Marta Gigli

A Review of the Giant Protein Titin in Clinical Molecular Diagnostics of Cardiomyopathies

Titin (TTN) is known as the largest sarcomeric protein that resides within the heart muscle. Due to alternative splicing of TTN, the heart expresses two major isoforms (N2B and N2BA) that incorporate four distinct regions termed the Z-line, I-band, A-band, and M-line. Next-generation sequencing allows a large number of genes to be sequenced simultaneously and provides the opportunity to easily analyze giant genes such as TTN. Mutations in the TTN gene can cause cardiomyopathies, in particular dilated cardiomyopathy (DCM). DCM is the most common form of cardiomyopathy, and it is characterized by systolic dysfunction and dilation of the left ventricle. TTN truncating variants have been described as the most common cause of DCM, while the real impact of TTN missense variants in the pathogenesis of DCM is still unclear. In a recent population screening study, rare missense variants potentially pathogenic based on bioinformatic filtering represented only 12.6% of the several hundred rare TTN missense variants found, suggesting that missense variants are very common in TTN and are frequently benign. The aim of this review is to understand the clinical role of TTN mutations in DCM and in other cardiomyopathies. Whereas TTN truncations are common in DCM, there is evidence that TTN truncations are rare in the hypertrophic cardiomyopathy (HCM) phenotype. Furthermore, TTN mutations can also cause arrhythmogenic right ventricular cardiomyopathy (ARVC) with distinct clinical features and outcomes. Finally, the identification of a rare TTN missense variant cosegregating with the restrictive cardiomyopathy (RCM) phenotype suggests that TTN is a novel disease-causing gene in this disease. Clinical diagnostic testing is currently able to analyze over 100 cardiomyopathy genes, including TTN; however, the size and presence of extensive genetic variation in TTN presents clinical challenges in determining significant disease-causing mutations. This review discusses the current knowledge of TTN genetic variations in cardiomyopathies and the impact of the diagnosis of TTN pathogenic mutations in the clinical setting.

Natural History of Dilated Cardiomyopathy in Children

Background The long‐term progression of idiopathic dilated cardiomyopathy (DCM) in pediatric patients compared with adult patients has not been previously characterized. In this study, we compared outcome and long‐term progression of pediatric and adult DCM populations. Methods and Results Between 1988 and 2014, 927 DCM patients were consecutively enrolled. The pediatric population (aged <18 years at enrollment) included 47 participants (5.1%). At presentation, the pediatric population compared with adult patients had a significantly increased occurrence of familial forms (P=0.03), shorter duration of heart failure (P=0.04), lower systolic blood pressure (P=0.01), decreased presence of left bundle‐branch block (P=0.001), and increased left ventricular ejection fraction (P=0.03). Despite these baseline differences, long‐term longitudinal trends of New York Heart Association class III to IV, left ventricular dimensions, left ventricular ejection fraction, and restrictive filling pattern were similar between the 2 populations. Regarding survival analysis, because of the size difference between the 2 populations, we compared the pediatric population with a sample of adult patients randomly matched using the above‐mentioned baseline differences in a 3:1 ratio (141 adult versus 47 pediatric patients). During a median follow‐up of 110 months, survival free from heart transplantation was significantly lower among pediatric patients compared with adults (P<0.001). Furthermore, pediatric age (ie, <18 years) was found to be associated with an increasing risk of both death from pump failure and life‐threatening arrhythmias. Conclusions Despite the pediatric DCM population having higher baseline left ventricular ejection fraction and similar long‐term echocardiographic progression compared with the adult DCM population, the pediatric DCM patients had worse cardiovascular prognosis.

Obscurin Variants in Patients With Left Ventricular Noncompaction

Left ventricular noncompaction (LVNC) is a rare type of cardiomyopathy, occurring less frequently than hypertrophic cardiomyopathy (HCM) and dilated CM (DCM). In our patient population, we identified a possible association between LVNC and variants in the obscurin ( OBSCN ) gene. Obscurins are giant

Association between mutation status and left ventricular reverse remodelling in dilated cardiomyopathy

Objective To explore the genetic landscape of a well selected dilated cardiomyopathy (DCM) cohort, assessing the possible relation between different genotypes and left ventricular reverse remodelling (LVRR). Methods A cohort of 152 patients with DCM from the Heart Muscle Disease Registry of Trieste has been studied by next-generation sequencing (NGS). Patients were grouped into different ‘gene-clusters’ with functionally homogeneous genetic backgrounds. LVRR was defined by left ventricular ejection fraction normalisation or increase ≥10% associated with normalisation in indexed left ventricular end-diastolic diameter or relative decrease ≥10% at 24 months follow-up. Results A pathogenic disease-related gene variant was identified in 57% of patients: 28 (18%) TTN; 7 (5%) LMNA; 16 (11%) structural cytoskeleton Z-disk genes; 9 (6%) desmosomal genes; 18 (12%) motor sarcomeric genes and 9 (6%) other genes. Baseline clinical features were similar throughout the different genotypes. A significant relationship was found between gene cluster subgroups and LVRR, with a lower rate of LVRR in structural cytoskeleton Z-disk gene mutation carriers (1/16 patients, 6%, p<0.05u2009vs the other subgroups). Of note, structural cytoskeleton Z-disk gene rare variants were independently and inversely associated with LVRR when adjusted for clinical predictors of LVRR (OR 0.065; 95% CI 0.008 to 0.535, p=0.011). Conclusions NGS confirmed a high genetic diagnostic yield in DCM. A specific ‘gene-clusters’ classification based on functional similarities in different genes might be helpful in the clinical management of genetically determined DCM. In this study, structural cytoskeleton Z-disk gene rare variants were independently associated with a lower rate of LVRR at follow-up.

Early Arrhythmic Events in Idiopathic Dilated Cardiomyopathy

OBJECTIVESnThe study sought to provide an insight into the prevalence, characterization and possible reliable indicators of early sudden cardiac death/malignant ventricular arrhythmias (SCD/MVAs) in a large cohort of dilated cardiomyopathy (DCM).nnnBACKGROUNDnDCM generally affects young individuals and is characterized by an unpredictable prognosis with a non-negligible risk of SCD/MVAs, particularly in early stages of disease.nnnMETHODSnFrom 1988 to 2014, 952 patients with DCM were consecutively included in the Heart Muscle Disease Registry of Trieste.nnnRESULTSnGlobally, 20 patients (2.1% of the overall population) experienced SCD/MVAs within the first 6 months after enrollment (primary endpoint). At baseline they showed a worse functional class (New York Heart Association functional class III to IV 42% vs. 22%, pxa0= 0.038), a longer QRS complex duration (127 ± 41 ms vs. 108 ± 33 ms; pxa0= 0.013) andxa0axa0larger indexed left ventricular end-systolic volume (LVESVI) (82 ± 49 ml/m2 vs. 67 ± 34 ml/m2; pxa0= 0.049), as compared to patients without early SCD/MVAs. Beta-blockers were less tolerated (59% vs. 83% in patients with no early SCD/MVAs; pxa0= 0.008), mostly due to hemodynamic intolerance. At multivariate analysis, LVESVI (odds ratio [OR]: 1.012; 95% confidence interval [CI]: 1.000 to 1.024; pxa0= 0.043) and QRS complex duration (OR: 1.017; 95% CI: 1.003 to 1.030; pxa0= 0.015) were independently associated with the primary endpoint, whereas beta-blockers demonstrated a protective effect (OR: 0.169, CI: 0.048 to 0.593; pxa0= 0.006).nnnCONCLUSIONSnPatients with DCM present a significant risk of major arrhythmic events in the first phase of the disease. Baseline LVESVI, QRS duration, and intolerance to beta-blocker therapy might be useful tools in the arrhythmic early risk assessment.

[Dilated cardiomyopathy: a dynamic disease - clinical course, reverse remodeling and prognostic stratification].

Dilated cardiomyopathy (DCM) is a relatively rare primary heart muscle disease with genetic or post-inflammatory etiology. In the last decade, the incidence and prevalence of the disease have significantly increased as a consequence of an earlier diagnosis supported by extensive familial screening programs and by the improvement in diagnostic techniques. Moreover, current therapeutic strategies have deeply modified the prognosis of DCM with a dramatic reduction in mortality. A significant number of patients with DCM present an impressive response to pharmacological and non-pharmacological therapy in terms of left ventricular reverse remodeling (reduction in ventricular size with improvement of systolic function), which confers a more favorable prognosis in the long term. However, the identification of patients with an increased likelihood of improvement after therapeutic optimization remains a challenging issue; in particular the assessment of arrhythmic risk carries important implications. Finally, the long-term follow-up of patients showing a significant left ventricular functional recovery under optimal treatment is still poorly known. Hence, the aim of the present review is to provide an insight into the clinical evolution/long-term follow-up of DCM, which should be actually considered a dynamic process rather than a static and chronic disease. Left ventricular reverse remodeling should be considered a key therapeutic goal, mostly associated with a long-standing recovery, but cannot be considered the expression of permanent healing, confirming the need for a systematic and careful follow-up over time in this setting.

Usefulness of Addition of Magnetic Resonance Imaging to Echocardiographic Imaging to Predict Left Ventricular Reverse Remodeling in Patients With Nonischemic Cardiomyopathy

Defining short-term prognosis in nonischemic cardiomyopathy (NICM) is challenging in clinical practice. Although left ventricular reverse remodeling (LVRR) is a key prognostic marker in NICM there are few parameters able to predict it. We investigated whether a complete structural and functional cardiac magnetic resonance imaging (cMRI) evaluation was incremental to the classic clinical-echocardiographic approach in predicting LVRR in a large cohort of NICM patients receiving evidence-based treatment. Patients with a recent diagnosis of NICM (<3 months) who underwent complete clinical, echocardiographic and cMRI assessment were consecutively enrolled from 2008 to 2016. LVRR was defined as an increase in ≥10 points or normalization of left ventricular ejection fraction, associated with a ≥10% reduction or normalization of left ventricular end-diastolic diameter at midterm (median time 20 months) echocardiographic follow-up. Among 80 NICM patients included in the study, LVRR was observed in 43 (54%). At multivariate analysis, the clinical-echocardiographic evaluation failed to identify independent predictors of LVRR. However, absence of late gadolinium enhancement (odds ratio [OR] 9.07; confidence interval [CI] 2.7 to 13.1; p value 0.0003), left ventricular mass (OR 1.018; CI 1.001 to 1.036; p value 0.045) and peak circumferential strain (OR 1.213; CI 1.011 to 1.470; p value 0.049) assessed by cMRI were independently associated with LVRR. A model for LVRR prediction based on cMRI and clinical-echocardiographic parameters performed significantly better than the clinical-echocardiographic model alone (area under curve 0.84 vs 0.72; p value 0.023). In conclusion, an integrated imaging approach with the addition of a structural and functional cMRI study to the standard-of-care evaluation improves the prediction of LVRR in a large cohort of patients with recently diagnosed NICM receiving evidence-based treatment.

Arrhythmic Risk Stratification in Patients with Idiopathic Dilated Cardiomyopathy.

Arrhythmic risk stratification in idiopathic dilated cardiomyopathy (IDC) remains a major concern. As the ventricles remodel in time, risk factors for arrhythmic death may change. A cohort of 710 patients with idiopathic dilated cardiomyopathy, without previous ventricular arrhythmias, was retrospectively studied to understand how risks vary in time. The primary end point was a composite of sudden cardiac death, ventricular fibrillation, sustained ventricular tachycardia, and appropriate implantable cardioverter-defibrillator interventions. The prediction of the arrhythmic outcome was assessed dynamically through landmark analysis. Patients were assessed at baseline, short term (12 months, interquartile range 6 to 18), and long-term (72 months, interquartile range 60 to 84). The strongest risk predictors at each evaluation were combined in 3 multivariate models. During a median follow-up of 102 months, 80 patients (11%) experienced the primary end point. At baseline, QRS duration (pu2009=u20090.008), disease duration (pu2009<0.001), and mitral regurgitation (pu2009=u20090.010) were significantly associated with the primary end point. The 12 months landmark model included disease duration (pu2009=u20090.049), syncope (pu2009=u20090.005), New York Heart Association classes III and IV (pu2009=u20090.02), and indexed left ventricular end-diastolic volume (pu2009=u20090.001). Finally, the 72 months landmark model combined the indexed left ventricular end-diastolic volume (pu2009=u20090.048), the left ventricular ejection fraction (pu2009=u20090.008), and the left atrial area (pu2009=u20090.001). All the 3 models provided a satisfactory accuracy (area under the curve ranging from 0.76 to 0.82, pu2009<0.001). With an implantable cardioverter-defibrillator, the natural course of the disease influences the effect of arrhythmic risk factors overtime. Different predictors should be considered for the risk stratification according to the timing of assessment. Impaired left ventricular ejection fraction was significantly associated with major arrhythmias only in the long term.