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Fabry disease (FD, OMIM 301500) is an X-linked lysosomal storage disease caused by pathogenic variants in the GLA gene. Cardiac involvement is common in FD and is responsible for impaired quality of life and premature death. The classic cardiac involvement is a nonobstructive form of hypertrophic cardiomyopathy, usually manifesting as concentric left ventricular hypertrophy, with subsequent arrhythmogenic intramural fibrosis. Treatment of patients with FD should be directed to prevent the disease progression to irreversible organ damage and organ failure. The aim of this review is to describe the current state of knowledge regarding cardiovascular involvement in FD, focusing on clinical and instrumental features, cardiovascular management, and targeted therapy.

Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome that has become a global health issue, with mortality ranging from 53% to 74% at 5 years. It is defined as the presence of signs and symptoms of heart failure associated with left ventricular ejection fraction greater than or equal to 50%. The definition and diagnosis of HFpEF in patients with unexplained dyspnea remain a clinical challenge in the absence of a unique diagnostic algorithm universally recognized. Clinical trials conducted so far did not show a significant improvement of prognosis, but forthcoming therapies could provide innovative solutions.

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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.

Objectives: The aim of this study was to evaluate the outcome of transcatheter mitral valve repair (TMVr) in patients with cardiogenic shock and significant mitral regurgitation (MR). Background: Patients in cardiogenic shock with severe MR have a poor prognosis in the setting of conventional medical therapy. Because of its favorable safety profile, TMVr is being increasingly used as an acute therapy in this population, though its efficacy remains unknown. Methods: A multicenter, collaborative, patient-level analysis was conducted. Patients with cardiogenic shock and moderate to severe (3+) or severe (4+) MR who were not surgical candidates were treated with TMVr. The primary outcome was in-hospital mortality. Secondary outcomes included 90-day mortality, heart failure (HF) hospitalization, and the combined event rate of 90-day mortality and HF hospitalization following dichotomization by TMVr device success. Results: Between January 2011 and February 2019, 141 patients across 14 institutions met the inclusion criteria. In-hospital mortality occurred in 22 patients (15.6%), at 90 days in 38 patients (29.5%), and at one year in 55 patients (42.6%). Median length of hospital stay following TMVr was 10 days (interquartile range: 6 to 20 days). HF hospitalization occurred in 26 patients (18.4%) at a median of 73 days (interquartile range: 26 to 546 days). When stratified by TMVr procedural results, successful TMVr reduced rates of in-hospital mortality (hazard ratio [HR]: 0.36; 95% confidence interval [CI]: 0.13 to 0.98; p = 0.04), 90-day mortality (HR: 0.36; 95% CI: 0.16 to 0.78; p = 0.01), and the composite of 90-day mortality and HF hospitalization (HR: 0.41; 95% CI: 0.19 to 0.90; p = 0.03). Conclusions: TMVr may improve short- and intermediate-term mortality in high-risk patients with cardiogenic shock and moderate to severe MR. Randomized studies are needed to definitively establish MR as a therapeutic target in patients with cardiogenic shock.

Nonischemic-dilated cardiomyopathy (NIDCM) is an entity that gathers extremely heterogeneous diseases. This awareness, although leading to continuous improvement in survival, has increased the complexity of NIDCM patients' management. Even though the endorsed 'red-flags' approach helps clinicians in pursuing an accurate etiological definition in clinical practice, it is not clear when and how peripheral centers should interact with referral centers with specific expertise in challenging scenarios (e.g. postmyocarditis and genetically determined dilated cardiomyopathy) and with easier access to second-line diagnostic tools and therapies. This position paper will summarize each step in NIDCM management, highlighting the multiple interactions between peripheral and referral centers, from first-line diagnostic workup and therapy to advanced heart failure management and long-term follow-up.

ObjectivesTo evaluate the role of the ECG in the differential diagnosis between Anderson-Fabry disease (AFD) and hypertrophic cardiomyopathy (HCM).MethodsIn this multicentre retrospective study, 111 AFD patients with left ventricular hypertrophy were compared with 111 patients with HCM, matched for sex, age and maximal wall thickness by propensity score. Independent ECG predictors of AFD were identified by multivariate analysis, and a multiparametric ECG score-based algorithm for differential diagnosis was developed.ResultsShort PR interval, prolonged QRS duration, right bundle branch block (RBBB), R in augmented vector left (aVL) ≥1.1 mV and inferior ST depression independently predicted AFD diagnosis. A point-by-point ECG score was then derived with the following diagnostic performances: c-statistic 0.80 (95% CI 0.74 to 0.86) for discrimination, the Hosmel-Lemeshow χ2 6.14 (p=0.189) for calibration, sensitivity 69%, specificity 84%, positive predictive value 82% and negative predictive value 72%. After bootstrap resampling, the mean optimism was 0.025, and the internal validated c-statistic for the score was 0.78.ConclusionsStandard ECG can help to differentiate AFD from HCM while investigating unexplained left ventricular hypertrophy. Short PR interval, prolonged QRS duration, RBBB, R in aVL ≥1.1 mV and inferior ST depression independently predicted AFD. Their systematic evaluation and the integration in a multiparametric ECG score can support AFD diagnosis.

Background The coexistence of cardiac amyloidosis (CA) and degenerative aortic stenosis (AS) is increasing but the diagnosis is challenging because these two conditions share a common echocardiographic phenotype (1). Different predictors have been proposed in the last few years, including clinical, ECG-graphic and echocardiographic features (2–3). Purpose To identify a new marker of concomitant CA in patients with severe AS analyzing computed tomography scan (CT). Methods 55 patients with severe AS and suspicion of concomitant CA were retrospectively enrolled. Patients with a bicuspid aortic valve, previous aortic valve replacement, or an incomplete diagnostic workup for CA were excluded. 33 patients underwent CT-scan and were included in the final analysis. Results None of the patients presented laboratory suspicion for AL amyloidosis; 12 patients (AS-CA) had positive 99m Tc-DPD bone scintigraphy (two with visual score 1, eight score 2 and two score 3), 21 patients (AS-alone) had negative bone scintigraphy. AS-CA patients had a median age of 85,5 years (versus 81,5) with only one female patient (versus 8 in the AS-alone group). AVA indexed were comparable between AS-CA and AS-alone groups (0,4 versus 0, 3 mm2/m2, p: 0.25). Stroke volume evaluated by pulsed Doppler, maximum and mean gradient were significatively lower in AS-CA group (respectively 30 versus 41 ml/m2, p: 0.017, 62 versus 74 mmHg, 0.038 and 33 versus 46 mmHg, p:0.022) with a higher percentage of low flow-low gradient aortic stenosis in AS-CA group (7 patients, 58% vs 3 patients in AS-alone 14%, p: 0.027), in line with the literature. ECG at first presentation in AS-CA group showed atrial fibrillation in 8 patients (67%), versus 2 patients in the AS-alone group (10%), and lower QRS voltages (peripheral QRS score 40 mV vs 51 mV, p-value:0.017; total QRS score 113 mV versus 155 mV, p-value: 0.005). The echocardiogram showed a more thickened IVS and PW in AS-CA patients (17 versus 15 mm, p: 0.05 and 15 versus 14 mm, p: 0.013), an augmented left ventricular mass (441 versus 356 g, p: 0.036) with a decreases longitudinal systolic function (septal S wave at TDI 4.4 versus 5.2 cm/s, p: 0.026, lateral S wave 4.1 versus 5.6 cm/s, p: 0.024) and a reduction in myocardial contraction fraction (12 versus 14%, p: 0.036). CT- aortic valve calcium was quantified by an experienced operator. A statistically significant difference between AS-CA and AS-alone groups was observed in calcium score (3345 versus 4785 Hounsfield units, p: 0.037) calcium volume (2411 versus 3626 mm2, p: 0.03) and calcium mass (687 versus 1147 g, p: 0.023) Conclusions This study is the first to our knowledge to use relative aortic valve calcium score evaluation from CT imaging to characterize patients with severe AS with or without concomitant CA in addition to the classical clinical, ECG graphic, echocardiographic parameters. CT-aortic valve calcium burner was significatively lower in patients with concomitant CA. Funding Acknowledgement Type of funding sources: None. CT scan and bone scintigraphy

Background Hereditary transthyretin-related amyloidosis (h-ATTR) is a systemic infiltrative disease caused by a single amino acid mutation on the transthyretin (TTR) gene, which destabilizes the protein and can determine its deposition on multiple organs, including heart and peripheral nervous system. Purpose We aimed to characterize and compare clinical, instrumental, and prognostic features of patients affected by h-ATTR by dividing the population into the disease's main phenotypes (unaffected carriers, cardiac, neurological or mixed phenotype). Methods Two hundred and eighty-five subjects of a single-centre cohort with a recognized pathogenic mutation on TTR gene were retrospectively included in the analysis. Phenotypes of disease were defined at baseline. Neurological phenotype (NP) was defined according to sensorimotor and/or autonomic dysfunction, while cardiac phenotype (CP) was defined in the presence of unexplained maximum wall thickness >12 mm and other typical echocardiographic findings. Unaffected carriers (UC) and mixed phenotypes (MP) presented none or both of the above-mentioned features, respectively. Results Two hundred and ten patients showed clinical signs of the disease, 37 (13%) with CP, 65 (23%) with NP and 108 (38%) with MP, while 75 subjects (26%) were UC. Ile68Leu was the most represented mutation (96 subjects, 34%), followed by Val30Met (21%) and Glu89Gln (13%). NP patients (mostly Val30Met) had mPND score >1 in 45% of patients, were younger at diagnosis (mean 47 years, p Conclusions H-ATTR is a rare systemic disorder whose natural history, including age of onset, clinical characteristics and instrumental findings, is strongly influenced by primary phenotypes, ranging from the excellent prognosis of unaffected carriers to the inauspicious outcome of mixed phenotypes. Funding Acknowledgement Type of funding sources: None.

Introduction Sudden cardiac death is the most common cause of mortality in childhood onset hypertrophic cardiomyopathy. Identifying individuals at highest risk is therefore an essential part of clinical care but remains challenging. The 12 lead electrocardiogram (ECG) has been proposed as a useful tool for risk stratification and an ECG risk score has been proposed. However, this has not been independently validated and the ECG phenotype of childhood HCM has not been previously described. The aim of this study was to describe the ECG phenotype of childhood HCM in a large, international, multi-centre cohort and investigate its role in risk prediction for arrhythmic events. Methods Participants with an available baseline resting 12-lead ECG were identified from a large, international, multi-centre, retrospective cohort of patients aged less than 16 years fulfilling the diagnostic criteria for HCM (n=1029). Resting baseline ECG was evaluated and ECG variables were extracted. In addition, the ECG risk score based on 8 parameters (deviation in QRS axis, pathological T-wave inversion in limb or precordial leads, ST-segment depression, dominant S-wave in V4, limb-lead amplitude sum, 12-lead amplitude duration product and QTc) was calculated as previously described. The primary study endpoint was a composite outcome of major cardiac events (MACE) defined as SCD, resuscitated cardiac arrest, appropriate implantable cardioverter defibrillator therapy, or sustained ventricular tachycardia (VT) with haemodynamic compromise. The discriminatory performance of using an ECG risk score >5 to identify patients at increased risk of MACE at 5 years was determined using Harrell’s C-index. Results Of 356 patients with childhood HCM (68.9% male, mean age at presentation 10.1 ± 4.5 years), 347 (97.5%) had baseline ECG abnormalities such as: repolarization abnormalities (n=277, 77.8%), left ventricular hypertrophy (n=240. 67.6%), abnormal QRS axis (n=126, 35.4%) or QT prolongation (n=131, 36.8%). Over a median follow up of 3.9 years (IQR 2.0-7.7), 25 (7%) had an arrhythmic event, with an overall annual event rate of 1.38 (95% CI 0.93-2.04). No ECG variables were associated with 5-year MACE on univariable or multivariable Cox regression analysis. Of the 164 participants with an ECG score >5, 153 (93.3%) did not have a MACE within 5 years. Harrell’s C-index (the probability of correctly distinguishing between high and low risk patients using an ECG risk score threshold of >5) was 0.60 (95% CI 0.484-0.715) at 5 years. The corresponding positive and negative predictive values were 6.7% (95% CI 4.7 – 9.4%) and 96.9% (95% CI 94.2 – 98.4%). Conclusions In a large, international, multi-centre cohort of children with HCM, ECG abnormalities are common. No ECG characteristic, either in isolation or combined in the ECG risk score, was associated with 5-year MACE risk. This suggests that the role of the baseline ECG phenotype in improving risk stratification in childhood HCM is limited. Conflict of Interest None

Aims The use of beta‐blocker therapy in cardiac amyloidosis (CA) is debated. We aimed at describing patterns of beta‐blocker prescription through a nationwide survey. Methods and results From 11 referral centres, we retrospectively collected data of CA patients with a first evaluation after 2016 (n = 642). Clinical characteristics at first and last evaluation were collected, with a focus on medical therapy. For patients in whom beta‐blocker therapy was started, stopped, or continued between first and last evaluation, the main reason for beta‐blocker management was requested. Median age of study population was 77 years; 81% were men. Arterial hypertension was found in 58% of patients, atrial fibrillation (AF) in 57%, and coronary artery disease in 16%. Left ventricular ejection fraction was preserved in 62% of cases, and 74% of patients had advanced diastolic dysfunction. Out of the 250 CA patients on beta‐blockers at last evaluation, 215 (33%) were already taking this therapy at first evaluation, while 35 (5%) were started it, in both cases primarily because of high‐rate AF. One‐hundred‐nineteen patients (19%) who were on beta‐blocker at first evaluation had this therapy withdrawn, mainly because of intolerance in the presence of heart failure with advanced diastolic dysfunction. The remaining 273 patients (43%) had never received beta‐blocker therapy. Beta‐blockers usage was similar between CA aetiologies. Patients taking vs. not taking beta‐blockers differed only for a greater prevalence of arterial hypertension, coronary artery disease, AF, and non‐restrictive filling pattern (P

Aims: In patients with heart failure and reduced ejection fraction (HFrEF) and secondary mitral regurgitation (SMR), impaired right ventricular function (RVF) may negatively influence the prognosis. Percutaneous mitral valve repair (pMVR) can promote the recovery of RVF. We sought to characterize the response of the right ventricle to pMVR in HFrEF with SMR and to assess the association between improved RVF after pMVR and outcomes. Methods and results: Overall, 221 patients with HFrEF and SMR ≥3+ successfully treated with pMVR in four tertiary care centres for heart failure were included. Improved RVF was defined as Δ right ventricular fractional area change (ΔRVFAC) ≥5% at early follow-up (median time 4 months). The primary endpoint was a composite of death/heart transplantation (D/HT). Mean age was 69 ± 11 years, mean left ventricular ejection fraction was 31 ± 8% and mean RVFAC was 34 ± 9%. ΔRVFAC ≥5% occurred in 88 patients (40%) and was independent of the measures of left ventricular reverse remodelling. During a median follow-up of 29 months (interquartile range 12–46), 81 patients (37%) reached the primary endpoint. After adjustment for other significant covariates, ΔRVFAC ≥5% was significantly associated with lower risk of D/HT (hazard ratio 0.52, 95% confidence interval 0.29–0.94, P = 0.030). In the secondary outcome analysis exploring the risk of heart failure hospitalizations, ΔRVFAC ≥5% confirmed the prognostic association with the endpoint. Conclusions: In patients with HFrEF and SMR, about 40% of patients improved RVF after pMVR. RVF improvement was associated with better long-term survival free from HT and lower risk of heart failure hospitalization.

Aims The 12-lead electrocardiogram (ECG) is routinely performed in children with hypertrophic cardiomyopathy (HCM). An ECG risk score has been suggested as a useful tool for risk stratification, but this has not been independently validated. This aim of this study was to describe the ECG phenotype of childhood HCM in a large, international, multi-centre cohort and investigate its role in risk prediction for arrhythmic events. Methods and results Data from 356 childhood HCM patients with a mean age of 10.1 years (±4.5) were collected from a retrospective, multi-centre international cohort. Three hundred and forty-seven (97.5%) patients had ECG abnormalities at baseline, most commonly repolarization abnormalities (n = 277, 77.8%); left ventricular hypertrophy (n = 240, 67.7%); abnormal QRS axis (n = 126, 35.4%); or QT prolongation (n = 131, 36.8%). Over a median follow-up of 3.9 years (interquartile range 2.0–7.7), 25 (7%) had an arrhythmic event, with an overall annual event rate of 1.38 (95% CI 0.93–2.04). No ECG variables were associated with 5-year arrhythmic event on univariable or multivariable analysis. The ECG risk score threshold of >5 had modest discriminatory ability [C-index 0.60 (95% CI 0.484–0.715)], with corresponding negative and positive predictive values of 96.7% and 6.7% Conclusion In a large, international, multi-centre cohort of childhood HCM, ECG abnormalities were common and varied. No ECG characteristic, either in isolation or combined in the previously described ECG risk score, was associated with 5-year sudden cardiac death risk. This suggests that the role of baseline ECG phenotype in improving risk stratification in childhood HCM is limited.

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Background: The X-linked Danon disease manifests by severe cardiomyopathy, myopathy, and neuropsychiatric problems. We designed this registry to generate a comprehensive picture of clinical presentations and outcome of patients with Danon disease in cardiomyopathy centers throughout Europe. Methods: Clinical and genetic data were collected in 16 cardiology centers from 8 European countries. Results: The cohort comprised 30 male and 27 female patients. The age at diagnosis was birth to 42 years in men and 2 to 65 in women. Cardiac involvement was observed in 96%. Extracardiac manifestations were prominent in men but not in women. Left ventricular (LV) hypertrophy was reported in 73% of male and 74% of female patients. LV systolic dysfunction was reported in 40% of men (who had LV ejection fraction, 34±11%) and 59% of women (LV ejection fraction, 28±13%). The risk of arrhythmia and heart failure was comparable among sexes. The age of first heart failure hospitalization was lower in men (18±6 versus 28±17 years; P Conclusions: Danon disease presents earlier in men than in women and runs a malignant course in both sexes, due to cardiac complications. Cardiomyopathy features, heart failure and arrhythmia, are similar among the sexes. Clinical diagnosis and management is extremely challenging in women due to phenotypic diversity and the absence of extracardiac manifestations.

Background Heart failure (HF) is one of the main features of amyloidotic cardiomyopathy (AC) and it is supposed to carry important prognostic implications. Despite the intrinsic etiologic heterogeneity of AC, HF has been mainly attributed to diastolic dysfunction, but the role played by the different amyloid subtypes of AC and by the clinical and hemodynamic factors in the pathophysiology of HF remains unclear. Objectives We aimed to assess the hemodynamic profile and outcome of patients with or without advanced HF (defined as NYHA class III-IV) at the time of first evaluation in light-chain (AL), hereditary transthyretin-related (h-ATTR) and non-mutant transthyretin-related (wt-ATTR) AC. Methods Among the 411 patients diagnosed with AC (156 AL, 131 h-ATTR, 124 wt-ATTR) at our Centre between 1990–2019, we analyzed central hemodynamic data, echocardiographic, clinical, ECG details and survival of the whole cohort. Cox regression analysis was used to stratify prognosis. Results 112 (27%) patients presented advanced HF at first evaluation and frequently showed severe symmetric left ventricle wall thickening (higher values in h-ATTR), non-dilated left ventricle, preserved ejection fraction and pathological global longitudinal strain and/or myocardial contraction fraction. At ECG, a significantly lower QRS voltage was present in advanced HF patients. Hemodynamically, elevated filing pressures on both cardiac sides were present in patients in NYHA III-IV class of the three etiologies. Overall survival at 2 years was 35% for AL, 83% for h-ATTR, 65% for wt-TTR. H-ATTR and wt-TTR were favorable predictors of survival, while reduced cardiac index and elevated filling pressures were indepedently associated with higher mortality. Conclusions The characterization of hemodynamic profile plays a central role in predicting the natural history of AC, since reduced stroke volume and elevated filling pressures are the best predictors of mortality, reflecting a physiopathological restrictive model of the disease. Conversely, left ventricular ejection fraction is rarely abnormal and it is not a reliable marker of poor prognosis, especially in the early stages of the disease. AL amyloidosis shows the worst outcome probably due to a combination of the underlying illness and light chains cardiotoxicity. LVEF and cardiac index in HF Funding Acknowledgement Type of funding source: None

Background Anderson Fabry (AF) disease is a X-linked lysosomal storage disorder with multiorgan involvement. Cardiac disease, mainly represented by left ventricular hypertrophy (LVH) and arrhythmias, is the most frequent cause of premature death. It is well know that specific therapy is less effective after the development of LVH and myocardial fibrosis, therefore early cardiac detection (before LVH) is important. New cardiac magnetic resonance (CMR) parametric imaging techniques (T1 and T2 maps) enable myocardial tissue changes associated with AF disease. Purpose To evaluate the relationship between CMR tissue characterization and clinical and instrumental manifestations of AF disease to find early markers of cardiac involvement. Methods 31 AF patients (9 males, mean age 49±16 years) underwent ECG, echocardiogram and contrast CMR. TnI, BNP, pro-BNP and serum lyso-Gb3 were dosed. T1 mapping was performed in a pre-contrast acquisition with the modified Look-Locker inversion recovery (MOLLI) sequences. CMR results were compared with those of 43 healthy age and gender-matched controls. Results In AF patients native septal T1 values were significantly lower compared to healthy controls (median 949 vs 991 msec, p=0.0137) and were inversely related to Lyso-Gb3 serum levels (p=0.003). Patients with LVH had lower T1 septal values in comparison with patients without LVH (892 vs 981 msec; p=0.0012). Patients with classic form had abnormal low T1 values more frequently than pts with late onset variant (78 vs 23%; p=0.038). In AF patients native septal T2 values were significantly higher compared to the control group (53 vs 49 msec; p=0.0004) and correlated with troponin I (p=0.008) and NT-pro BNP (p=0.006) serum levels. No difference was found between pts with and without LVH (53.5 vs 52.5 ms; p=0.797) and the prevalence of abnormal high T2 values was similar between patients with late onset AF and pts with classical form (53% vs 50%; p=1.000). All patients with late onset AF and high T2 values were females. Conclusions CMR T1 (low values) and T2 (high values) mapping are useful tools to detect early cardiac involvement before LVH and to better understand the pathophysiology of cardiac disease in AF patients. Subclinical tissue inflammation, detectable through T2 maps, seems to be an additional pathogenetic mechanism related to the Gb3 storage that contributes to organ damage and precedes LVH, particularly in females patients with late onset phenotype. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Sant'Orsola-Malpighi Hospital

Background Differential diagnosis between Anderson-Fabry (AF) and sarcomeric hypertrophic cardiomyopathy (HCM) is often very challenging particularly in AF patients with late onset cardiac involvement. Purpose To gain new insights from standard electrocardiogram (ECG) in AF disease for differential diagnosis from sarcomeric HCM. Additionally, to better understand ECG features in AF patients, a correlation substudy ECG-cardiac magnetic resonance (CMR) has been performed. Methods From 162 patients with definite diagnosis of AF disease, 111 [65 males, median age 57 (51–67) years] with pathologic left ventricular hypertrophy (LVH) (Group A) were compared with 111 sarcomeric HCM patients (Group B) sex, age and maximal wall thickness matched by 1:1 propensity score. Results AF patients showed shorter PR interval [155 (140–180) vs 163 (149–184) msec; p=0.005) and wider QRS interval [110 (100–134) vs 100 (90–106) msec; p Conclusions Compared to matched sarcomeric HCM, AF patients had a shorter PR, wider QRS and a higher percentage of RBBB in relation to to the different aetiology (storage vs “pure” hypertrophy). The higher total QRS score and the absence of inferior Q waves could reflect the more frequent concentric distribution of LVH. Additionally negative T waves, especially in inferior leads, are related to the presence of LGE on CMR (often in the postero-lateral wall). Funding Acknowledgement Type of funding source: None

Aims The European Society of Cardiology (ESC) European Observational Research Programme (EORP) Cardiomyopathy Registry is a prospective multinational registry of consecutive patients with cardiomyopathies. The objective of this report is to describe the short-term outcomes of adult patients (≥18 years old). Methods and results Out of 3208 patients recruited, follow-up data at 1 year were obtained in 2713 patients (84.6%) [1420 with hypertrophic (HCM); 1105 dilated (DCM); 128 arrhythmogenic right ventricular (ARVC); and 60 restrictive (RCM) cardiomyopathies]. Improvement of symptoms (dyspnoea, chest pain, and palpitations) was globally observed over time (P Conclusions Despite symptomatic improvement, patients with cardiomyopathies remain prone to major clinical events in the short term. Outcomes were different not only according to cardiomyopathy subtypes but also in relatives vs. index patients, and according to European regions.

Interventional cardiology procedures require full anticoagulation to prevent thrombus formation on catheters and devices with potential development of embolic complications. Bivalirudin, a short half-life direct thrombin inhibitor, has been largely used during percutaneous coronary interventions and represents the preferred alternative to heparin in patients with heparin-induced thrombocytopenia (HIT). However, few data are available about intraprocedural use of bivalirudin during transcatheter structural heart disease interventions. Activated clotting time (ACT) monitoring during bivalirudin infusion presents some limitations and it is not mandatory. We report a case of bivalirudin use in a patient with type-2 HIT during percutaneous mitral valve repair with the Mitraclip system (Abbott, Abbott Park, Illinois, United States). Despite use of standard bivalirudin dose (0.75 mg/kg bolus and 1.4 mg/kg/min infusion—reduced infusion rate was motivated by a glomerular filtration rate of 37 mL/min), the patient developed a large thrombus on the second clip during its orientation toward the mitral orifice. ACT was measured at that time and was suboptimal (240 seconds). The case was successfully managed with clip and thrombus retrieval, adjunctive 0.3 mg/kg bivalirudin bolus and increased infusion rate, and clip repositioning with ACT monitoring. This report makes the case for mandatory ACT checking and drug titration during high-risk catheter–based structural heart disease interventions, even when thromboprophylaxis is performed with bivalirudin. Additional coagulation tests may be useful to monitor bivalirudin response in similar cases.

International audience; Among rare diseases caused by mutations in LMNA gene, Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B are characterized by muscle weakness and wasting, joint contractures, cardiomyopathy with conduction system disorders. Circulating biomarkers for these pathologies have not been identified. Here, we analyzed the secretome of a cohort of patients affected by these muscular laminopathies in the attempt to identify a common signature. Multiplex cytokine assay showed that transforming growth factor beta 2 (TGF β2) and interleukin 17 serum levels are consistently elevated in the vast majority of examined patients, while interleukin 6 and basic fibroblast growth factor are altered in subgroups of patients. Levels of TGF β2 are also increased in fibroblast and myoblast cultures established from patient biopsies as well as in serum from mice bearing the H222P Lmna mutation causing Emery-Dreifuss Muscular Dystrophy in humans. Both patient serum and fibroblast conditioned media activated a TGF β2-dependent fibrogenic program in normal human myoblasts and tenocytes and inhibited myoblast differentiation. Consistent with these results, a TGF β2 neutralizing antibody avoided fibrogenic marker activation and myogenesis impairment. Cell intrinsic TGF β2-dependent mechanisms were also determined in laminopathic cells, where TGF β2 activated AKT/mTOR phosphorylation. These data show that TGF β2 contributes to the pathogenesis of Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B and can be considered a potential biomarker of those diseases. Further, the evidence of TGF β2 pathogenetic effects in tenocytes provides the first mechanistic insight into occurrence of joint contractures in muscular laminopathies.

Laminopathies are a wide and heterogeneous group of rare human diseases caused by mutations of the LMNA gene or related nuclear envelope genes. The variety of clinical phenotypes and the wide spectrum of histopathological changes among patients carrying an identical mutation in the LMNA gene make the prognostic process rather difficult, and classical genetic screens appear to have limited predictive value for disease development. The aim of this study was to evaluate whether a comprehensive profile of circulating cytokines may be a useful tool to differentiate and stratify disease subgroups, support clinical follow-ups and contribute to new therapeutic approaches. Serum levels of 51 pro- and anti-inflammatory molecules, including cytokines, chemokines and growth factors, were quantified by a Luminex multiple immune-assay in 53 patients with muscular laminopathy (Musc-LMNA), 10 with non-muscular laminopathy, 22 with other muscular disorders and in 35 healthy controls. Interleukin-17 (IL-17), granulocyte colony-stimulating factor (G-CSF) and transforming growth factor beta (TGF-&beta, 2) levels significantly discriminated Musc-LMNA from controls, interleukin-1&beta, (IL-1&beta, ), interleukin-4 (IL-4) and interleukin-8 (IL-8) were differentially expressed in Musc-LMNA patients compared to those with non-muscular laminopathies, whereas IL-17 was significantly higher in Musc-LMNA patients with muscular and cardiac involvement. These findings support the hypothesis of a key role of the immune system in Musc-LMNA and emphasize the potential use of cytokines as biomarkers for these disorders.

Background The EORP Cardiomyopathy Registry is a prospective, observational, multinational registry of consecutive patients with cardiomyopathies. The objective of this report is to describe the outcomes at one year of follow-up of adult patients (> 18 years old) enrolled in the registry. Methods A total of 3208 patients [median age: 55.0 (43.0;64.0) years, males: 65.1%] were recruited at baseline. Follow-up data at 1 year were obtained in 2,713 patients (84.6%), including 1420 with hypertrophic (HCM), 1,105 dilated (DCM), 128 arrhythmogenic right ventricular (ARVC) and 60 restrictive cardiomyopathy (RCM) ( Fig. 1 ). Results Improvement of symptoms (NYHA, chest pain, syncope) was globally observed over time (P Conclusions Despite symptomatic improvement in most cases, there is still a significant burden of arrhythmic and heart failure events in patients with cardiomyopathies. Outcomes were different not only according to cardiomyopathy subtypes but also in relatives versus index patients.

In an era of rapid technological development and evolving diagnostic possibilities, the electrocardiogram (ECG) is living an authentic "renaissance" in myocardial diseases. To date, the ECG remains an irreplaceable first step when evaluating patients with hypertrophic cardiomyopathy (HCM) and an abnormal ECG may be the only manifestation of disease at an early stage. In some instances, specific electrical anomalies may differentiate HCM from phenocopies such as cardiac amyloidosis and glycogen storage diseases. The exponential growth in knowledge of the complexity of HCM has led to new challenges in terms of early identification of the disease, differential diagnosis, risk stratification, and development of targeted therapies. In this scenario, the apparently "old fashioned" ECG and the array of ECG-based techniques, ranging from Holter monitoring and loop recorders to exercise testing, are as contemporary as ever. In the present review, we discuss the current role of the ECG in the diagnosis and management of HCM, focusing on various clinical settings where its appropriate use and interpretation can make a difference.

BACKGROUND Cardiac Masses (CM) represent an heterogeneous group with a prevalence of 0.3% at autopsy, divided in benign masses (primary tumors and pseudotumors) and malignant ones (primitive tumors and metastasis). 2-D Echocardiography is nowadays the first line approach to define nature and management of CM, but is it enough to guide a therapeutic strategy? PURPOSE To evaluate echocardiographic diagnosis accuracy for CM in patients admitted to our Centre between 1997 and 2017. MATERIALS AND METHODS We retrospectively evaluated a population of 180 consecutive patients (45% males; mean age 60 ± 16 years; BMI 25 ± 5 Kg/m2), referred to our echocardiographic lab with suspicion CM. All patients were examined in both left lateral and supine position, and heart was visualized from all available echocardiographic windows. Definite diagnosis was obtained by histologic examination of biopsy, surgical samples or, in cases of cardiac thrombi, by radiological evidence of thrombus resolution after adequate anticoagulant treatment. We excluded normal anatomical variants in the group of pseudotumors due to the impossibility of obtaining histological examination. Sensitivity, specificity, predictive accuracy for a positive test, and predictive accuracy for a negative test were calculated by standard formulas (corrected for prevalence by Bayes theorem). RESULTS We detected 129 benign CM and 51 malignant cardiac tumors. In 7 cases a poor acoustic window did not allow an optimal examination; in remaining 173 patients, the classical 2-D echocardiogram identified 157 masses with a diagnostic accuracy of 91%. Of 173 CM diagnosed, 146 were classified by echocardiographer as benign masses (125 true benign on histological examination) and 27 as malignant ones (all malignant after histological confirmation); the results showed 56% sensitivity, 100% specificity, 100% positive predictive value, 98% negative predictive value, with 88% overall diagnostic accuracy in identifying the nature of masses. 23 cases were undetermined and needed second level instrumental investigations to be characterized. Diagnostic accuracy for distinguishing primary benign tumors and pseudotumors decreased to 80%, with a significant increase in both "false" benign tumors (9 out of 91) and "false" pseudotumors (15 out of 34) with 85% sensitivity, 68% specificity, 10% positive predictive value, 99% negative predictive value. CONCLUSION 2D Echocardiography is an excellent, non invasive technique for first line evaluation of patients with suspicion CM. It is safe, reliable with a high predictive value and diagnostic accuracy in identifying CM and their benign or malignant nature. In contrast, these results were insufficient to start an anticoagulant in suspicion thrombus or cardiac surgery for primary tumor, since second level instrumental examinations needed. 2D Echocardiography alone seems unuseful for classifying malignant masses in primitive or metastasis.

Aims The optimization of guideline‐directed medical therapy (GDMT) in reduced ejection fraction heart failure (HFrEF) is associated with improved survival and can reduce the severity of secondary mitral regurgitation (SMR). Highest tolerated doses should be achieved before percutaneous mitral valve repair (pMVR) and drugs titration further pursued after procedure. The degree of GDMT titration in patients with HFrEF and SMR treated with pMVR remains unexplored. We sought to evaluate the adherence to GDMT in HFrEF in patients undergoing pMVR and to explore the association between changes in GDMT post‐pMVR and prognosis. Methods and results We included all the patients with HFrEF and SMR ≥ 3 + treated with pMVR between 2012 and 2019 and with available follow‐up. GDMT, comprehensive of dosages, was systematically recorded. The study endpoint was a composite of death and heart transplantation. Among 133 patients successfully treated, 121 were included (67 ± 12 years old, 77% male patients). Treatment rates of angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor neprilysin inhibitor (ACEIs/ARBs/ARNI), beta‐blockers, and mineralcorticoid receptor antagonist at baseline and follow‐up were 73% and 79%, 85% and 84%, 70% and 70%, respectively. At baseline, 33% and 32% of patients were using >50% of the target dose of ACEI/ARB/ARNI and beta‐blockers. At follow‐up (median time 4 months), 33% of patients unchanged, 34% uptitrated, and 33% of patients downtitrated GDMT. Downtitration of GDMT was independently associated with higher risk of death/heart transplantation (hazard ratio: 2.542, 95%confidence interval: 1.377–4.694, P = 0.003). Conclusions Guideline‐directed medical therapy is frequently underdosed in HFrEF patients with SMR undergoing pMVR. Downtitration of medications after procedure is associated with poor prognosis.

Fabry disease is classified as a rare X-linked disease caused by a complete or partial defect of enzyme alpha-galactosidase, due to GLA gene mutations. This disorder leads to intracellular globotriaosylceramide (Gb3) deposition associated with increased Gb3 plasma levels. Most of the symptoms of the disease, involving kidneys, heart and nervous system, result from this progressive Gb3 deposition. The incidence is estimated in 1/50,000 to 1/117,000 in males. Fabry nephropathy begins with microalbuminuria and/or proteinuria, which, in the classic form, appear from childhood. Thus, a progressive decline of renal function can start at a young age, and evolve to kidney failure, requiring dialysis or renal transplantation. Enzyme replacement therapy (ERT), available since 2001 for Fabry disease, has been increasingly introduced into the clinical practice, with overall positive short-term and long-term effects in terms of ventricular hypertrophy and renal function. Kidney transplantation represents a relevant therapeutic option for Fabry nephropathy management, for patients reaching end-stage renal disease, but little is known about long-term outcomes, overall patient survival or the possible role of ERT after transplant. The purpose of this review is to analyze the literature on every aspect related to kidney transplantation in patients with Fabry nephropathy: from the analysis of transplant outcomes, to the likelihood of disease recurrence, up to the effects of ERT and its possible interference with immunosuppression.

BACKGROUND Cardiac Masses (CM) represent a rare and heterogeneous group with a prevalence of 0.3% at autopsy, divided in benign masses - primary tumors and pseudotumors - and malignant ones - primitive tumors and metastasis, either directly invading the heart and pericardium or as a consequence of hematologic spread. 2-D Echocardiography is nowadays the first line approach to define nature and management of CM, but is it enough to guide a therapeutic strategy? PURPOSE To evaluate echocardiographic CM malignancy features in patients admitted to our Centre between 1997 and 2017. MATERIALS AND METHODS We retrospectively evaluated a population of 180 consecutive patients (45% males; mean age 60 ± 16 years; BMI 25 ± 5 Kg/m2), referred to our echocardiographic lab with suspicion CM. All patients were examined in both left lateral and supine position, and heart was visualized from all available echocardiographic windows. Definite diagnosis was obtained by histologic examination of biopsy, surgical samples or, in cases of cardiac thrombi, by radiological evidence of thrombus resolution after adequate anticoagulant treatment. We excluded normal anatomical variants in the group of pseudotumors due to the impossibility of obtaining histological examination. Comparisons between categorical variables were performed by Chi-square or Fisher exact test. P values ≤ 0.05 were considered significant. Variables with statistical signification lower than p ≤ 0.05 in univariable analysis were included in logistic regression analysis to determinate independent predictors of malignant masses. RESULTS We detected 129 benign CM (76% primitive tumors and 24% pseudotumors) and 51 malignant cardiac tumors (45% primitive tumors and 55% metastasis). In 7 cases a poor acoustic window did not allow an optimal examination; in remaining 173 patients, the classical 2-D echocardiogram identified 157 masses with a diagnostic accuracy of 91%. Benign tumors and pseudotumours were localized predominantly in left heart chambers, while malignant primitive tumors and metastasis were mainly detected in right heart, in pericardium or in pulmonary artery branches (p < 0.001). The largest ecocardiographic diameter appeared greater for the malignant masses (mean of 49 ± 26 mm) than benign ones (30 ± 16 mm, p = 0.003). The occurrance of any pericardial effusion (p < 0.001), extension to pericardium (p = 0.01) or to main vessels (p = 0.006) were also associated with malignant masses. Finally, multivariate analysis showed only largest diameter (p = 0.001) and pericardial effusion (p < 0.001) were independent predictors of malignancy. CONCLUSION 2D Echocardiography is an excellent, non invasive technique for first line evaluation of patients with suspicion CM. It is safe, accurate and have high diagnostic accuracy in identifying CM and their benign or malignant nature. In particular, a large mass associated with any pericardial effusion must pose suspect of malignancy.

Objective To investigate differences in cardiac manifestations of patients affected by laminopathy, according to the presence or absence of neuromuscular involvement at presentation. Methods We prospectively analyzed 40 consecutive patients with a diagnosis of laminopathy followed at a single centre between 1998 and 2017. Additionally, reports of clinical evaluations and tests prior to referral at our centre were retrospectively evaluated. Results Clinical onset was cardiac in 26 cases and neuromuscular in 14. Patients with neuromuscular presentation experienced first symptoms earlier in life (11 vs 39 years; p p = 0.013] and 30 vs 44 years [p = 0.086] respectively), despite a similar overall prevalence of AF (57% vs 65%; p = 0.735) and atrio-ventricular (A-V) block (50% vs 65%; p = 0.500). Those with a neuromuscular presentation developed a cardiomyopathy less frequently (43% vs 73%; p = 0.089) and had a lower rate of sustained ventricular tachyarrhythmias (7% vs 23%; p = 0.387). In patients with neuromuscular onset rhythm disturbances occurred usually before evidence of cardiomyopathy. Despite these differences, the need for heart transplantation and median age at intervention were similar in the two groups (29% vs 23% [p = 0.717] and 43 vs 46 years [p = 0.593] respectively). Conclusions In patients with laminopathy, the type of disease onset was a marker for a different natural history. Specifically, patients with neuromuscular presentation had an earlier cardiac involvement, characterized by a linear and progressive evolution from rhythm disorders (AF and/or A-V block) to cardiomyopathy.

Aim To look for differences in cardiac phenotype and natural history of patients affected by laminopathy, according to the presence or less of neuromuscular involvement at clinical presentation. Methods We prospectively analyzed 47 consecutive pts with a genetic diagnosis of laminopathy followed at a single centre between 1994 and 2017. Additionally, reports of clinical and instrumental evaluations before referral at our centre were retrospectively evaluated. Results Neuromuscular presentation, mainly as Emery-Dreifuss muscular dystrophy (EDMD), was present in 21 (46%) cases (14 LMNA and 7 EMD gene mutations). These pts had symptoms earlier (9 vs 39 years, p Conclusions In pts affected by laminopathy neuromuscular involvement, when present, was most often the first clinical manifestation and preceded cardiological involvement, with a long time frame in some cases. Except for sinus node dysfunction, much more frequent in patients with EDMD, a similar prevalence of rhythm disturbances was reported, although pts with neuromuscular clinical onset were younger at diagnosis of AF and at PM implantation. Pts without neuromuscular presentation had a higher prevalence of CMP and ventricular arrhythmias, albeit a similar rate of heart transplantation. In pts with neuromuscular onset, cardiac involvement was characterized by a stepwise progression from rhythm disturbances to CMP, where a strict temporal progression from rhythm disturbances to CMP was not observed in the group of pts without neuromuscular clinical onset.

Background Cardiac involvement is one of the most frequent and disabling organ damage in Anderson-Fabry (AF) disease, causing hypertrophic cardiomyopathy (HCM), conduction disturbances, arrhythmias and coronary disease. Differential diagnosis from sarcomeric HCM is often very challenging, especially for patients with exclusive cardiac involvement. Purpose To gain new insights from standard electrocardiogram (ECG) in AF disease, and identify ECG differences from sarcomeric HCM. Methods Sixty-two consecutive patients (27 males, mean age: 62±16 years) with definite diagnosis of AF disease from 2 Italian centres were evaluated for ECG analysis and divided in 2 groups, according to the presence (Group A, N=39) or the absence (Group B, N=26) of cardiac involvement [hypertrophy detected at echocardiogram or cardiac magnetic resonance (CMR)]. All ECGs were analysed by 2 independent investigators. For Group A, when CMR was performed, a correlation between CMR and ECG was assessed. Patients with cardiac involvement were matched with 78 sarcomeric HCM patients according to sex, age and septal wall thickness on echocardiogram. Results Two AF patients out 39 with cardiac involvement (5%) had normal ECG. Short PR and I degree atrio-ventricular (AV) block were both reported in 6 (15%) cases. Twenty-six (67%) patients showed left ventricular hypertrophy and the majority (85%) had abnormal repolarization. CMR was performed in 22 patients (56%); the 11 (50%) patients with replacement fibrosis had a higher mean Sokolow-Lyon score (4.1±1.8 vs 2.9±1.0 mV; p=0.05), more frequent ST segment depression (82 vs 27%; p=0.03) and negative T waves (91 vs 36%; p=0.027; sensitivity: 90%; specificity: 63%), compared with the 11 without replacement fibrosis. When compared with sarcomeric HCM, AF patients with cardiac involvement had a significantly wider QRS (120±30 vs 100±16 msec; p Among Group B AF patients (26, mean age: 36±12 years), 4 had short PR and 5 incomplete RBBB. Four had an abnormal ECG (1 left atrial enlargement, 2 unspecific repolarization abnormalities, 1 Sokolow score of 3.5 mV). Conclusions Standard ECG can detect cardiac involvement in AF disease. A good correlation was reported between repolarization abnormalities and replacement fibrosis on CMR. Wide QRS and RBBB were more frequent among AF patients compared to age-sex-matched sarcomeric HCM ones, probably due to the different aetiology of the diseases (infiltrative disease vs pure hypertrophy).

Aims Truncating titin mutations (tTTN) occur in 25% of dilated cardiomyopathy (DCM) cases, but the phenotype and severity of disease they cause have not yet been systematically studied. We studied whether tTTN variants are associated with a clinically distinguishable form of DCM. Methods and results We compared clinical data on DCM probands and relatives with a tTTN mutation (n = 45, n = 73), LMNA mutation (n = 28, n = 29), and probands who tested negative for both genes [idiopathic DCM (iDCM); n = 60]. Median follow-up was at least 2.5 years in each group. TTN subjects presented with DCM at higher age than LMNA subjects (probands 47.9 vs. 40.4 years, P = 0.004; relatives 59.8 vs. 47.0 years, P = 0.01), less often developed LVEF

AIMS: Despite troponin assay being a part of the diagnostic work up in many conditions with acute chest pain, little is known about its frequency and clinical implications in acute aortic syndromes (AASs). In our study we assessed frequency, impact on diagnostic delay, inappropriate treatments, and prognosis of troponin elevation in AAS.METHODS AND RESULTS: Data were collected from a prospective metropolitan AAS registry (398 patients diagnosed between 2000 and 2013). Cardiac troponin test, using either standard or high sensitivity assay, was performed according to standard protocol used in chest pain units. Troponin T values were available in 248 patients (60%) of the registry population; the overall frequency of troponin positivity was 28% (ranging from 16% to 54%, using standard or high sensitivity assay respectively, p = 0.001). Troponin positivity was frequently associated with acute coronary syndromes (ACS)-like electrocardiogram findings, and with a twofold increased risk of long in-hospital diagnostic time (odds ratio (OR) 1.92, 95% confidence interval (CI) 1.05-3.52, p = 0.03). The combination of positive troponin and ACS-like electrocardiogram abnormalities resulted in a significantly increased risk of in-hospital delay/coronary angiography/antithrombotic therapy due to a misdiagnosis of ACS (OR 2.48, 95% CI 1.12-5.54, p = 0.02). However, troponin positivity was not associated with in-hospital mortality (OR 1.63, 95% CI 0.86-3.10, p = 0.131).CONCLUSIONS: Troponin positivity was a frequent finding in AAS patients, particularly when a high sensitivity assay was employed. Abnormal troponin values were strongly associated with ACS-like electrocardiogram findings and with in-hospital diagnostic delay but apparently they did not influence in-hospital mortality.

Anderson-Fabry disease (AFD) is a rare X-linked lysosomal storage disease, caused by defects of the alpha-galactosidase A (GLA) gene. AFD can affect the heart, brain, kidney, eye, skin, peripheral nerves, and gastrointestinal tract. Cardiology (hypertrophic cardiomyopathy), neurology (cryptogenic stroke), and nephrology (end-stage renal failure) screening studies suggest the prevalence of GLA variants is 0.62%, with diagnosis confirmation in 0.12%. OBJECTIVES: This study sought to expand screening from these settings to include ophthalmology, dermatology, gastroenterology, internal medicine, pediatrics, and medical genetics to increase diagnostic yield and comprehensively evaluate organ involvement in AFD patients. METHODS: In a 10-year prospective multidisciplinary, multicenter study, we expanded clinical, genetic, and biochemical screening to consecutive patients enrolled from all aforementioned clinical settings. We tested the GLA gene and α-galactosidase A activity in plasma and leukocytes. Inclusion criteria comprised phenotypical traits and absence of male-to-male transmission. Screening was extended to relatives of probands harboring GLA mutations. RESULTS: Of 2,034 probands fulfilling inclusion criteria, 37 (1.8%) were carriers of GLA mutations. Cascade family screening identified 60 affected relatives; clinical data were available for 4 affected obligate carriers. Activity of α-galactosidase A in plasma and leukocytes was diagnostic in male subjects, but not in female subjects. Of the 101 family members harboring mutations, 86 were affected, 10 were young healthy carriers, and 5 refused clinical evaluation. In the 86 patients, involved organs or organ systems included the heart (69%), peripheral nerves (46%), kidney (45%), eye (37%), brain (34%), skin (32%), gastrointestinal tract (31%), and auditory system (19%). Globotriaosylceramide accumulated in organ-specific and non-organ-specific cells in atypical and classic variants, respectively. CONCLUSIONS: Screening probands with clinically suspected AFD significantly increased diagnostic yield. The heart was the organ most commonly involved, independent of the clinical setting in which the patient was first evaluated. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

The coexistence of GLA (Pro259Ser, c.775C>T) and MYBPC3 (c.1351+2T>C) mutations was found in a female patient with hypertrophic cardiomyopathy. Histology documented abundant vacuolisation with osmiophilic lamellar bodies and positive Gb3 immunohistochemistry. In the presence of a hypertrophic cardiomyopathy phenotype, the systematic search for unusual findings is mandatory to rule out a phenocopy.

Background: Although imaging techniques have demonstrated the existence of microvascular abnormalities in hypertrophic cardiomyopathy (HCM), a detailed histopathological assessment is lacking as well as a comparison between different phases of the disease. We aimed to compare microvasculopathy and myocardial fibrosis in hypertrophic obstructive cardiomyopathy (HOCM) versus end-stage (ES) HCM. Methods: 27 myectomy specimens of HOCM patients and 30 ES-HCM explanted hearts were analyzed. Myocardial fibrosis was quantitatively determined with dedicated software and qualitatively classified as scar-like or interstitial. Intramural coronary arteries were evaluated separately according to lumen diameter: 100–500 μ versus

Lamin A/C gene mutations can be associated with cardiac diseases, usually referred to as ‘cardiolaminopathies’ characterized by arrhythmic disorders and/or left ventricular or biventricular dysfunction up to an overt picture of heart failure. The phenotypic cardiac manifestations of laminopathies are frequently mixed in complex clinical patterns and specifically may include bradyarrhythmias (sinus node disease or atrioventricular blocks), atrial arrhythmias (atrial fibrillation, atrial flutter, atrial standstill), ventricular tachyarrhythmias and heart failure of variable degrees of severity. Family history, physical examination, laboratory findings (specifically serum creatine phosphokinase values) and ECG findings are often important ‘red flags’ in diagnosing a ‘cardiolaminopathy’. Sudden arrhythmic death, thromboembolic events or stroke and severe heart failure requiring heart transplantation are the most dramatic complications of the evolution of cardiolaminopathies and appropriate risk stratification is clinically needed combined with clinical follow-up. Treatment with cardiac electrical implantable devices is indicated in case of bradyarrhythmias (implant of a device with pacemaker functions), risk of life-threatening ventricular tachyarrhythmias (implant of an ICD) or in case of heart failure with wide QRS interval (implant of a device for cardiac resynchronization). New technologies introduced in the last 5 years can help physicians to reduce device-related complications, thanks to the extension of device longevity and availability of leadless pacemakers or defibrillators, to be implanted in appropriately selected patients. An improved knowledge of the complex pathophysiological pathways involved in cardiolaminopathies and in the determinants of their progression to more severe forms will help to improve clinical management and to better target pharmacological and non-pharmacological treatments.

Aims Although acute heart failure (AHF) is a potential complication of acute aortic syndromes (AAS), its clinical details and management implications have been scarcely evaluated. This study aimed to assess prevalence, pathophysiological mechanisms, impact on treatment, and in-hospital mortality of AHF in AAS. Methods and results Data were collected from a prospective AAS registry (398 patients diagnosed between 2000 and 2013). Patients with AHF were identified by the presence of dyspnoea as the presentation symptom or radiological signs of pulmonary congestion or cardiogenic shock, including patients with cardiac tamponade (CT). AHF frequency was 28% (Stanford type A 32% vs. type B 20%, P = 0.01). Four mechanisms leading to AHF were identified, alone or in combination: CT (26%), aortic regurgitation (25%), myocardial ischaemia (17%), and hypertensive crisis (10%). In type A patients, aortic regurgitation and CT were the most frequent mechanisms, whereas myocardial ischaemia and hypertensive crisis were the most frequent in type B patients. Although no difference was noted for diagnostic times, AHF at presentation led to a longer surgical delay in type A AAS. In-hospital mortality was higher in patients with AHF compared with those without (34% vs. 17%, P < 0.001). After multivariable analysis, AHF was associated with increased risk of in-hospital death (adjusted odds ratio 1.97, 95% confidence interval 1.14–3.36, P = 0.014). Conclusion AHF occurs in more than a quarter of patients with AAS of both type A and type B, is due to a variety of pathophysiological mechanisms, and is associated with increased surgical delay and in-hospital mortality.

ObjectiveIn 2014, the European Society of Cardiology (ESC) recommended the use of a novel risk prediction model (HCM Risk-SCD) to guide use of implantable cardioverter defibrillators (ICD) for the primary prevention of sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HCM). We sought to determine the performance of HCM Risk-SCD by conducting a systematic review and meta-analysis of articles reporting on the prevalence of SCD within 5 years of evaluation in low, intermediate and high-risk patients as defined by the 2014 guidelines (predicted risk MethodsThe protocol was registered with PROSPERO (registration number: CRD42017064203). MEDLINE and manual searches for papers published from October 2014 to December 2017 were performed. Longitudinal, observational cohorts of unselected adult patients, without history of cardiac arrest were considered. The original HCM Risk-SCD development study was included a priori. Data were pooled using a random effects model.ResultsSix (0.9%) out of 653 independent publications identified by the initial search were included. The calculated 5-year risk of SCD was reported in 7291 individuals (70% low, 15% intermediate; 15% high risk) with 184 (2.5%) SCD endpoints within 5 years of baseline evaluation. Most SCD endpoints (68%) occurred in patients with an estimated 5-year risk of ≥4% who formed 30% of the total study cohort. Using the random effects method, the pooled prevalence of SCD endpoints was 1.01% (95% CI 0.52 to 1.61) in low-risk patients, 2.43% (95% CI 1.23 to 3.92) in intermediate and 8.4% (95% CI 6.68 to 10.25) in high-risk patients.ConclusionsThis meta-analysis demonstrates that HCM Risk-SCD provides accurate risk estimations that can be used to guide ICD therapy in accordance with the 2014 ESC guidelines.Registration numberPROSPERO CRD42017064203;Pre-results.

Background Patients with heart failure (HF) and severe symptomatic functional mitral regurgitation (FMR) may benefit from MitraClip implantation. With increasing numbers of patients being treated the success of procedure becomes a key issue. We sought to investigate the pre-procedural predictors of device failure in patients with advanced HF treated with MitraClip. Methods From April 2012 to November 2016, 76 patients with poor functional class (NYHA class III–IV) and severe left ventricular (LV) remodeling underwent MitraClip implantation at University Hospitals of Trieste and Bologna (Italy). Device failure was assessed according to MVARC criteria. Patients were subsequently followed to additionally assess the patient success after 12months. Results Mean age was 67±12years, the mean Log-EuroSCORE was 23.4±16.5%, and the mean LV end-diastolic volume index and ejection fraction (EF) were 112±33ml/m 2 and 30.6±8.9%, respectively. At short-term evaluation, device failure was observed in 22 (29%) patients. Univariate predictors of device failure were LVEF, LV and left atrial volumes and anteroposterior mitral annulus diameter. Annulus dimension (OR 1.153, 95% CI 1.002–1.327, p =0.043) and LV end-diastolic volume (OR 1.024, 95% CI 1.000–1.049, p =0.049) were the only variables independently associated with the risk of device failure at the multivariate model. Conclusions Pre-procedural anteroposterior mitral annulus diameter accurately predicted the risk of device failure after MitraClip in the setting of advanced HF. Its assessment might aid the selection of the best candidates to percutaneous correction of FMR.

Importance: Sudden cardiac death (SCD) is the most common mode of death in childhood hypertrophic cardiomyopathy (HCM), but there is no validated algorithm to identify those at highest risk.Objective: To develop and validate an SCD risk prediction model that provides individualized risk estimates.Design, Setting, and Participants: A prognostic model was developed from a retrospective, multicenter, longitudinal cohort study of 1024 consecutively evaluated patients aged 16 years or younger with HCM. The study was conducted from January 1, 1970, to December 31, 2017.Exposures: The model was developed using preselected predictor variables (unexplained syncope, maximal left-ventricular wall thickness, left atrial diameter, left-ventricular outflow tract gradient, and nonsustained ventricular tachycardia) identified from the literature and internally validated using bootstrapping.Main Outcomes and Measures: A composite outcome of SCD or an equivalent event (aborted cardiac arrest, appropriate implantable cardioverter defibrillator therapy, or sustained ventricular tachycardia associated with hemodynamic compromise).Results: Of the 1024 patients included in the study, 699 were boys (68.3%); mean (interquartile range [IQR]) age was 11 (7-14) years. Over a median follow-up of 5.3 years (IQR, 2.6-8.3; total patient years, 5984), 89 patients (8.7%) died suddenly or had an equivalent event (annual event rate, 1.49; 95% CI, 1.15-1.92). The pediatric model was developed using preselected variables to predict the risk of SCD. The model's ability to predict risk at 5 years was validated; the C statistic was 0.69 (95% CI, 0.66-0.72), and the calibration slope was 0.98 (95%, CI 0.59-1.38). For every 10 implantable cardioverter defibrillators implanted in patients with 6% or more of a 5-year SCD risk, 1 patient may potentially be saved from SCD at 5 years.Conclusions and Relevance: This new, validated risk stratification model for SCD in childhood HCM may provide individualized estimates of risk at 5 years using readily obtained clinical risk factors. External validation studies are required to demonstrate the accuracy of this model's predictions in diverse patient populations.

To assess the accuracy of cardiac magnetic resonance (CMR) for the diagnosis of angiographic stenosis after percutaneous coronary intervention (PCI) of left main coronary artery (LMCA). Patients undergone in the last year PCI of unprotected LMCA and scheduled for conventional X-ray coronary angiography (CXA) were evaluated with stress perfusion CMR within 2 weeks before CXA. Main contraindications to CMR were exclusion criteria. Stress perfusion CMR was performed to follow a bolus of contrast Gadobutrol after 3 min of adenosine infusion. Between the 50 patients enrolled, only 1 did not finish the CMR protocol and 49 patients with median age 71 (65–75) years (38 male, 11 female) were analyzed. Between 784 coronary angiographic segments evaluated we found 75 stenosis or occlusions (prevalence 9.5%), but only 13 stenosis or occlusions in proximal segments (prevalence 6.6%). Patients with coronary stenosis (n = 12, 24%) showed a significantly (p = 0.002) higher prevalence of diabetes (7 of 12, 58%). At CMR examination, late gadolinium enhancement was present in 25 (51%), reversible perfusion defects in 12 (24%), and fixed perfusion defects in 6 subjects (12%). The only patient with LMCA restenosis resulted positive at perfusion CMR. The accuracy of stress perfusion CMR in diagnosis of coronary stenosis was higher when the analysis was performed only in proximal coronary arteries (95%, CI 86–99) compared to overall vessels (84%, CI 70–92). Stress perfusion CMR could strongly reduce the need for elective CXA in follow up of LMCA PCI and should be validated in further multicenter prospective studies.

Objectives Atrial fibrillation (AF) is associated with increased morbidity and mortality in patients with hypertrophic cardiomyopathy (HCM). The primary aim of this study (HCM Risk-AF) was to determine the predictors of AF in a large multicentre cohort of patients with HCM. Exploratory analyses were performed to investigate the association between AF and survival and the efficacy of antiarrhythmic therapy in maintaining sinus rhythm (SR). Methods A retrospective, longitudinal cohort of patients recruited between 1986 and 2008 in seven centres was used to develop multivariable Cox regression models fitted with preselected predictors. HCM was defined as unexplained hypertrophy (maximum left ventricular wall thickness of ≥15 mm or in accordance with published criteria for the diagnosis of familial disease). 28% of patients (n=1171) had coexistent hypertension. The primary end point was paroxysmal, permanent or persistent AF detected on ECG, Holter monitoring or implantable device interrogation. Results Of the 4248 patients with HCM without pre-existing AF, 740 (17.4%) reached the primary end point. Multivariable Cox regression revealed an association between AF and female sex, age, left atrial diameter, New York Heart Association (NYHA) class, hypertension and vascular disease. The proportion of patients with cardiovascular death at 10 years was 4.9% in the SR group and 10.9% in the AF group (difference in proportions=5.9%; 95% CI (4.1% to 7.8%)). The proportion of patients with non-cardiovascular death at 10 years was 3.2% in the SR group and 5.9% in the AF group (difference in proportions=2.8%; 95% CI (0.1% to 4.2%)). An intention-to-treat propensity score analysis demonstrated that β-blockers, calcium channel antagonists and disopyramide initially maintained SR during follow-up, but their protective effect diminished with time. Amiodarone therapy did not prevent AF during follow-up. Conclusion This study shows that patients with HCM who are at risk of AF development can be identified using readily available clinical parameters. The development of AF is associated with a poor prognosis but there was no evidence that antiarrhythmic therapy prevents AF in the long term.

Importance Diagnostic screening for Anderson-Fabry cardiomyopathy (AFC) is performed in the presence of specific clinical red flags in patients with hypertrophic cardiomyopathy (HCM) older than 25 years. However, left ventricular outflow tract obstruction (LVOTO) has been traditionally considered an exclusion criteria for AFC. Objective To examine a series of patients diagnosed with HCM and severe basal LVOTO undergoing myectomy in whom the diagnosis of AFC was suspected by the cardiac surgeon intraoperatively and confirmed by histological and genetic examinations. Design, Setting, and Participants This retrospective analysis of patients undergoing surgical septal reduction strategies was conducted in 3 European tertiary referral centers for HCM from July 2013 to December 2016. Patients with a clinical diagnosis of obstructive HCM referred for surgical management of LVOTO were observed for at least 18 months after the procedure (mean [SD] follow-up, 33 [14] months). Main Outcomes and Measures Etiology of patients with HCM who underwent surgical myectomy. Results From 2013, 235 consecutive patients with a clinical diagnosis of HCM underwent septal myectomy. The cardiac surgeon suspected a storage disease in 3 patients (1.3%) while inspecting their heart samples extracted from myectomy. The mean (SD) age at diagnosis for these 3 patients was 42 (4) years; all were male. None of the 3 patients presented with extracardiac features suggestive of AFC. All patients showed asymmetrical left ventricular hypertrophy, with maximal left ventricular thickness in the basal septum (19-31 mm), severe basal LVOTO (70-120 mm Hg), and left atrial dilatation (44-57 mm). Only 1 patient presented with late gadolinium enhancement on cardiovascular magnetic resonance at the right ventricle insertion site. The mean (SD) age at surgical procedure was 63 (5) years. On tactile sensation, the surgeon felt a spongy consistency of the surgical samples, different from the usual stony-elastic consistency typical of classic HCM, and this prompted histological examinations. Histology showed evidence of intracellular storage, and genetic analysis confirmed a GLA A gene mutation (p.Asn215Ser) in all 3 patients. Conclusions and Relevance Screening for AFC should be performed even in the absence of red flags in patients with HCM older than 25 years.

Background The role of percutaneous mitral valve repair (PMVR) in patients with end-stage heart failure (HF) and functional mitral regurgitation (FMR) is unclear. Methods Seventy-five consecutive patients with FMR grade ≥ 3 + and severe HF symptoms despite optimal medical therapy and resynchronization therapy underwent PMVR with the MitraClip system (Abbott, Abbott Park, IL, USA) at 3 centers. Clinical evaluation, echocardiography and pro-BNP measurement were performed at baseline and at 6-month. Results Mean age was 67 ± 11 years, logistic EuroSCORE = 23 ± 18%, left ventricle ejection fraction (LVEF) 30 ± 9%. In 6 patients (8%) PMVR was performed as a bridge to heart transplant; many patients were dependent from iv diuretics and/or inotropes. Rate of serious adverse in-hospital events was 1.3% (1 patient who died after conversion to cardiac surgery). Sixty-three patients (84%) were discharged with MR ≤ 2 +. At 6-month, 4 patients died (5%), 80% had MR ≤ 2 + and 75% were in New York Heart Association class ≤ II. Median pro-BNP decreased from 4395 pg/ml to 2594 pg/ml (p = 0.04). There were no significant changes in LV end-diastolic volume (222 ± 75 ml vs. 217 ± 79, p = 0.19), end-systolic volume (LVESV, 154 ± 66 ml vs. 156 ± 69, p = 0.54) and LVEF (30 ± 9% vs. 30 ± 12%, p = 0.86). Significant reverse remodeling (reduction of LVESV ≥ 10%) was observed in 25%, without apparent association with baseline characteristics. The number of hospitalizations for HF in comparison with the 6 months before PMVR were reduced from 1.1 ± 0.8 to 0.3 ± 0.6 (p

Background— Although noninvasively detected myocardial fibrosis (MF) has clinical implications in hypertrophic cardiomyopathy, the extent, type, and distribution of ventricular MF have never been extensively pathologically characterized. We assessed the overall amount, apex-to-base, circumferential, epicardial–endocardial distribution, pattern, and type of MF in 30 transplanted hearts of end-stage, hypertrophic cardiomyopathy. Methods and Results— Visual and morphometric histological analyses at basal, midventricular, and apical levels were performed. Overall MF ranged from 23.1% to 55.9% (mean=37.3±8.4%). Prevalent types of MF were as follows: replacement in 53.3%, interstitial-perimyocyte in 13.3%, and mixed in 33.3%. Considering left ventricular base-to-apex distribution, MF was 31.9%, 43%, and 46.2% at basal, midventricular, and apical level, respectively ( P Conclusions— In end-stage, hypertrophic cardiomyopathy patients undergoing transplantation, more than one-third of the left ventricular myocardium was replaced by fibrosis, mainly of replacement type. MF preferentially involved the left ventricular apex and the midwall. Inferior and anterior walls and septum were maximally involved, whereas inferolateral and right ventricular were usually spared. These observations reflect the complex pathophysiology of hypertrophic cardiomyopathy and may provide clues for the timely recognition of disease progression by imaging techniques capable of quantifying MF.

BACKGROUND: Severe left ventricular (LV) systolic dysfunction is an uncommon complication of hypertrophic cardiomyopathy (HCM) that is associated with poor prognosis. Small observational series suggest that patients with rare causes of HCM are more likely to develop systolic impairment than those with idiopathic disease or mutations in cardiac sarcomeric protein genes. The aim of this study was to test this hypothesis by comparing the prevalence of systolic dysfunction and its impact on prognosis in patients with different causes of HCM. METHODS AND RESULTS: 1697 patients (52 (40-63) years, 1160 (68%) males) with HCM followed at two European referral centres were studied. Diagnosis of specific aetiologies was made on the basis of clinical examination, cardiac imaging and targeted genetic and biochemical testing. The primary survival outcome was all-cause mortality or heart transplantation (HTx) for end-stage heart failure (HF). Secondary outcomes were HF-related death, sudden cardiac death, stroke-related death and non-cardiovascular death. Systolic dysfunction (LV ejection fraction