetically heterogeneous and is caused by mutations in one of several genes including KCNQ1, KCNH2, KCNE1, and KCNE2 encoding potassium channel subunits, the cardiac sodium channel gene SCN5A, and the L-type calcium channel gene CACNA1C.

Heart Rhythm, May 1, 2005

Circulation, Jan 23, 2007

Background-Mutations in genes responsible for the congenital long-QT syndrome, especially SCN5A, ... more Background-Mutations in genes responsible for the congenital long-QT syndrome, especially SCN5A, have been identified in some cases of sudden infant death syndrome. In a large-scale collaborative genetic screen, several SCN5A variants were identified in a Norwegian sudden infant death syndrome cohort (nϭ201). We present functional characterization of 7 missense variants (S216L, R680H, T1304M, F1486L, V1951L, F2004L, and P2006A) and 1 in-frame deletion allele (delAL586-587) identified by these efforts. Methods and Results-Whole-cell sodium currents were measured in tsA201 cells transiently transfected with recombinant wild-type or mutant SCN5A cDNA (hH1) coexpressed with the human ␤1 subunit. All variants exhibited defects in the kinetics and voltage dependence of inactivation. Five variants (S216L, T1304M, F1486L, F2004L, and P2006A) exhibited significantly increased persistent sodium currents (range, 0.5% to 1.7% of peak current) typical of SCN5A mutations associated with long-QT syndrome. These same 5 variants also displayed significant depolarizing shifts in voltage dependence of inactivation (range, 5 to 14 mV) and faster recovery from inactivation, but F1486L uniquely exhibits a depolarizing shift in the conductance-voltage relationship. Three alleles (delAL586-587, R680H, and V1951L) exhibited increased persistent current only under conditions of internal acidosis (R680H) or when expressed in the context of a common splice variant (delQ1077), indicating that they have a latent dysfunctional phenotype. Conclusions-Our present results greatly expand the spectrum of functionally characterized SCN5A variants associated with sudden infant death syndrome and provide further biophysical correlates of arrhythmia susceptibility in this syndrome. (Circulation. 2007;115:368-376.) Key Words: death, sudden Ⅲ genetics Ⅲ ion channels Ⅲ long-QT syndrome S udden infant death syndrome (SIDS) is a leading cause of death during the first year of life in developed countries. 1,2 Cardiac mechanisms, including life-threatening arrhythmias, have been suspected to cause a proportion of SIDS cases, 3 and recent evidence indicates that mutations in genes responsible for the congenital long-QT syndrome (LQTS) are found in as many as 9% of victims. 4,5 Molecular evidence for a link between SIDS and LQTS supports earlier observations that there is an increased risk of SIDS in infants with a QTc Ͼ440 ms based on ECG measurements in 34 000 Italian neonates. 6

Archives of Cardiovascular Diseases Supplements, 2012

Archives of Cardiovascular Diseases Supplements 2012) 4, 90-96 educational level, alcohol consump... more Archives of Cardiovascular Diseases Supplements 2012) 4, 90-96 educational level, alcohol consumption, smoking, blood pressure, LDL-and HDL-cholesterol. The adjusted Hazard Ratio for all-cause mortality was 2.77 [95% confidence interval: 0.70-10.88] for untreated diabetics, 2.15 [0.91-5.08] for diabetics with metformin alone, 1.53 [0.81-2.89] for diabetics with sulfonylurea (alone or in combination) and 5.03 [1.99-12.71] for diabetics with insulin (alone or in combination) versus non-diabetic subjects. Conclusions: Diabetics treated with insulin at baseline were at increased risk of all-cause mortality. We did not find any harmful signal regarding allcause mortality risk associated with the use of other hypoglycemic drugs. 289 Role of Krox20 during cardiac valve development, remodeling and maturation Gaëlle Odelin [Orateur] (1), Frank Kober (2), Jean François Avierinos (3), Sarah Arab (1), Piotr Topilko (4), Patrick Charnay (4), Patrick Cozzone (2), Monique Bernard (2), Stéphane Zaffran (1)

European Heart Journal, Sep 10, 2021

AimsMutation type, location, dominant-negative I Ks reduction, and possibly loss of cyclic adeno... more AimsMutation type, location, dominant-negative I Ks reduction, and possibly loss of cyclic adenosine monophosphate (cAMP)-dependent I Ks stimulation via protein kinase A (PKA) influence the clinical severity of long QT syndrome type 1 (LQT1). Given the malignancy of KCNQ1-p.A341V, we assessed whether mutations neighbouring p.A341V in the S6 channel segment could also increase arrhythmic risk.Methods and resultsClinical and genetic data were obtained from 1316 LQT1 patients [450 families, 166 unique KCNQ1 mutations, including 277 p.A341V-positive subjects, 139 patients with p.A341-neighbouring mutations (91 missense, 48 non-missense), and 900 other LQT1 subjects]. A first cardiac event represented the primary endpoint. S6 segment missense variant characteristics, particularly cAMP stimulation responses, were analysed by cellular electrophysiology. p.A341-neighbouring mutation carriers had a QTc shorter than p.A341V carriers (477 ± 33 vs. 490 ± 44 ms) but longer than the remaining LQT1 patient population (467 ± 41 ms) (P < 0.05 for both). Similarly, the frequency of symptomatic subjects in the p.A341-neighbouring subgroup was intermediate between the other two groups (43% vs. 73% vs. 20%; P < 0.001). These differences in clinical severity can be explained, for p.A341V vs. p.A341-neighbouring mutations, by the p.A341V-specific impairment of I Ks regulation. The differences between the p.A341-neighbouring subgroup and the rest of LQT1 mutations may be explained by the functional importance of the S6 segment for channel activation.Conclusion KCNQ1 S6 segment mutations surrounding p.A341 increase arrhythmic risk. p.A341V-specific loss of PKA-dependent I Ks enhancement correlates with its phenotypic severity. Cellular studies providing further insights into I Ks-channel regulation and knowledge of structure-function relationships could improve risk stratification. These findings impact on clinical management. Open in a separate windowUpper panel: Topology of KCNQ1 missense and non-missense mutations identified in all studied long QT syndrome type 1 patients (n = 1316), according to their amino acid position along the KCNQ1 channel. Location of p.A341V and p.A341-neighbouring mutations in the KCNQ1-S6 segment is highlighted in red and blue, respectively. Exemplary I Ks traces for p.A341V (red) and p.A341V-neighbouring mutation (blue), with and without cyclic adenosine monophosphate/okadaic acid are depicted on the left. Left lower panel: structural image of the pore of the I Ks channel. Amino acid position A341 is indicated in red and the A341-neighbouring amino acids in blue. Right lower panel: Cumulative event-free survival of patients with p.A341V (red; n = 269), p.A341-neighbouring mutations (blue; n = 91), and all other KCNQ1-missense mutations located outside the S6 region (black; n = 611).

Human Genetics, Nov 7, 2006

Current protocols in stem cell biology, 2009

This unit describes how to generate human induced pluripotent stem (iPS) cells and evaluate the q... more This unit describes how to generate human induced pluripotent stem (iPS) cells and evaluate the qualities of the generated iPS cells. The methods for establishment and maintenance of human iPS cells are similar to those for mouse iPS cells but not identical. In addition, these protocols include excellent procedures for passaging and cryopreservation of human iPS cells established by ES cell researchers, which result in an easy way to culture human iPS cells. Moreover, we include methods for characterizing iPS cells for further research. RT-PCR and immunocytochemistry for detection of pluripotent cell markers, embryoid body differentiation, and teratoma differentiation are used to determine pluripotency in vitro and in vivo, respectively.

Biomolecules

Arrhythmogenic cardiomyopathy (ACM) is a rare inherited disorder, whose genetic cause is elusive ... more Arrhythmogenic cardiomyopathy (ACM) is a rare inherited disorder, whose genetic cause is elusive in about 50–70% of cases. ACM presents a variable disease course which could be influenced by genetics. We performed next-generation sequencing on a panel of 174 genes associated with inherited cardiovascular diseases on 82 ACM probands (i) to describe and classify the pathogenicity of rare variants according to the American College of Medical Genetics and Genomics both for ACM-associated genes and for genes linked to other cardiovascular genetic conditions; (ii) to assess, for the first time, the impact of common variants on the ACM clinical disease severity by genotype-phenotype correlation and survival analysis. We identified 15 (likely) pathogenic variants and 66 variants of uncertain significance in ACM-genes and 4 high-impact variants in genes never associated with ACM (ABCC9, APOB, DPP6, MIB1), which deserve future consideration. In addition, we found 69 significant genotype-pheno...

This record contains raw data related to the article "Oxidized LDL-dependent pathway as new ... more This record contains raw data related to the article "Oxidized LDL-dependent pathway as new pathogenic trigger in Arrhythmogenic Cardiomyopathy". Arrhythmogenic Cardiomyopathy (ACM) is hallmarked by ventricular fibro-adipogenic alterations, contributing to cardiac dysfunctions and arrhythmias. Although genetically-determined (e.g. <em>PKP2</em> mutations), ACM phenotypes are highly variable. More data on phenotype modulators, clinical prognosticators, and etiological therapies are awaited. We hypothesized that oxidized low-density-lipoproteins (oxLDL)-dependent activation of PPARγ, a recognized effector of ACM adipogenesis, contribute to disease pathogenesis. ACM patients showing high plasma concentration of oxLDL display severe clinical phenotypes in terms of fat infiltration, ventricular dysfunction, and major arrhythmic event risk. In ACM patient-derived cardiac cells, we demonstrated that oxLDL are major cofactors of adipogenesis. Mechanistically, the incre...

Background Primary myelofibrosis (PMF) is an acquired clonal disease of the hematopoietic stem ce... more Background Primary myelofibrosis (PMF) is an acquired clonal disease of the hematopoietic stem cell compartment, characterized by bone marrow fibrosis, anemia, splenomegaly and extrame-dullary hematopoiesis. About 60 % of patients with PMF harbor a somatic mutation of the JAK2 gene (JAK2-V617F) in their hematopoietic lineage. Recently, a splicing isoform of JAK2, lacking exon 14 (JAK2Δ14) was described in patients affected by myeloproliferative diseases. Materials and Methods By using a specific RT-qPCRmethod, we measured the ratio between the splicing isoform and the JAK2 full-length transcript (JAK2+14) in granulocytes, isolated from peripheral blood, of forty-four patients with PMF and nine healthy donors. Results We found that JAK2Δ14 was only slightly increased in patients and, at variance with pub-lished data, the splicing isoform was also detectable in healthy controls. We also found that,