Diagnostic Delay in Arrhythmogenic Cardiomyopathy

Aims Diagnosis of arrhythmogenic cardiomyopathy (ACM) may be challenging, as it comprises diverse phenotypes (right dominant, biventricular, and left dominant), and each may overlap with other clinical entities. The issue of differential diagnosis with conditions mimicking ACM has been previously highlighted; however, a systematic analysis of ACM diagnostic delay, and of its clinical implications, is lacking. Methods and results Data of all ACM patients from three Italian Cardiomyopathy Referral Centres were reviewed to assess the time from first medical contact to definitive ACM diagnosis; a significant diagnostic delay was defined as a time to ACM diagnosis >= 2 years. Baseline characteristics and clinical course of patients with and without diagnostic delay were compared. Of 174 ACM patients, 31% experienced diagnostic delay, with a median time to diagnosis of 8 years (20% in right-dominant ACM, 33% in left-dominant ACM, and 39% in biventricular). Patients with diagnostic delay, when compared with those without, more frequently exhibited an ACM phenotype with left ventricular (LV) involvement (74 vs. 57%, P = 0.04) and a specific genetic background (none had plakophilin-2 variants). The most common initial (mis)diagnoses were dilated cardiomyopathy (51%), myocarditis (21%), and idiopathic ventricular arrhythmia (9%). At follow-up, all-cause mortality was greater in those with diagnostic delay (P = 0.03). Conclusion Diagnostic delay is common in patients with ACM, particularly in the presence of LV involvement, and is associated with greater mortality at follow-up. Clinical suspicion and increasing use of tissue characterization by cardiac magnetic resonance in specific clinical settings are of key importance for the timely identification of ACM.Lay Summary Almost one-third of patients with arrhythmogenic cardiomyopathy (ACM) experience a diagnostic delay >2 years. These patients are mostly affected by an ACM phenotype with left ventricular (LV) involvement and present worse mortality compared with those without diagnostic delay.Diagnostic delay is common in patients with ACM, particularly in the presence of LV involvement, and is associated with greater mortality at follow-up.The most common initial (mis)diagnoses were dilated cardiomyopathy, myocarditis, and idiopathic ventricular arrhythmia. Clinical suspicion and increasing use of tissue characterization by cardiac magnetic resonance in these specific clinical settings are of key importance to identify ACM in a timely fashion

[Mitral valve prolapse and mitral annulus disjunction: be aware of a potential arrhythmogenic substrate]

: Mitral valve prolapse is a relatively common disease with a good overall prognosis. However, in specific clinical and instrumental contexts, patients at high risk of ventricular arrhythmias and sudden cardiac death can be identified. Female sex, history of palpitations or syncope, bi-leaflet myxomatous valve, ECG repolarization abnormalities in the inferior leads, complex ventricular arrhythmias, left ventricular fibrosis detected by cardiac magnetic resonance correlate with a higher risk clinical profile. Additionally, morpho-functional abnormalities of the mitral valve annulus, particularly mitral annulus disjunction, may cause a mechanical stretch at the inferior basal ventricular wall and posterior papillary muscles, predisposing to myocardial fibrosis and arrhythmias. A risk stratification strategy is needed to identify patients with mitral valve prolapse and/or mitral annulus disjunction at high risk of arrhythmias; however, few data are available. Further prospective multicenter studies are warranted, focusing on medical therapy, the role of implantable cardioverter-defibrillators for primary prevention, efficacy of targeted catheter ablation or mitral valve surgery

From the phenotype to precision medicine. an update on the cardiomyopathies diagnostic workflow

Cardiomyopathies are disease of the cardiac muscle largely due to genetic alterations of proteins with 'structural' or 'functional' roles within the cardiomyocyte, going from the regulation of contraction-relaxation, metabolic and energetic processes to ionic fluxes. Modifications occurring to these proteins are responsible, in the vast majority of cases, for the phenotypic manifestations of the disease, including hypertrophic, dilated, arrhythmogenic and restrictive cardiomyopathies. Secondary nonhereditary causes to be excluded include infections, toxicity from drugs or alcohol or medications, hormonal imbalance and so on. Obtaining a phenotypic definition and an etiological diagnosis is becoming increasingly relevant and feasible, thanks to the availability of new tailored treatments and the diagnostic advancements made particularly in the field of genetics. This is, for example, the case for transthyretin cardiac amyloidosis, Fabry disease or dilated cardiomyopathies due to laminopathies. For these diseases, specific medications have been developed, and a more tailored arrhythmic risk stratification guides the implantation of a defibrillator. In addition, new medications directly targeting the altered protein responsible for the phenotype are becoming available (including the myosin inhibitors mavacantem and aficamten, monoclonal antibodies against Ras-MAPK, genetic therapies for sarcoglycanopathies), thus making a precision medicine approach less unrealistic even in the field of cardiomyopathies. For these reasons, a contemporary approach to cardiomyopathies must consider diagnostic algorithms founded on the clinical suspicion of the disease and developed towards a more precise phenotypic definition and etiological diagnosis, based on a multidisciplinary methodology putting together specialists from different disciplines, facilities for advanced imaging testing and genetic and anatomopathological competencies

Percutaneous Mitral Valve Repair with the MitraClip System in the Current Clinical Practice

Severe mitral valve regurgitation (MR) carries a significant burden both in prognosis and quality of life of patients, as well as on healthcare systems, with high rates of hospitalization for heart failure. While mitral valve surgery constitutes the first-line treatment option for primary MR in suitable patients, surgical treatment for secondary severe MR remains controversial, with a substantial lack of evidence on a survival benefit. In recent decades, percutaneous mitral valve repair has emerged as an alternative treatment for patients deemed not suitable for surgery. Among several devices under development or evaluation, the MitraClip system is the most widespread and is supported by the strongest evidence. While the role of MitraClip in patients with chronic primary MR who are not deemed suitable for surgery is well established, with consistent data showing improvement in both prognosis and quality of life, MitraClip treatment in secondary MR is a rapidly evolving field. Two recent randomized clinical trials generated apparently controversial results but actually provided an interesting pathophysiologic frame that could help discerning patients who will benefit from the procedure versus patients who will not. In this review, we will discuss current treatment options for mitral regurgitation, focusing on percutaneous mitral valve repair with the MitraClip system

Diagnosis and Management of Rare Cardiomyopathies in Adult and Paediatric Patients. A Position Paper of the Italian Society of Cardiology (SIC) and Italian Society of Paediatric Cardiology (SICP)

Cardiomyopathies (CMPs) are myocardial diseases in which the heart muscle is structurally and functionally abnormal in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to cause the observed myocardial abnormality. Thought for a long time to be rare diseases, it is now clear that most of the CMPs can be easily observed in clinical practice. However, there is a group of specific heart muscle diseases that are rare in nature whose clinical/echocardiographic phenotypes resemble those of the four classical morphological subgroups of hypertrophic, dilated, restrictive, arrhythmogenic CMPs. These rare CMPs, often but not solely diagnosed in infants and paediatric patients, should be more properly labelled as specific CMPs. Emerging consensus exists that these conditions require tailored investigation and management. Indeed, an appropriate understanding of these conditions is mandatory for early treatment and counselling. At present, however, the multisystemic and heterogeneous presentation of these entities is a challenge for clinicians, and time delay in diagnosis is a significant concern. The aim of this paper is to define practical recommendations for diagnosis and management of the rare CMPs in paediatric or adult age. A modified Delphi method was adopted to grade the recommendations proposed by each member of the writing committee

Correlations Between Cardiac Magnetic Resonance and Myocardial Histologic Findings in Fabry Disease

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Clinical presentations leading to arrhythmogenic left ventricular cardiomyopathy

Objectives To describe a cohort of patients with arrhythmogenic left ventricular cardiomyopathy (ALVC), focusing on the spectrum of the clinical presentations.Methods Patients were retrospectively evaluated between January 2012 and June 2020. Diagnosis was based on (1) >= 3 contiguous segments with subepicardial/midwall late gadolinium enhancement in the left ventricle (LV) at cardiac magnetic resonance plus a likely pathogenic/pathogenic arrhythmogenic cardiomyopathy (AC) associated genetic mutation and/or familial history of AC and/or red flags for ALVC (ie, negative T waves in V4-6/ aVL, low voltages in limb leads, right bundle branch block like ventricular tachycardia) or (2) pathology examination of explanted hearts or autoptic cases suffering sudden cardiac death (SCD). Significant right ventricular involvement was an exclusion criterion.Results Fifty-two patients (63% males, age 45 years (31-53)) composed the study cohort. Twenty-one (41%) had normal echocardiogram, 13 (25%) a hypokinetic nondilated cardiomyopathy (HNDC) and 17 (33%) a dilated cardiomyopathy (DCM). Of 47 tested patients, 29 (62%) were carriers of a pathogenic/likely pathogenic DNA variant. Clinical contexts leading to diagnosis were SCD in 3 (6%), ventricular arrhythmias in 15 (29%), chest pain in 8 (15%), heart failure in 6 (12%) and familial screening in 20 (38%). Thirty patients (57%) had previously received a diagnosis other than ALVC with a diagnostic delay of 6 years (IOR 1-7).Conclusions ALVC is hidden in different clinical scenarios with a phenotypic spectrum ranging from normal LV to HNDC and DCM. Ventricular arrhythmias, chest pain, heart failure and SCD are the main clinical presentations, being familial screening essential for the affected relatives' identification

Clinical characteristics and outcome of end stage hypertrophic cardiomyopathy: Role of age and heart failure phenotypes

Background: A minority of patients with hypertrophic cardiomyopathy (HCM) presents advanced heart failure (HF) during their clinical course, in the context of left ventricular (LV) remodeling with reduced LV ejection fraction (LVEF), or of severe diastolic dysfunction without impaired LVEF. Aim of this study was to describe a multicentric end stage (ES) HCM population and analyze clinical course and outcome among its different phenotypes. Methods: Data of all HCM patients from 7 Italian referral centres were retrospectively evaluated. ES was diagnosed in presence of: LVEF <50% (ES-rEF) or NYHA functional class ≥II with severe diastolic dysfunction (ES-pEF). Outcomes were: HCM-related and all-cause mortality; combined arrhythmic events; advanced HF treatments. Results: Study population included 331 ES patients; 87% presented ES-rEF and 13% ES-pEF. At ES recognition, patients with ES-pEF were more commonly females, had more frequently NYHA III/IV, atrial fibrillation and greater maximal LV wall thickness. Over a median follow-up of 5.6 years, 83 (25%) patients died, 46 (15%) experienced arrhythmic events and (26%) 85 received advanced HF treatments. Incidence of HCM-related and all-cause mortality, and of combined arrhythmic events did not differ in ES-pEF and ES-rEF patients, but ES-pEF patients were less likely to receive advanced HF treatments. Older age at ES recognition was an independent predictor of increased HCM-related mortality (p = 0.01) and reduced access to advanced HF treatments (p < 0.0001). Conclusions: Two different HCM-ES phenotypes can be recognized, with ES-pEF showing distinctive features at ES recognition and receiving less frequently advanced HF treatments. Older age at ES recognition has a major impact on outcomes

Clinical application of CMR in cardiomyopathies: evolving concepts and techniques : A position paper of myocardial and pericardial diseases and cardiac magnetic resonance working groups of Italian society of cardiology

none24noCardiac magnetic resonance (CMR) has become an essential tool for the evaluation of patients affected or at risk of developing cardiomyopathies (CMPs). In fact, CMR not only provides precise data on cardiac volumes, wall thickness, mass and systolic function but it also a non-invasive characterization of myocardial tissue, thus helping the early diagnosis and the precise phenotyping of the different CMPs, which is essential for early and individualized treatment of patients. Furthermore, several CMR characteristics, such as the presence of extensive LGE or abnormal mapping values, are emerging as prognostic markers, therefore helping to define patients' risk. Lastly new experimental CMR techniques are under investigation and might contribute to widen our knowledge in the field of CMPs. In this perspective, CMR appears an essential tool to be systematically applied in the diagnostic and prognostic work-up of CMPs in clinical practice. This review provides a deep overview of clinical applicability of standard and emerging CMR techniques in the management of CMPs.Merlo, Marco; Gagno, Giulia; Baritussio, Anna; Bauce, Barbara; Biagini, Elena; Canepa, Marco; Cipriani, Alberto; Castelletti, Silvia; Dellegrottaglie, Santo; Guaricci, Andrea Igoren; Imazio, Massimo; Limongelli, Giuseppe; Musumeci, Maria Beatrice; Parisi, Vanda; Pica, Silvia; Pontone, Gianluca; Todiere, Giancarlo; Torlasco, Camilla; Basso, Cristina; Sinagra, Gianfranco; Filardi, Pasquale Perrone; Indolfi, Ciro; Autore, Camillo; Barison, AndreaMerlo, Marco; Gagno, Giulia; Baritussio, Anna; Bauce, Barbara; Biagini, Elena; Canepa, Marco; Cipriani, Alberto; Castelletti, Silvia; Dellegrottaglie, Santo; Guaricci, Andrea Igoren; Imazio, Massimo; Limongelli, Giuseppe; Musumeci, Maria Beatrice; Parisi, Vanda; Pica, Silvia; Pontone, Gianluca; Todiere, Giancarlo; Torlasco, Camilla; Basso, Cristina; Sinagra, Gianfranco; Filardi, Pasquale Perrone; Indolfi, Ciro; Autore, Camillo; Barison, Andre