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Featured researches published by Marco Merlo.

The New England Journal of Medicine | 2012

Truncations of Titin Causing Dilated Cardiomyopathy

Daniel S. Herman; Lien Lam; Libin Wang; Polakit Teekakirikul; Danos C. Christodoulou; Lauren Conner; Steven R. DePalma; Barbara McDonough; Elizabeth Sparks; Debbie Lin Teodorescu; Allison L. Cirino; Nicholas R. Banner; Dudley J. Pennell; Sharon Graw; Marco Merlo; Gianfranco Sinagra; J. Martijn Bos; Michael J. Ackerman; Richard N. Mitchell; Charles E. Murry; Neal K. Lakdawala; Carolyn Y. Ho; Stuart A. Cook; Luisa Mestroni; Christine E. Seidman

BACKGROUND Dilated cardiomyopathy and hypertrophic cardiomyopathy arise from mutations in many genes. TTN, the gene encoding the sarcomere protein titin, has been insufficiently analyzed for cardiomyopathy mutations because of its enormous size. METHODS We analyzed TTN in 312 subjects with dilated cardiomyopathy, 231 subjects with hypertrophic cardiomyopathy, and 249 controls by using next-generation or dideoxy sequencing. We evaluated deleterious variants for cosegregation in families and assessed clinical characteristics. RESULTS We identified 72 unique mutations (25 nonsense, 23 frameshift, 23 splicing, and 1 large tandem insertion) that altered full-length titin. Among subjects studied by means of next-generation sequencing, the frequency of TTN mutations was significantly higher among subjects with dilated cardiomyopathy (54 of 203 [27%]) than among subjects with hypertrophic cardiomyopathy (3 of 231 [1%], P=3×10(-16)) or controls (7 of 249 [3%], P=9×10(-14)). TTN mutations cosegregated with dilated cardiomyopathy in families (combined lod score, 11.1) with high (>95%) observed penetrance after the age of 40 years. Mutations associated with dilated cardiomyopathy were overrepresented in the titin A-band but were absent from the Z-disk and M-band regions of titin (P≤0.01 for all comparisons). Overall, the rates of cardiac outcomes were similar in subjects with and those without TTN mutations, but adverse events occurred earlier in male mutation carriers than in female carriers (P=4×10(-5)). CONCLUSIONS TTN truncating mutations are a common cause of dilated cardiomyopathy, occurring in approximately 25% of familial cases of idiopathic dilated cardiomyopathy and in 18% of sporadic cases. Incorporation of sequencing approaches that detect TTN truncations into genetic testing for dilated cardiomyopathy should substantially increase test sensitivity, thereby allowing earlier diagnosis and therapeutic intervention for many patients with dilated cardiomyopathy. Defining the functional effects of TTN truncating mutations should improve our understanding of the pathophysiology of dilated cardiomyopathy. (Funded by the Howard Hughes Medical Institute and others.).

Journal of the American College of Cardiology | 2011

Prevalence and prognostic significance of left ventricular reverse remodeling in dilated cardiomyopathy receiving tailored medical treatment.

Marco Merlo; Stylianos A. Pyxaras; Bruno Pinamonti; Andrea Di Lenarda; Gianfranco Sinagra

OBJECTIVES The purpose of this study was to determine the prevalence and prognostic role of left ventricular reverse remodeling (LVRR) in idiopathic dilated cardiomyopathy (IDCM). BACKGROUND Tailored medical therapy can lead to LVRR in IDCM. The prevalence and prognostic impact of LVRR remain unclear. METHODS We consecutively enrolled 361 IDCM patients. LVRR was defined as a left ventricular ejection fraction increase of ≥10 U or a left ventricular ejection fraction of ≥50% and a decrease in indexed left ventricular end-diastolic diameter of ≥10% or indexed left ventricular end-diastolic diameter of ≥33 mm/m(2) at 24 months (range 9 to 36 months). Follow-up echocardiographic data were available for 242 patients (67%), 34 (9%) died/underwent heart transplantation (HTx) before re-evaluation, and 85 (24%) did not have a complete re-evaluation. After re-evaluation, the surviving patients were followed for 110 ± 53 months; there were 55 deaths (23%) and 32 HTx (13%). RESULTS LVRR was found in 89 of 242 patients (37%). Baseline predictors of LVRR were higher systolic blood pressure (p = 0.047) and the absence of left bundle branch block (p = 0.009). When added to a prognostic baseline model including male sex, heart failure duration, New York Heart Association functional classes III to IV, LVEF, significant mitral regurgitation, and beta-blockers, LVRR, New York Heart Association functional classes III to IV, and significant mitral regurgitation after 24 months emerged as independent predictors of death/HTx and heart failure death/HTx. The model including follow-up variables showed additional prognostic power with respect to baseline model (for death/HTx, area under the curve: 0.80 vs. 0.70, respectively, p = 0.004). Furthermore, only LVRR was significantly associated with sudden death/major ventricular arrhythmia in the long-term. CONCLUSIONS LVRR characterized approximately one-third of IDCM patients surviving 2 years while receiving optimal medical therapy and allowed a more accurate long-term prognostic stratification of the disease.

European Journal of Heart Failure | 2014

Long-term prognostic impact of therapeutic strategies in patients with idiopathic dilated cardiomyopathy: changing mortality over the last 30 years

Marco Merlo; Alberto Pivetta; Bruno Pinamonti; Davide Stolfo; Massimo Zecchin; Andrea Di Lenarda; Gianfranco Sinagra

ACE‐inhibitors, β‐blockers, implantable cardioverter–defibrillator (ICD) and cardiac resynchronization therapy (CRT) improved prognosis of heart failure. We sought to analyse the long‐term prognostic impact of evidence‐based integrated therapeutic strategies in patients with idiopathic dilated cardiomyopathy (IDCM).

Journal of the American College of Cardiology | 2016

Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies

Martin Ortiz-Genga; Sofía Cuenca; Matteo Dal Ferro; Esther Zorio; Ricardo Salgado-Aranda; Vicente Climent; Laura Padrón-Barthe; Iria Duro-Aguado; Juan Jiménez-Jáimez; Víctor M. Hidalgo-Olivares; Enrique García-Campo; Chiara Lanzillo; M. Paz Suárez-Mier; Hagith Yonath; Sonia Marcos-Alonso; Juan Pablo Ochoa; José L. Santomé; Diego García-Giustiniani; Jorge Rodriguez-Garrido; Fernando Dominguez; Marco Merlo; Julián Palomino; María L. Peña; Juan P. Trujillo; Alicia Martín-Vila; Davide Stolfo; Pilar Molina; Enrique Lara-Pezzi; Francisco E. Calvo-Iglesias; Eyal Nof

BACKGROUND Filamin C (encoded by the FLNC gene) is essential for sarcomere attachment to the plasmatic membrane. FLNC mutations have been associated with myofibrillar myopathies, and cardiac involvement has been reported in some carriers. Accordingly, since 2012, the authors have included FLNC in the genetic screening of patients with inherited cardiomyopathies and sudden death. OBJECTIVES The aim of this study was to demonstrate the association between truncating mutations in FLNC and the development of high-risk dilated and arrhythmogenic cardiomyopathies. METHODS FLNC was studied using next-generation sequencing in 2,877 patients with inherited cardiovascular diseases. A characteristic phenotype was identified in probands with truncating mutations in FLNC. Clinical and genetic evaluation of 28 affected families was performed. Localization of filamin C in cardiac tissue was analyzed in patients with truncating FLNC mutations using immunohistochemistry. RESULTS Twenty-three truncating mutations were identified in 28 probands previously diagnosed with dilated, arrhythmogenic, or restrictive cardiomyopathies. Truncating FLNC mutations were absent in patients with other phenotypes, including 1,078 patients with hypertrophic cardiomyopathy. Fifty-four mutation carriers were identified among 121 screened relatives. The phenotype consisted of left ventricular dilation (68%), systolic dysfunction (46%), and myocardial fibrosis (67%); inferolateral negative T waves and low QRS voltages on electrocardiography (33%); ventricular arrhythmias (82%); and frequent sudden cardiac death (40 cases in 21 of 28 families). Clinical skeletal myopathy was not observed. Penetrance was >97% in carriers older than 40 years. Truncating mutations in FLNC cosegregated with this phenotype with a dominant inheritance pattern (combined logarithm of the odds score: 9.5). Immunohistochemical staining of myocardial tissue showed no abnormal filamin C aggregates in patients with truncating FLNC mutations. CONCLUSIONS Truncating mutations in FLNC caused an overlapping phenotype of dilated and left-dominant arrhythmogenic cardiomyopathies complicated by frequent premature sudden death. Prompt implantation of a cardiac defibrillator should be considered in affected patients harboring truncating mutations in FLNC.

Circulation | 2013

Long-Term Evolution and Prognostic Stratification of Biopsy-Proven Active Myocarditis

Marco Anzini; Marco Merlo; G. Sabbadini; Gherardo Finocchiaro; Bruno Pinamonti; Alessandro Salvi; Andrea Perkan; Andrea Di Lenarda; Rossana Bussani; Jozef Bartunek; Gianfranco Sinagra

Background— Active myocarditis is characterized by large heterogeneity of clinical presentation and evolution. This study describes the characteristics and the long-term evolution of a large sample of patients with biopsy-proven active myocarditis, looking for accessible and valid early predictors of long-term prognosis. Methods and Results— From 1981 to 2009, 82 patients with biopsy-proven active myocarditis were consecutively enrolled and followed-up for 147±107 months. All patients underwent clinical and echocardiographic evaluation at baseline and at 6 months. At this time, improvement/normality of left ventricular ejection fraction (LVEF), defined as a LVEF increase > 20 percentage points or presence of LVEF≥50%, was assessed. At baseline, left ventricular dysfunction (LVEF<50%) and left atrium enlargement were independently associated with long-term heart transplantation–free survival, regardless of the clinical pattern of disease onset. At 6 months, improvement/normality of LVEF was observed in 53% of patients. Persistence of New York Heart Association III to IV classes, left atrium enlargement, and improvement/normality of LVEF at 6 months emerged as independent predictors of long-term outcome. Notably, the short-term reevaluation showed a significant incremental prognostic value in comparison with the baseline evaluation (baseline model versus 6 months model: area under the curve 0.79 versus 0.90, P=0.03). Conclusions— Baseline left ventricular function is a marker for prognosis regardless of the clinical pattern of disease onset, and its reassessment at 6 months appears useful for assessing longer-term outcome.

Journal of Cardiovascular Medicine | 2009

Natural history of dilated cardiomyopathy: from asymptomatic left ventricular dysfunction to heart failure--a subgroup analysis from the Trieste Cardiomyopathy Registry.

Aneta Aleksova; G. Sabbadini; Marco Merlo; Bruno Pinamonti; Massimo Zecchin; Rossana Bussani; Furio Silvestri; Anna Maria Iorio; Davide Stolfo; Matteo Dal Ferro; Andreea M. Dragos; Gennaro Meringolo; Stelios Pyxaras; Francesco Lo Giudice; Andrea Perkan; Andrea Di Lenarda; Gianfranco Sinagra

Background Few data are available in the literature regarding the characteristics and prognosis of asymptomatic patients with idiopathic dilated cardiomyopathy (DCM). Aim To determine the frequency with which patients affected by DCM are diagnosed in the asymptomatic state as well as to evaluate the natural history of such patients and the factors influencing their outcome. Moreover, we sought to compare the outcome of asymptomatic patients with that of patients with signs of overt heart failure at the time of first evaluation. Methods and results We analyzed the data of 747 patients with DCM enlisted in the Heart Muscle Disease Registry of Trieste from 1978 to 2007. We divided our population into four groups; group 1 comprised 118 asymptomatic [New York Heart Association (NYHA) I] patients without a history of congestive symptoms (16%), group 2 comprised 102 asymptomatic (NYHA I) patients (14%) with a positive anamnesis for heart failure stabilized in medical therapy, group 3 comprised 327 patients (44%) with signs of mild heart failure (NYHA II) and group 4 comprised 200 patients (26%) in NYHA III–IV. During the follow-up of 112 ± 63 months, 46 (21%) of 220 asymptomatic patients with DCM died or underwent heart transplantation. By Cox proportional model, left ventricular ejection fraction of 30% or less was a unique independent predictor either for death/heart transplantation (hazard ratio 3.15, 95% confidence interval 1.5–6.7, P = 0.003) or for sudden death/major ventricular arrhythmias (hazard ratio 3.9, 95% confidence interval 1.7–9.3, P = 0.002). Patients from group 1 had a trend for a better outcome with respect to those from group 2 (P = 0.06). In comparison with the asymptomatic patients, those with signs of overt heart failure at baseline had a worse prognosis. Conclusion The proportion of asymptomatic patients with DCM at the moment of first evaluation at our center is significant (30%). Among them, those without a previous history of heart failure had a less advanced disease and a trend for a better long-term outcome on optimal medical treatment. Therefore, early diagnosis may offer better long-term quality of life and even better survival. Further studies on larger populations are indicated.

Journal of the American Heart Association | 2015

Persistent Recovery of Normal Left Ventricular Function and Dimension in Idiopathic Dilated Cardiomyopathy During Long‐Term Follow‐up: Does Real Healing Exist?

Marco Merlo; Davide Stolfo; Marco Anzini; Francesco Negri; Bruno Pinamonti; Federica Ramani; Andrea Di Lenarda; Gianfranco Sinagra

Background An important number of patients with idiopathic dilated cardiomyopathy have dramatically improved left ventricular function with optimal treatment; however, little is known about the evolution and long‐term outcome of this subgroup, which shows apparent healing. This study assesses whether real healing actually exists in dilated cardiomyopathy . Methods and Results Persistent apparent healing was evaluated among 408 patients with dilated cardiomyopathy receiving tailored medical treatment and followed over the very long‐term. Persistent apparent healing was defined as left ventricular ejection fraction ≥50% and indexed left ventricular end‐diastolic diameter ≤33 mm/m2 at both mid‐term (19±4 months) and long‐term (103±9 months) follow‐up. At mid‐term, 63 of 408 patients (15%) were apparently healed; 38 (60%; 9% of the whole population) showed persistent apparent healing at long‐term evaluation. No predictors of persistent apparent healing were found. Patients with persistent apparent healing showed better heart transplant–free survival at very long‐term follow‐up (95% versus 71%; P=0.014) compared with nonpersistently normalized patients. Nevertheless, in the very long term, 37% of this subgroup experienced deterioration of left ventricular systolic function, and 5% died or had heart transplantation. Conclusions Persistent long‐term apparent healing was evident in a remarkable proportion of dilated cardiomyopathy patients receiving optimal medical treatment and was associated with stable normalization of main clinical and laboratory features. This condition can be characterized by a decline of left ventricular function over the very long term, highlighting the relevance of serial and individualized follow‐up in all patients with dilated cardiomyopathy, especially considering the absence of predictors for long‐term apparent healing.

European Journal of Heart Failure | 2010

Prognostic impact of familial screening in dilated cardiomyopathy.

M. Moretti; Marco Merlo; Andrea Di Lenarda; Francesca Brun; Bruno Pinamonti; Dario Gregori; Luisa Mestroni; Gianfranco Sinagra

Familial screening of patients with dilated cardiomyopathy (DCM) allows an early diagnosis of the disease in family members. It is unclear if familial forms (FDC) have a different long‐term outcome compared with sporadic DCM. Our aim was to compare the long‐term prognosis of FDC and sporadic forms in order to assess the role of familial screening.

Journal of Cardiovascular Medicine | 2013

Clinical presentation and long-term follow-up of perimyocarditis.

Alessandra Buiatti; Marco Merlo; Bruno Pinamonti; Marzia De Biasio; Rossana Bussani; Gianfranco Sinagra

Background The natural history of perimyocarditis (PMY) is not yet completely known. We aimed to analyse the clinical laboratory data of PMY at diagnosis and during follow-up, in order to assess the natural history and prognostic stratification of the disease (including different aetiology). Methods We enrolled 62 consecutive patients (men 79%, aged 38 ± 18 years) with PMY (84% idiopathic, 8% autoimmune, 8% infective) from August 2002 to July 2010. The diagnosis has been made according to clinical and laboratory data (significant increase of troponin I in all patients). After at least 1 year (mean follow-up: 1635 ± 298 days), 59 patients (95%) had available data. Results Chest pain was present in 59 patients (95%), flu-like syndrome in 36 (58%) and pericardial rubs in 15 (24%). None of the patients showed heart failure at presentation. At admission, eight patients (13%) presented mild–moderate left ventricular systolic dysfunction, 13 (22%) showed wall motion abnormalities, and 10 (17%) showed mild pericardial effusion. At 1 year no patients died, developed heart failure or showed abnormal echocardiogram. NSAIDs were the first choice therapy in 61 (98%) patients with clinical resolution in 58 (95%) of them. Seven patients (12%) experienced intermittent recurrences without development of constrictive pericarditis or heart failure. Conclusion This study underlines the benign mid- to long-term outcome of PMY regardless of clinical laboratory characteristics at presentation, different aetiology and possibility of relapses; minimizing the role of endomyocardial biopsy in these specific patients.

Pacing and Clinical Electrophysiology | 2008

Are Nonsustained Ventricular Tachycardias Predictive of Major Arrhythmias in Patients with Dilated Cardiomyopathy on Optimal Medical Treatment

Massimo Zecchin; Andrea Di Lenarda; Dario Gregori; Marco Merlo; Alberto Pivetta; Giancarlo Vitrella; G. Sabbadini; Luisa Mestroni; Gianfranco Sinagra

Background: To evaluate the role of nonsustained ventricular tachycardias (NSVT) for the prediction of major ventricular arrhythmias (MVA) in patients with idiopathic dilated cardiomyopathy (DCM) after optimization of medical treatment.


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Luisa Mestroni

University of Colorado Denver

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