Fabry disease in W162C mutation: a case report of two patients and a review of literature.

BACKGROUND: Fabry disease is a multisystemic disorder characterized by deposition of globotriaosylceramide (Gb3) and its deacylated form in multiple organs, sometimes localized in specific systems such as the nervous or cardiovascular system. As disease-modifying therapies are now available, early diagnosis is paramount to improving life quality and clinical outcomes. Despite the widespread use of non-invasive techniques for assessing organ damage, such as cardiac magnetic resonance imaging (MRI) for patients with cardiac disease, organ biopsy remains the gold standard to assess organ involvement. CASE PRESENTATION: The cases of two patients, father and daughter with a W162C mutation, are described. The father presented with late-onset, cardiac Fabry disease, subsequently developing systolic dysfunction and heart failure. His daughter, while asymptomatic and with normal cardiac assessment (except for slightly reduced native T1 values by cardiac MRI), had already initial myocyte Gb3 deposits on the endomyocardial biopsy, allowing her to start therapy precociously and potentially modifying the course of her disease. A review of the literature concerning the W162C mutation is then provided, showing that it is usually associated to classic, multisystemic Fabry disease rather than the cardiac-restricted form as in these two cases. CONCLUSIONS: Three main points can be concluded from this report. First, the W162C mutation can present with a more variegate phenotype than that predicted on a molecular basis. Second, endomyocardial biopsy was shown in this case to precede non-invasive investigation in determining organ involvement, justifying further studies on this potentially reliable technique, Third, difficulties can arise in the management of asymptomatic female carriers.

Characterization and natural history of different phenotypes in hereditary transthyretin amyloidosis: 40-year experience at a single Italian referral centre.

AIMS: Hereditary transthyretin amyloidosis (ATTRv) is one of the leading aetiologies of systemic amyloidosis with more than 135 mutations described and a broad spectrum of clinical manifestations. We aimed to provide a systematic description of a population of individuals carrying pathogenic mutations of transthyretin (TTR) gene and to investigate the major clinical events during follow-up. METHODS AND RESULTS: This was an observational, retrospective, cohort study including consecutive patients with mutations of TTR gene, admitted to a tertiary referral centre in Bologna, Italy, between 1984 and 2022. Three hundred twenty-five patients were included: 106 asymptomatic carriers, 49 cardiac phenotype, 49 neurological phenotype, and 121 mixed phenotype. Twenty-two different mutations were found, with Ile68Leu (41.8%), Val30Met (19%), and Glu89Gln (10%) being the most common. After a median follow-up of 51 months, 111 patients (38.3%) died and 9 (11.5%) of the 78 asymptomatic carriers developed ATTRv. Carriers had a prognosis comparable with healthy population, while no significant differences were seen among the three phenotypes adjusted by age. Age at diagnosis, New York Heart Association class III, left ventricular ejection fraction, modified polyneuropathy disability score IV, and disease-modifying therapy were independently associated with survival. CONCLUSION: This study offers a wide and comprehensive overview of ATTRv from the point of view of a tertiary referral centre in Italy. Three main phenotypes can be identified (cardiac, neurological, and mixed) with specific clinical and instrumental features. Family screening programmes are essential to identify paucisymptomatic affected patients or unaffected carriers of the mutation, to be followed through the years. Lastly, disease-modifying therapy represents an evolving cornerstone of the management of ATTRv, with a great impact on mortality.

A total of 325 consecutive patients harbouring a pathogenic mutation in the TTR gene, admitted to a tertiary referral centre in Bologna, Italy, between 1984 and 2022, were included in the study.These patients exhibited significant clinical diversity: 106 were asymptomatic carriers, 49 presented with a cardiac phenotype, 49 had a neurological phenotype, and 121 had a mixed phenotype.Asymptomatic carriers demonstrated a prognosis comparable with healthy population, but some of them may develop signs and symptoms of the disease during follow-up.Survival curves adjusted by age are similar among the three phenotypes.Age at diagnosis, New York Heart Association class, modified polyneuropathy disability score, left ventricular ejection fraction, and disease-modifying therapy were identified as independent factors associated with prognosis.

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.

Real-world candidacy to mavacamten in a contemporary hypertrophic obstructive cardiomyopathy population.

AIMS: In the EXPLORER-HCM trial, mavacamten reduced left ventricular outflow tract obstruction (LVOTO) and improved functional capacity of symptomatic hypertrophic obstructive cardiomyopathy (HOCM) patients. We sought to define the potential use of mavacamten by comparing real-world HOCM patients with those enrolled in EXPLORER-HCM and assessing their eligibility to treatment. METHODS AND RESULTS: We collected information on HOCM patients followed up at 25 Italian HCM outpatient clinics and with significant LVOTO (i.e. gradient ≥30 mmHg at rest or ≥50 mmHg after Valsalva manoeuvre or exercise) despite pharmacological or non-pharmacological therapy. Pharmacological or non-pharmacological therapy resolved LVOTO in 1044 (61.2%) of the 1706 HOCM patients under active follow-up, whereas 662 patients (38.8%) had persistent LVOTO. Compared to the EXPLORER-HCM trial population, these real-world HOCM patients were older (62.1 ± 14.3 vs. 58.5 ± 12.2 years, p = 0.02), had a lower body mass index (26.8 ± 5.3 vs. 29.7 ± 4.9 kg/m2 , p < 0.0001) and a more frequent history of atrial fibrillation (21.5% vs. 9.8%, p = 0.027). At echocardiography, they had lower left ventricular ejection fraction (LVEF, 66 ± 7% vs. 74 ± 6%, p < 0.0001), higher left ventricular outflow tract gradients at rest (60 ± 27 vs. 52 ± 29 mmHg, p = 0.003), and larger left atrial volume index (49 ± 16 vs. 40 ± 12 ml/m2 , p < 0.0001). Overall, 324 (48.9%) would have been eligible for enrolment in the EXPLORER-HCM trial and 339 (51.2%) for treatment with mavacamten according to European guidelines. CONCLUSIONS: Real-world HOCM patients differ from the EXPLORER-HCM population for their older age, lower LVEF and larger atrial volume, potentially reflecting a more advanced stage of the disease. About half of real-world HOCM patients were found eligible to mavacamten.

SCN5A mutation is associated with a higher Shanghai Score in patients with type 1 Brugada ECG pattern.

AIMS: Brugada syndrome (BrS) is an inherited arrhythmic disease characterized by a coved ST-segment elevation in the right precordial electrocardiogram leads (type 1 ECG pattern) and is associated with a risk of malignant ventricular arrhythmias and sudden cardiac death. In order to assess the predictive value of the Shanghai Score System for the presence of a SCN5A mutation in clinical practice, we studied a cohort of 125 patients with spontaneous or fever/drug-induced BrS type 1 ECG pattern, variably associated with symptoms and a positive family history. METHODS: The Shanghai Score System items were collected for each patient and PR and QRS complex intervals were measured. Patients were genotyped through a next-generation sequencing (NGS) custom panel for the presence of SCN5A mutations and the common SCN5A polymorphism (H558R). RESULTS: The total Shanghai Score was higher in SCN5A+ patients than in SCN5A- patients. The 81% of SCN5A+ patients and the 100% of patients with a SCN5A truncating variant exhibit a spontaneous type 1 ECG pattern. A significant increase in PR (P = 0.006) and QRS (P = 0.02) was detected in the SCN5A+ group. The presence of the common H558R polymorphism did not significantly correlate with any of the items of the Shanghai Score, nor with the total score of the system. CONCLUSION: Data from our study suggest the usefulness of Shanghai Score collection in clinical practice in order to maximize genetic test appropriateness. Our data further highlight SCN5A mutations as a cause of conduction impairment in BrS patients.

Prognostic Implications of the Extent of Cardiac Damage in Patients With Fabry Disease.

BACKGROUND: There is limited evidence on the risk stratification of cardiovascular outcomes in patients with Fabry disease (FD). OBJECTIVES: This study sought to classify FD patients into disease stages, based on the extent of the cardiac damage evaluated by echocardiography, and to assess their prognostic impact in a multicenter cohort. METHODS: Patients with FD from 5 Italian referral centers were categorized into 4 stages: stage 0, no cardiac involvement; stage 1, left ventricular (LV) hypertrophy (LV maximal wall thickness >12 mm); stage 2, left atrium (LA) enlargement (LA volume index >34 mL/m2); stage 3, ventricular impairment (LV ejection fraction <50% or E/e' ≥15 or TAPSE <17 mm). The study endpoint was the composite of all-cause death, hospitalization for heart failure, new-onset atrial fibrillation, major bradyarrhythmias or tachyarrhythmias, and ischemic stroke. RESULTS: A total of 314 patients were included. Among them, 174 (56%) were classified as stage 0, 41 (13%) as stage 1, 57 (18%) as stage 2 and 42 (13%) as stage 3. A progressive increase in the composite event rate at 8 years was observed with worsening stages of cardiac damage (log-rank P < 0.001). On multivariable Cox regression analysis, the staging was independently associated with the risk of cardiovascular events (HR: 2.086 per 1-stage increase; 95% CI: 1.487-2.927; P < 0.001). Notably, cardiac staging demonstrated a stronger and additive prognostic value, as compared with the degree of LV hypertrophy. CONCLUSIONS: In FD patients, a novel staging classification of cardiac damage, evaluated by echocardiography, is strongly associated with cardiovascular outcomes and may be helpful to refine risk stratification.

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.

Screening approaches to cardiac amyloidosis in different clinical settings: Current practice and future perspectives.

Cardiac amyloidosis is a serious and progressive infiltrative disease caused by the deposition of amyloid fibrils in the heart. In the last years, a significant increase in the diagnosis rate has been observed owing to a greater awareness of its broad clinical presentation. Cardiac amyloidosis is frequently associated to specific clinical and instrumental features, so called "red flags", and it appears to occur more commonly in particular clinical settings such as multidistrict orthopedic conditions, aortic valve stenosis, heart failure with preserved or mildly reduced ejection fraction, arrhythmias, plasma cell disorders. Multimodality approach and new developed techniques such PET fluorine tracers or artificial intelligence may contribute to strike up extensive screening programs for an early recognition of the disease.

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.

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.

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.

Cardiac 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.

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.

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 non-dilated 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 (IQR 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.

[Mitral valve prolapse and mitral annulus disjunction: be aware of a potential arrhythmogenic substrate]. / Prolasso valvolare mitralico e disgiunzione mitro-anulare. La consapevolezza di un possibile substrato aritmico.

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.

Pediatric Restrictive Cardiomyopathies.

Restrictive cardiomyopathy (RCM) is the least frequent phenotype among pediatric heart muscle diseases, representing only 2.5-3% of all cardiomyopathies diagnosed during childhood. Pediatric RCM has a poor prognosis, high incidence of pulmonary hypertension (PH), thromboembolic events, and sudden death, is less amenable to medical or surgical treatment with high mortality rates. In this scenario, heart transplantation remains the only successful therapeutic option. Despite a shared hemodynamic profile, characterized by severe diastolic dysfunction and restrictive ventricular filling, with normal ventricle ejection fraction and wall thickness, RCM recognizes a broad etiological spectrum, consisting of genetic/familial and acquired causes, each of which has a distinct pathophysiology and natural course. Hence, the aim of this review is to cover the causes, clinical presentation, diagnostic evaluation, treatment, and prognosis of pediatric RCM.