[Show abstract][Hide abstract] ABSTRACT: Dilated Cardiomyopathy (DCM) is a primary heart muscle disease characterized by a progressive dilation and dysfunction of either the left or both ventricles. The management of DCM is currently challenging for clinicians. The persistent lack of knowledge about the etiology and pathophysiology of this disease continues to determine important fields of uncertainty in managing this condition. Molecular cardiology and genetics currently represents the most crucial horizon of increasing knowledge. Understanding the mechanisms underlying the disease allow clinicians to treat this disease more effectively and to further improve outcomes of DCM patients through advancements in etiologic characterization, prognostic stratification and individualized therapy. Left ventricular reverse remodeling predicts a lower rate of major cardiac adverse events independently from other factors. Optimized medical treatment and device implantation are pivotal in inducing left ventricular reverse remodeling. Newly identified targets, such as angiotensin-neprilysin inhibition, phosphodiesterase inhibition and calcium sensitizing are important in improving prognosis in patients affected by DCM.
Expert Review of Cardiovascular Therapy 11/2015; DOI:10.1586/14779072.2016.1125292
[Show abstract][Hide abstract] ABSTRACT: Background:
The titin gene (TTN) encodes the largest human protein, which plays a central role in sarcomere organization and passive myocyte stiffness. TTN truncating mutations cause dilated cardiomyopathy (DCM); however, the role of TTN missense variants in DCM has been difficult to elucidate because of the presence of background TTN variation.
Methods and results:
A cohort of 147 DCM index subjects underwent DNA sequencing for 313 TTN exons covering the N2B and N2BA cardiac isoforms of TTN. Of the 348 missense variants, we identified 44 "severe" rare variants by using a bioinformatic filtering process in 37 probands. Of these, 5 probands were double heterozygotes (additional variant in another DCM gene) and 7 were compound heterozygotes (2 TTN "severe" variants). Segregation analysis allowed the classification of the "severe" variants into 5 "likely" (cosegregating), 5 "unlikely" (noncosegregating), and 34 "possibly" (where family structure precluded segregation analysis) disease-causing variants. Patients with DCM carrying "likely" or "possibly" pathogenic TTN "severe" variants did not show a different outcome compared with "unlikely" and noncarriers of a "severe" TTN variant. However, the "likely" and "possibly" disease-causing variants were overrepresented in the C-zone of the A-band region of the sarcomere.
TTN missense variants are common and present a challenge for bioinformatic classification, especially when informative families are not available. Although DCM patients carrying bioinformatically "severe" TTN variants do not appear to have a worse clinical course than noncarriers, the nonrandom distribution of "likely" and "possibly" disease-causing variants suggests a potential biological role for some TTN missense variants.
Journal of the American Heart Association 11/2015; 4(11):e002645-e002645. DOI:10.1161/JAHA.115.002645 · 4.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Patients with dilated cardiomyopathy (DCM) may present with ventricular arrhythmias early in the disease course, unrelated to the severity of left ventricular dysfunction. These patients may be classified as having an arrhythmogenic DCM (AR-DCM). We investigated the phenotype and natural history of patients with AR-DCM.
Methods and results:
Two hundred eighty-five patients with a recent diagnosis of DCM (median duration of the disease 1 month, range 0 to 7 months) and who had Holter monitoring at baseline were comprehensively evaluated and followed for 107 months (range 29 to 170 months). AR-DCM was defined by the presence of ≥1 of the following: unexplained syncope, rapid nonsustained ventricular tachycardia (≥5 beats, ≥150 bpm), ≥1000 premature ventricular contractions/24 hours, and ≥50 ventricular couplets/24 hours, in the absence of overt heart failure. The primary end points were sudden cardiac death (SCD), sustained ventricular tachycardia (SVT), or ventricular fibrillation (VF). The secondary end points were death from congestive heart failure or heart transplantation. Of the 285 patients, 109 (38.2%) met criteria for AR-DCM phenotype. AR-DCM subjects had a higher incidence of SCD/SVT/VF compared with non-AR-DCM patients (30.3% vs 17.6%, P=0.022), with no difference in the secondary end points. A family history of SCD/SVT/VF and the AR-DCM phenotype were statistically significant and cumulative predictors of SCD/SVT/VF.
One-third of DCM patients may have an arrhythmogenic phenotype associated with increased risk of arrhythmias during follow-up. A family history of ventricular arrhythmias in DCM predicts a poor prognosis and increased risk of SCD.
Journal of the American Heart Association 10/2015; 4(10). DOI:10.1161/JAHA.115.002149 · 4.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although the cause of myocarditis often remains unknown, a large variety of infections, systemic diseases, drugs and toxins have been associated with this disease. In most cases, myocarditis is induced by cardiotropic viruses and often evolves silently without discernible prognostic impact. However, in some patients, the lack of complete viral clearance and/or the association of a heart-specific inflammation can cause persistent myocyte damage, ultimately leading to progressive myocardial dilation and dysfunction or life-threatening arrhythmias. Spontaneous improvement of left ventricular function is described for 40-50% of patients. The diagnostic work-up and prognostic assessment of myocarditis should be multiparametric and all available resources should be employed, i.e. biomarkers of myocardial damage and ventricular dysfunction (troponin I, brain natriuretic peptide), advanced echocardiography, cardiac magnetic resonance and, in selected cases, endomyocardial biopsy (with histopathologic, immunohistochemical and virological analyses). These are the necessary prerequisites for an evidence-based and personalized management of myocarditis, which may require in some cases specific immunoactive treatments. However, controversial issues regarding diagnosis (such as role and timing of cardiac magnetic resonance imaging, role of endomyocardial biopsy) and therapy of myocarditis still remain unsolved. The purpose of this review is to analyze these crucial features in order to provide useful instructions for clinical practice.
Giornale italiano di cardiologia (2006) 10/2015; 14(7):504-16. DOI:10.1714/1308.14459
[Show abstract][Hide abstract] ABSTRACT: Functional mitral regurgitation (FMR) is associated with reduced survival in dilated cardiomyopathy (DCM). Cardiac resynchronization therapy (CRT) can improve FMR. We sought to identify the predictors of FMR improvement after CRT in DCM.
From January 2003 to December 2013, 430 DCM patients consecutively enrolled were retrospectively analysed. Inclusion criteria were successful CRT implantation in presence of conventional indications (i.e. left bundle-branch block, left ventricular ejection fraction (LVEF) ≤35%, NYHA functional class ≥II) and moderate to severe FMR at the time of procedure. Early echocardiographic evaluation after CRT-implantation (median 2.5 days) has been performed in each patient. Improvement in FMR (absent/absent) at mid-term (7 months; IQR 4-10) was considered as the primary study end-point.
A total of 44 patients (10% of the overall cohort) were included. A significant reduction in FMR severity was observed in 21 patients (48%) at mid-term after CRT (median time 7 months). No pre-implantation variables predicted FMR evolution, but FMR improvement at mid-term was strongly predicted by an acute favorable hemodynamic response (persistence/persistence of normal right ventricular function and 10 mmHg decrease or normalization - ≤35 mmHg - of systolic pulmonary artery pressure) at post-implantation echocardiography (OR 13.7; 95% CI 1.27-42.8; p = 0.016). FMR improvement at mid-term was stable during follow-up and was associated with superior long-term transplant-free survival (p = 0.022).
Stable FMR improvement frequently occurs after CRT-implantation in DCM and is associated with improved transplant-free survival. Echocardiographic evaluation of acute hemodynamic response to CRT is helpful to early identify the favourable FMR evolution. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Pulmonary artery aneurysm unassociated to congenital heart disease and pulmonary hypertension is exceedingly rare. Its pathogenesis and correct management remain unknown. Sarcoidosis is a systemic disease that can exceptionally involve large vessels, leading to stenosis and dilatation. Pulmonary artery aneurysm has never been described in association with sarcoidosis. Surgical approach should prevent aneurysm rupture, but it is not known when surgery should be preferred to strict medical follow-up. In this report we present a case of large pulmonary artery aneurysm associated to systemic sarcoidosis underlining problematic management of diseases 'forgotten' by evidence based medicine.
Journal of Cardiovascular Medicine 01/2015; 16 Suppl 14:S77-S78. DOI:10.2459/JCM.0b013e328365a04f · 1.51 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose: We have previously demonstrated that multi-line transmit (MLT) beam forming can provide high quality full field-of-view (90° sector) B-mode images at very high frame rates, i.e. up to 500 fps. The purpose of this study was to test the feasibility of this technique in imaging the mechanical intraventricular waves such as the one associated with activation of the left ventricle.
Methods: A dedicated pulse sequence using MLT was implemented on the ULA-OP research scanner equipped with a 2.0 MHz phased array to obtain 90° sector images at a frame rate of 436 fps. The left ventricle of a healthy volunteer was imaged from the apical 4 chamber view and the RF data was acquired. Subsequently, the strain rate was extracted from the RF data using a normalized cross-correlation method.
Results: As expected, during the early filling phase, myocardium lengthening (positive strain rate) was observed propagating from the base of the septum to the apex and back (Figure a). A similar wave was detected in the lateral wall, although a brief shortening (negative strain rate) was detected in the mid-wall which could be the result of reverberations (Figure b). During isovolumetric contraction, the septal wall shortened before the lateral wall (as expected) - moreover - there seemed to be an intra-wall base-apex shortening gradient (Figure c and d).
Conclusions: Our preliminary results show that visualization of the cardiac mechanical activation could be feasible using MLT based high frame rate imaging. Further research is required to examine this in depth, which is the topic of on-going work.
[Show abstract][Hide abstract] ABSTRACT: The aims of this study were to investigate the clinical outcomes of patients with low-gradient aortic stenosis despite preserved left ventricular ejection fraction and to assess reliable prognostic clinical-instrumental features in patients experiencing or not experiencing aortic valve replacement (AVR). Clinical-laboratory and echocardiographic data from 167 patients (median age 78 years, interquartile range 69 to 83) with aortic valve areas <1.0 cm(2), mean gradients ≤30 mm Hg, and preserved left ventricular ejection fraction (≥55%), enrolled from 2005 to 2010, were analyzed. During a mean follow-up period of 44 ± 23 months, 33% of patients died. On multivariate analysis, independent predictors of death were baseline New York Heart Association functional class III or IV (hazard ratio 2.16, p = 0.038) and atrial fibrillation (hazard ratio 2.00, p = 0.025). Conversely, AVR was protective (hazard ratio 0.25, p = 0.01). The magnitude of the protective effect of AVR seemed to be relatively more important in patients with atrial fibrillation than in those in sinus rhythm, independently of the severity of symptoms. Age >70 years showed a trend toward being a prognostic predictor (p = 0.082). In conclusion, in patients with low-gradient aortic stenosis despite a preserved left ventricular ejection fraction, AVR was strongly correlated with a better prognosis. Patients with atrial fibrillation associated with advanced New York Heart Association class had the worst prognosis if treated medically but at the same time a relative better benefit from surgical intervention.
The American Journal of Cardiology 09/2014; 114(11). DOI:10.1016/j.amjcard.2014.09.007 · 3.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Genotype–phenotype correlations are poorly characterised in arrhythmogenic right ventricular cardiomyopathy (ARVC). We investigated whether carriers of rare variants in desmosomal genes (DC) and titin gene (TTN) display different phenotypes and clinical outcomes compared with non-carriers (NT-ND).
Methods and results Thirty-nine ARVC families (173 subjects, 67 affected) with extensive follow-up (mean 9 years), prospectively enrolled in the International Familial Cardiomyopathy Registry since 1991, were screened for rare variants in TTN and desmosomal genes (DSP, PKP2, DSG2, DSC2). Multiple clinical and outcome variables were compared between three genetic groups (TTN, DC, NT-ND) to define genotype–phenotype associations. Of the 39 ARVC families, 13% (5/39) carried TTN rare variants (11 affected subjects), 13% (5/39) DC (8 affected), while 74% (29/39) were NT-ND (48 affected). When compared with NT-ND, DC had a higher prevalence of inverted T waves in V2-3 (75% vs 31%, p=0.004), while TTN had more supraventricular arrhythmias (46% vs 13%, p=0.013) and conduction disease (64% vs 6% p<0.001). When compared with the NT-ND group, the DC group experienced a worse prognosis (67% vs 11%, p=0.03) and exhibited a lower survival free from death or heart transplant (59% vs 95% at 30 years, and 31% vs 89% at 50 years, HR 9.66, p=0.006), while the TTN group showed an intermediate survival curve (HR 4.26, p=0.037).
Conclusions TTN carriers display distinct phenotypic characteristics including a greater risk for supraventricular arrhythmias and conduction disease. Conversely, DC are characterised by negative T waves in anterior leads, severe prognosis, high mortality and morbidity.
Journal of Medical Genetics 08/2014; 51(10). DOI:10.1136/jmedgenet-2014-102591 · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent studies suggested that resting heart rate (RHR) might be an independent predictor of cardiovascular mortality and morbidity. Nonetheless, the interrelation between RHR and cardiovascular diseases is not clear. In order to resolve this puzzle, the importance of genetic determinants of RHR has been recently suggested, but it needs to be further investigated.
The aim of this study was to estimate the contribution of common genetic variations on RHR using Genome Wide Association Study.
We performed a Genome Wide Association Study in an isolated population cohort of 1737 individuals, the Italian Network on Genetic Isolates - Friuli Venezia Giulia (INGI-FVG). Moreover, a haplotype analysis was performed. A regression tree analysis was run to highlight the effect of each haplotype combination on the phenotype.
A significant level of association (p<5×10(-8)) was detected for Single Nucleotide Polymorphisms (SNPs) in two genes expressed in the heart: MAML1 and CANX. Founding that the three different variants of the haplotype, which encompass both genes, yielded a phenotypic correlation. Indeed, a haplotype in homozygosity is significantly associated with the lower quartile of RHR (RHR≤58bpm). Moreover no significant association was found between cardiovascular risk factors and the different haplotype combinations.
Mastermind-like 1 and Calnexin were found to be associated with RHR. We demonstrated a relation between a haplotype and the lower quartile of RHR in our populations. Our findings highlight that genetic determinants of RHR may be implicated in determining cardiovascular diseases and could allow a better risk stratification.
[Show abstract][Hide abstract] ABSTRACT: 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).
From 1978 to 2007, 853 IDCM patients (45 ± 15 years, 72% males) were enrolled and classified as follows: Group 1, 110 patients (12.8%) enrolled during 1978-1987; Group 2, 376 patients (44.1%) enrolled during 1988-1997; Group 3, 367 patients (43.1%) enrolled during 1998-2007. ACE-inhibitors/angiotensin receptor blockers were administered in 34%, 93%, and 93% (P <0.001), and β-blockers in 11%, 82%, and 86% (P <0.001) in Groups 1, 2, and 3, respectively; ICDs were implanted in 2%, 14%, and 13% (P = 0.005); mean time to device implantation was lower in Group 3. At 8 years, heart transplant (HTx)-free survival rates were 55%, 71%, and 87% in Groups 1, 2, and 3, respectively (P <0.001). Similar progressive improvement was found for pump-failure death (DHF)/HTx, while survival free from sudden death (SD) was significantly improved only in Group 3. Multivariable models considering competing risk indicated early diagnosis (i.e. a baseline less advanced disease stage) and tailored medical therapy (HR 0.44, CI 95% 0.19-0.98) as independent protectors against DHF/HTx. Concerning SD, lower left ventricular ejection fraction emerged as a predictor, while ICD was the only therapy with a protective role (HR 0.08, CI 95% 0.01-0.61). Treatment with digitalis emerged as a predictor of both DHF/HTx and SD.
An effective management and evidence-based integrated therapeutic approach progressively and significantly improved the long-term prognosis of IDCM during the last three decades.
European Journal of Heart Failure 03/2014; 16(3). DOI:10.1002/ejhf.16 · 6.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose: With the advent of percutaneous transcatheter device closures in congenital heart defects and the emergence of percutaneous left atrial appendage closure, there is an increasingly important role for echocardiographic guidance and control of device position and function. Disc occluder devices frequently present as an unexplained ‘figure-of-8’ on echocardiography. The aim of this study was to clarify this ‘figure-of-8’ display and to relate its morphology to transducer position and device type.
Methods: A mathematical model was developed to resemble disc occluder geometry and to allow a numerical simulation of the echocardiographic appearance. In addition, we developed an in vitro set-up for echocardiographic analysis of various disc occluders and various transducer positions.
Results: In the mathematical model of an epitrochoid curve (closely resembling disc occluder geometry) a ‘figure-of-8’ display is obtained when emphasizing points with tangent vector perpendicular to the direction of ultrasound waves. Decreasing imaging depth results in a more asymmetric ‘figure-of-8’, with small upper part and wide lower part. Clinical and in vitro data are in close agreement with these results (Figure 1). Furthermore a ‘figure-of-8’ display is only obtained in a coronal imaging position, and is similar for different commercially available disc occluder types.
Conclusions: The ‘figure-of-8’ display in the ultrasound image of a disc occluder is an imaging artifact due to the specific ‘epitrochoidal’ geometry of a deployed device and its interaction with ultrasound waves. The morphology of the ‘figure-of-8’ depends on transducer position, i.e. imaging depth, and is similar for different device types.
[Show abstract][Hide abstract] ABSTRACT: Dilated cardiomyopathy (DCM) commonly causes heart failure and shows extensive genetic heterogeneity that may be amenable to newly developed next-generation DNA sequencing of the exome. In this study we report the successful use of exome sequencing to identify a pathogenic variant in the TNNT2 gene using segregation analysis in a large DCM family. Exome sequencing was performed on three distant relatives from a large family with a clear DCM phenotype. Missense, nonsense, and splice variants were analyzed for segregation among the three affected family members and confirmed in other relatives by direct sequencing. A c.517T C>T, Arg173Trp TNNT2 variant segregated with all affected family members and was also detected in one additional DCM family in our registry. The inclusion of segregation analysis using distant family members markedly improved the bioinformatics filtering process by removing from consideration variants that were not shared by all affected subjects. Haplotype analysis confirmed that the variant found in both DCM families was located on two distinct haplotypes, supporting the notion of independent mutational events in each family. In conclusion, an exome sequencing strategy that includes segregation analysis using distant affected relatives within a family represents a viable diagnostic strategy in a genetically heterogeneous disease like DCM.
PLoS ONE 10/2013; 8(10):e78104. DOI:10.1371/journal.pone.0078104 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In dilated cardiomyopathy (DCM), the clinical and prognostic implications of rare variants in sarcomeric genes remain poorly understood. To address this question, we analyzed the outcome of rare sarcomeric gene variants in patients enrolled in our Familial Cardiomyopathy Registry.
DCM families harboring rare sarcomeric variants in MYH6, MYH7, MYBPC3, TNNT2, and TTN were identified. Genotype-phenotype association analysis was performed, and long-term survival-free from death or heart transplant was compared between carriers and noncarriers.
We found 24 rare variants (3 in MYH6, 3 in MYH7, 3 in MYBPC3, 2 in TNNT2, and 13 in TTN) affecting 52 subjects in 25 families. The phenotypes of variant carriers were severe (3 sudden deaths, 6 heart failure deaths, 8 heart transplants, 2 ventricular fibrillations). There was no difference in the overall long-term survival between carriers and the 33 noncarriers (p = 0.322). However after 50 years of age, the combined endpoint of death or transplant was decreased in carriers as compared to noncarriers (p = 0.026).
Patients with DCM carrying rare variants in sarcomeric genes manifest a poorer prognosis as compared to noncarriers after the age of 50 years. These data further support the role of genetic testing in DCM for risk stratification.
[Show abstract][Hide abstract] ABSTRACT: Active myocarditis (AM) 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 AM, looking for accessible and valid early predictors of long-term prognosis.
From 1981 to 2009, 82 patients with biopsy-proven AM 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 and/or presence of LVEF≥50%, was assessed. At baseline, left ventricular (LV) dysfunction (LVEF <50%) and left atrium enlargement were independently associated with long-term heart transplantation (HTx)-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 NYHA III-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 revaluation showed a significant incremental prognostic value when compared to the baseline evaluation (baseline model vs 6 months model: Area Under the Curve 0.79 vs 0.90, p=0.03).
Baseline LV 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.
[Show abstract][Hide abstract] ABSTRACT: The management of refractory recurrent pericarditis is challenging. Previous clinical reports have noted a beneficial effect of high-dose intravenous human immunoglobulins (IvIgs) in isolated and systemic inflammatory disease-related forms. In this article, we analyzed retrospectively our clinical experience with IvIg therapy in a series of clinical cases of pericarditis refractory to conventional treatment. We retrospectively analyzed 9 patients (1994 to 2010) with refractory recurrent pericarditis, who received high-dose IvIg as a part of their medical treatment. Nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, or colchicine treatment was not discontinued during IvIg treatment. No patients had a history of autoimmune or connective tissue diseases. During an average period of 11 months from the first recurrence, patients had experienced a mean of 5 relapses before the first IvIg treatment. In 4 cases, patients showed complete clinical remission with no further relapse after the first IvIg cycle. Two patients experienced a single minor relapse, responsive to short-term nonsteroidal anti-inflammatory drugs. In 2 patients, we performed a second cycle of IvIg after a recurrence of pericarditis, with subsequent complete remission. One patient did not respond to 3 cycles of IvIg and subsequently underwent pericardial window and long-term immunosuppressive treatment. No major adverse effect was observed in consequence of IvIg administration in all the cases. In conclusion, although IvIg mode of action is still poorly understood in this setting, this treatment can be considered as an option in patients with recurrent pericarditis refractory to conventional medical treatment and, in our small series, has proved to be effective in 8 of 9 cases.
The American journal of cardiology 08/2013; 112(9). DOI:10.1016/j.amjcard.2013.06.036 · 3.28 Impact Factor