Center for Inherited Cardiovascular Diseases

Pavia, Italy

Center for Inherited Cardiovascular Diseases

Pavia, Italy
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Zaragoza M.V.,University of California at Irvine | Fass J.,University of California at Davis | Diegoli M.,Center for Inherited Cardiovascular Diseases | Lin D.,University of California at Davis | Arbustini E.,Center for Inherited Cardiovascular Diseases
PLoS ONE | Year: 2010

Mutations in mitochondrial DNA (mtDNA) may cause maternally-inherited cardiomyopathy and heart failure. In homoplasmy all mtDNA copies contain the mutation. In heteroplasmy there is a mixture of normal and mutant copies of mtDNA. The clinical phenotype of an affected individual depends on the type of genetic defect and the ratios of mutant and normal mtDNA in affected tissues. We aimed at determining the sensitivity of next-generation sequencing compared to Sanger sequencing for mutation detection in patients with mitochondrial cardiomyopathy. We studied 18 patients with mitochondrial cardiomyopathy and two with suspected mitochondrial disease. We "shotgun" sequenced PCR-amplified mtDNA and multiplexed using a single run on Roche's 454 Genome Sequencer. By mapping to the reference sequence, we obtained 1,3006 × average coverage per case and identified high-confidence variants. By comparing these to >400 mtDNA substitution variants detected by Sanger, we found 98% concordance in variant detection. Simulation studies showed that >95% of the homoplasmic variants were detected at a minimum sequence coverage of 20 × while heteroplasmic variants required >200× coverage. Several Sanger "misses" were detected by 454 sequencing. These included the novel heteroplasmic 7501T>C in tRNA serine 1 in a patient with sudden cardiac death. These results support a potential role of next-generation sequencing in the discovery of novel mtDNA variants with heteroplasmy below the level reliably detected with Sanger sequencing. We hope that this will assist in the identification of mtDNA mutations and key genetic determinants for cardiomyopathy and mitochondrial disease. © 2010 Zaragoza et al.


De Haas H.J.,Mount Sinai School of Medicine | De Haas H.J.,University of Groningen | Arbustini E.,Center for Inherited Cardiovascular Diseases | Fuster V.,Mount Sinai School of Medicine | And 2 more authors.
Circulation Research | Year: 2014

In almost all cardiac diseases, an increase in extracellular matrix (ECM) deposition or fibrosis occurs, mostly consisting of collagen I. Whereas replacement fibrosis follows cardiomyocyte loss in myocardial infarction, reactive fibrosis is triggered by myocardial stress or inflammatory mediators and often results in ventricular stiffening, functional deterioration, and development of heart failure. Given the importance of ECM deposition in cardiac disease, ECM imaging could be a valuable clinical tool. Molecular imaging of ECM may help understand pathology, evaluate impact of novel therapy, and may eventually find a role in predicting the extent of ECM expansion and development of personalized treatment. In the current review, we provide an overview of ECM imaging including the assessment of ECM volume and molecular targeting of key players involved in ECM deposition and degradation. The targets comprise myofibroblasts, intracardiac renin-angiotensin axis, matrix metalloproteinases, and matricellular proteins. © 2014 American Heart Association, Inc.


Van Rijsingen I.A.W.,Heart Failure Research Center | Arbustini E.,Center for Inherited Cardiovascular Diseases | Elliott P.M.,Heart Hospital London | Mogensen J.,Aarhus University Hospital | And 17 more authors.
Journal of the American College of Cardiology | Year: 2012

Objectives: The purpose of this study was to determine risk factors that predict malignant ventricular arrhythmias (MVA) in Lamin A/C (LMNA) mutation carriers. Background: LMNA mutations cause a variety of clinical phenotypes, including dilated cardiomyopathy and conduction disease. Many LMNA mutation carriers have a poor prognosis, because of a high frequency of MVA and progression to end-stage heart failure. However, it is unclear how to identify mutation carriers that are at risk for MVA. Methods: In this multicenter cohort of 269 LMNA mutation carriers, we evaluated risk factors for MVA, defined as sudden cardiac death, resuscitation, and appropriate implantable cardioverter-defibrillator (ICD) treatment. Results: In a median follow-up period of 43 months (interquartile range: 17 to 101 months), 48 (18%) persons experienced a first episode of MVA: 11 persons received successful cardiopulmonary resuscitation, 25 received appropriate ICD treatment, and 12 persons died suddenly. Independent risk factors for MVA were nonsustained ventricular tachycardia, left ventricular ejection fraction <45% at the first clinical contact, male sex, and non-missense mutations (ins-del/truncating or mutations affecting splicing). MVA occurred only in persons with at least 2 of these risk factors. There was a cumulative risk for MVA per additional risk factor. Conclusions: Carriers of LMNA mutations with a high risk of MVA can be identified using these risk factors. This facilitates selection of LMNA mutation carriers who are most likely to benefit from an ICD. © 2012 American College of Cardiology Foundation.


Bollati M.,University of Milan | Barbiroli A.,University of Milan | Favalli V.,Center for Inherited Cardiovascular Diseases | Arbustini E.,Center for Inherited Cardiovascular Diseases | And 2 more authors.
Biochemical and Biophysical Research Communications | Year: 2012

Dilated cardiomyopathy (DCM) is a condition whereby the normal muscular function of the myocardium is altered by specific or multiple aetiologies. About 25-35% of DCM patients show familial forms of the disease, with most mutations affecting genes encoding cytoskeletal proteins. Most of the DCM-related mutations fall in the Lamin AC gene, in particular in the Coil2B domain of the encoded protein. In this context, we focussed our studies on the crystal structures of two lamin Coil2B domain mutants (R335W and E347K). Both R335 and E347 are higly conserved residues whose substitution has little effects on the Coil2B domain three-dimensional structure; we can thus hypothesize that the mutations may interfere with the binding of components within the nuclear lamina, or of nuclear factors, that have been proposed to interact/associate with lamin A/C. © 2012 Elsevier Inc.


Disertori M.,Healthcare Research and Innovation Program | Disertori M.,Santa Chiara Hospital | Quintarelli S.,Santa Chiara Hospital | Mazzola S.,Santa Chiara Hospital | And 4 more authors.
Europace | Year: 2013

Left ventricular ejection fraction (LVEF) ≤35% is a major determinant for implantable cardioverter-defibrillator (ICD) therapy for primary prevention of sudden death (SD) in patients with non-ischaemic dilated cardiomyopathy (DCM). However, as a risk marker for SD, low LVEF has limited sensibility and specificity. Selecting patients according to the current guidelines shows that most DCM patients do not actually benefit from ICD implantation and may suffer collateral effects and that many patients who are at risk of SD are not identified because a large proportion of SD patients exhibit only mildly depressed LVEF. Identifying patients who are at risk of SD on the sole basis of LVEF appears to be an over-simplification which does not maximize the benefit of ICD therapy. Owing to the complexity of the substrates underlying SD, multiple risk factors used in combination could probably predict the risk of SD better than any individual risk marker. Among non-invasive tests, microvolt T-wave alternans and cardiac magnetic resonance with late gadolinium enhancement may contribute to a better SD risk stratification by their high negative predictive value. Genetics may further contribute because approximately one-third of DCM patients have evidence of familial disease, and mutations in some known disease genes, including LMNA, have been associated with a high risk of SD. In this review, we critically analyse the current indications for ICD implantation and we explore existing knowledge about potentially predicting markers for selecting DCM patients who are at high and low risk of SD. © 2013 The Author.


Arbustini E.,Center for Inherited Cardiovascular Diseases | Narula N.,New York Medical College | Tavazzi L.,Maria Cecilia Hospital | Serio A.,Center for Inherited Cardiovascular Diseases | And 7 more authors.
Journal of the American College of Cardiology | Year: 2014

Most cardiomyopathies are familial diseases. Cascade family screening identifies asymptomatic patients and family members with early traits of disease. The inheritance is autosomal dominant in a majority of cases, and recessive, X-linked, or matrilinear in the remaining. For the last 50 years, cardiomyopathy classifications have been based on the morphofunctional phenotypes, allowing cardiologists to conveniently group them in broad descriptive categories. However, the phenotype may not always conform to the genetic characteristics, may not allow risk stratification, and may not provide pre-clinical diagnoses in the family members. Because genetic testing is now increasingly becoming a part of clinical work-up, and based on the genetic heterogeneity, numerous new names are being coined for the description of cardiomyopathies associated with mutations in different genes; a comprehensive nosology is needed that could inform the clinical phenotype and involvement of organs other than the heart, as well as the genotype and the mode of inheritance. The recently proposed MOGE(S) nosology system embodies all of these characteristics, and describes the morphofunctional phenotype (M), organ(s) involvement (O), genetic inheritance pattern (G), etiological annotation (E) including genetic defect or underlying disease/substrate, and the functional status (S) of the disease using both the American College of Cardiology/American Heart Association stage and New York Heart Association functional class. The proposed nomenclature is supported by a web-assisted application and assists in the description of cardiomyopathy in symptomatic or asymptomatic patients and family members in the context of genetic testing. It is expected that such a nomenclature would help group cardiomyopathies on their etiological basis, describe complex genetics, and create collaborative registries. © 2014 by the American College of Cardiology Foundation.


Yahagi K.,CVPath Institute Inc. | Davis H.R.,CVPath Institute Inc. | Arbustini E.,Center for Inherited Cardiovascular Diseases | Virmani R.,CVPath Institute Inc.
Atherosclerosis | Year: 2015

Cardiovascular disease (CVD) remains the most frequent cause of death in both men and women. Many studies on CVD have included mostly men, and the knowledge about coronary artery disease (CAD) in women has largely been extrapolated from studies primarily focused on men. The influence of various risk factors is different between men and women; untoward effects of smoking of CAD are greater in women than men. Furthermore, the effect of the menopause is important in women, with higher incidence of plaque erosion in young women versus greater incidence of plaque rupture in older women. This review focuses on differences in plaque morphology in men and women presenting with sudden coronary death and acute myocardial infarction. © 2015 Elsevier Ireland Ltd.


Disertori M.,Santa Chiara Hospital | Disertori M.,Healthcare Research and Innovation Program | Mase M.,University of Trento | Marini M.,Santa Chiara Hospital | And 6 more authors.
Journal of Cardiovascular Electrophysiology | Year: 2014

Evaluation of the Substrate in Genetic Atrial Arrhythmias. Introduction: Although atrial arrhythmiasmay have genetic causes, very few data are available on evaluation of the arrhythmic substrate in genetic atrial diseases in humans. In this study, we evaluate the nature and evolution of the atrial arrhythmic substrate in a genetic atrial cardiomyopathy.Methods and Results: Repeated electroanatomic mapping and tomographic evaluations were used to investigate the evolving arrhythmic substrate in 5 patients with isolated arrhythmogenic atrial cardiomyopathy, caused by Natriuretic Peptide Precursor A (NPPA) gene mutation. Atrial fibrosis was assessed using late gadolinium enhancement magnetic resonance imaging (LGE-MRI). The substrate of atrial tachycardia (AT) and atrial fibrillation (AF) was biatrial dilatation with patchy areas of low voltage and atrial wall scarring (in the right atrium: 68.5%±6.0% and 22.2%±10.2%, respectively). The evolution of the arrhythmic patterns to sinus node disease with atrial standstill (AS) was associated with giant atria with extensive low voltage and atrial scarring areas (in the right atrium: 99.5% ± 0.7% and 57.5% ± 33.2%, respectively). LGE-MRI-proven biatrial fibrosis (Utah stage IV) was associated with AS. Atrial conduction was slow and heterogeneous, with lines of conduction blocks. The progressive extension and spatial distribution of the scarring/fibrosis were strictly associated with the different types of arrhythmias.Conclusion: The evolution of the amount and distribution of atrial scarring/fibrosis constitutes the structural substrate for the different types of atrial arrhythmias in a pure genetic model of arrhythmogenic atrial cardiomyopathy.


Zaragoza M.V.,University of California at Irvine | Brandon M.C.,University of California at Irvine | Diegoli M.,University of California at Irvine | Arbustini E.,University of California at Irvine | And 2 more authors.
European Journal of Human Genetics | Year: 2011

Pathogenic mitochondrial DNA (mtDNA) mutations leading to mitochondrial dysfunction can cause cardiomyopathy and heart failure. Owing to a high mutation rate, mtDNA defects may occur at any nucleotide in its 16 569 bp sequence. Complete mtDNA sequencing may detect pathogenic mutations, which can be difficult to interpret because of normal ethnic/geographic-associated haplogroup variation. Our goal is to show how to identify candidate mtDNA mutations by sorting out polymorphisms using readily available online tools. The purpose of this approach is to help investigators in prioritizing mtDNA variants for functional analysis to establish pathogenicity. We analyzed complete mtDNA sequences from 29 Italian patients with mitochondrial cardiomyopathy or suspected disease. Using MITOMASTER and PhyloTree, we characterized 593 substitution variants by haplogroup and allele frequencies to identify all novel, non-haplogroup-associated variants. MITOMASTER permitted determination of each variant's location, amino acid change and evolutionary conservation. We found that 98% of variants were common or rare, haplogroup-associated variants, and thus unlikely to be primary cause in 80% of cases. Six variants were novel, non-haplogroup variants and thus possible contributors to disease etiology. Two with the greatest pathogenic potential were heteroplasmic, nonsynonymous variants: m.15132T>C in MT-CYB for a patient with hypertrophic dilated cardiomyopathy and m.6570GT in MT-CO1 for a patient with myopathy. In summary, we have used our automated information system, MITOMASTER, to make a preliminary distinction between normal mtDNA variation and pathogenic mutations in patient samples; this fast and easy approach allowed us to select the variants for traditional analysis to establish pathogenicity. © 2011 Macmillan Publishers Limited All rights reserved.


Borroni R.G.,Center for Inherited Cardiovascular Diseases
Giornale Italiano di Dermatologia e Venereologia | Year: 2014

Different responses, in terms both of efficacy and toxicity, are commonly observed for any drug administered to apparently homogeneous groups of patients. It is estimated that adverse drug reactions (ADRs) cause 3-6% of all hospitalizations, accounting for 5% to 9% of hospital admission costs. The skin is often involved in ADRs and although most cutaneous ADRs have a favorable course, they may present as severe adverse cutaneous drug reactions (SCARs), such as Stevens-Johnson syndrome, toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (also referred to as drug-induced hypersensitivity syndrome), and acute generalized exanthematous pustulosis. SCARs are associated with significant mortality and require prompt diagnosis and adequate treatment Pharmacogenetics studies individual variants in the DNA sequence associated with drug efficacy and toxicity, allowing prescription of a drug to patients expected to benefit from it, and excluding from treatment those who are at risk of developing ADRs. Pharmacogenetics already achieved several important results in the prevention of SCARs, and pharmacogenetic testing is now recommended by regulatory agencies before administration of abacavir and carbamazepine, leading to reduced incidence of SCARs. In this review, the pharmacogenetic associations of SCARs that have been validated in independent, case-control association studies will be presented. By familiarizing with principles of pharmacogenetics, dermatologists should be able to correlate specific cutaneous ADR phenotypes to the underlying genotype, thus contributing to better drug safety and facilitating drug discovery, development and approval.

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