Publications by authors named "Maurizio Pieroni"

105 Publications

Cytosorb treatment in severe COVID-19 cardiac and pulmonary disease.

Eur Heart J Case Rep 2021 Apr 12;5(4):ytab123. Epub 2021 Apr 12.

Cardiovascular, Respiratory and Neurological Department, Via Pietro Nenni 22, San Donato Hospital, Arezzo 52100, Italy.

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http://dx.doi.org/10.1093/ehjcr/ytab123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039116PMC
April 2021

Cardiac Involvement in Fabry Disease: JACC Review Topic of the Week.

J Am Coll Cardiol 2021 Feb;77(7):922-936

Hôpitaux Universitaires de Genève, Genève, Switzerland.

Fabry disease (FD) is a rare X-linked inherited lysosomal storage disorder caused by deficient α-galactosidase A activity that leads to an accumulation of globotriasylceramide (Gb3) in affected tissues, including the heart. Cardiovascular involvement usually manifests as left ventricular hypertrophy, myocardial fibrosis, heart failure, and arrhythmias, which limit quality of life and represent the most common causes of death. Following the introduction of enzyme replacement therapy, early diagnosis and treatment have become essential to slow disease progression and prevent major cardiac complications. Recent advances in the understanding of FD pathophysiology suggest that in addition to Gb3 accumulation, other mechanisms contribute to the development of Fabry cardiomyopathy. Progress in imaging techniques have improved diagnosis and staging of FD-related cardiac disease, suggesting a central role for myocardial inflammation and setting the stage for further research. In addition, with the recent approval of oral chaperone therapy and new treatment developments, the FD-specific treatment landscape is rapidly evolving.
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http://dx.doi.org/10.1016/j.jacc.2020.12.024DOI Listing
February 2021

Right ventricular strain in Anderson-Fabry disease.

Int J Cardiol 2021 May 15;330:84-90. Epub 2021 Feb 15.

Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Catholic University of the Sacred Heart, Rome, Italy.

Background: 2D speckle tracking echocardiography (2DSTE) is superior to standard echocardiography in the assessment of subtle right ventricle (RV) systolic dysfunction. In this study we aimed to: 1) test the hypothesis that 2DSTE may unveil subtle RV systolic dysfunction in patients with Fabry disease; 2) investigate whether the physiologic difference between the 3-segment (RV-FWS) and the 6-segment (RV-GLS) RV strain (∆RV strain) is preserved in Fabry patients.

Methods And Results: Standard echocardiography and 2DSTE were performed in 49 Fabry patients and 49 age- and sex-matched healthy controls. Fabry patients were divided in two groups according to the presence/absence of left ventricular hypertrophy (LVH+: left ventricular wall thickness > 12 mm, 49% of total Fabry patients). RV systolic function assessed by standard echocardiography was normal in the majority of Fabry patients (92%) while RV-GLS and RV-FWS were impaired in about 40%. RV-GLS and RV-FWS were significantly worse in patients LVH+ vs LVH- and vs controls (RV-GLS: LVH+ vs LVH-: -18.4 ± -4.3% vs -23.8 ± -3.1% p<0.001; LVH+ vs controls: -18.4 ± -4.3% vs -23.9 ± -2.8% p<0.001; RV-FWS: LVH+ vs LVH-: -21.8 ± -5.3% vs -26.7 ± -3.8% p = 0.002, LVH+ vs controls -21.8 ± -5.3% vs -26.8 ± -3.9% p<0.001). No difference was found between LVH- patients and controls in both RV-GLS (p = 0.65) and RV-FWS (p = 0.79). ∆RV strain was similar among the groups.

Conclusions: In Fabry cardiomyopathy impaired RV-GLS and RV-FWS is a common finding, while RV strain is preserved in Fabry patients without overt cardiac involvement. The physiologic difference between RV-FWS and RV-GLS is maintained in Fabry patients, regardless of the presence of cardiomyopathy.
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http://dx.doi.org/10.1016/j.ijcard.2021.02.038DOI Listing
May 2021

Assessment of patients presenting with life-threatening ventricular arrhythmias and suspected myocarditis: The key role of endomyocardial biopsy.

Heart Rhythm 2021 Jan 29. Epub 2021 Jan 29.

Dipartimento di Scienze Cardiovascolari, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Istituto di Cardiologia, Università Cattolica del Sacro Cuore, Rome, Italy.

Background: Life-threatening ventricular tachyarrhythmias (VAs) represent a significant cause of death in myocarditis.

Objective: The purpose of this study was to identify predictors of sustained VAs in patients with myocarditis and ventricular phenotype diagnosed by workflow including endomyocardial biopsy (EMB) guided by 3D electroanatomic mapping (3D-EAM).

Methods: We prospectively enrolled patients with suspected myocarditis and VAs, undergoing cardiac magnetic resonance, coronary angiography, 3D-EAM, and EMB guided by 3D-EAM. At follow-up, sustained VAs were detected by device interrogation and 24-hour electrocardiographic Holter monitoring.

Results: We enrolled 54 consecutive patients (mean age 41 ± 14 years; 32 men) with normal ventricular function; left ventricular and right ventricular (RV) late gadolinium enhancement was present, respectively, in 21 (46%) and 6 (13%) of the 46 patients who underwent cardiac magnetic resonance. In 31 patients, the histological diagnosis was myocarditis, while in 14 patients, focal replacement myocardial fibrosis (FRMF); in 9 patients, specimens were inadequate (diagnostic yield of EMB 83%). 3D-EAM showed a larger endocardial scar area for both ventricles in myocarditis than in FRMF (RV bipolar mean scar area 22 ± 16 cm vs 3 ± 2 cm; P = .02; left ventricular bipolar mean scar area 13 ± 5 cm vs 4 ± 2 cm; P = .02, respectively). At a follow-up of 21 months, freedom from sustained VAs was 58% in myocarditis and 92% in FRMF (log-rank, P = .008). Histological diagnosis of myocarditis and RV endocardial scar were independent predictors of sustained VAs (P = .02 for both).

Conclusion: Our data highlight the need for 3D-EAM-guided EMB in apparently healthy young patients with suspected myocarditis and VAs.
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http://dx.doi.org/10.1016/j.hrthm.2021.01.025DOI Listing
January 2021

Trabecular complexity as an early marker of cardiac involvement in Fabry disease.

Eur Heart J Cardiovasc Imaging 2021 Jan 22. Epub 2021 Jan 22.

Multimodality Cardiac Imaging Section, IRCCS Policlinico San Donato, San Donato Milanese, Via Morandi 30, Milan 20097, Italy.

Aims: Fabry cardiomyopathy is characterized by glycosphingolipid storage and increased myocardial trabeculation has also been demonstrated. This study aimed to explore by cardiac magnetic resonance whether myocardial trabecular complexity, quantified by endocardial border fractal analysis, tracks phenotype evolution in Fabry cardiomyopathy.

Methods And Results: Study population included 20 healthy controls (12 males, age 32±9) and 45 Fabry patients divided into three groups: 15 left ventricular hypertrophy (LVH)-negative patients with normal T1 (5 males, age 28±13; Group 1); 15 LVH-negative patients with low T1 (9 males, age 33±9.6; Group 2); 15 LVH-positive patients (11 males, age 53.5±9.6; Group 3). Trabecular fractal dimensions (Dfs) (total, basal, mid-ventricular, and apical) were evaluated on cine images. Total Df was higher in all Fabry groups compared to controls, gradually increasing from controls to Group 3 (1.27±0.02 controls vs. 1.29±0.02 Group 1 vs. 1.30±0.02 Group 2 vs. 1.34±0.02 Group 3; P<0.001). Group 3 showed significantly higher values of all Dfs compared to the other Groups. Both basal and total Dfs were significantly higher in Group 1 compared with controls (basal: 1.30±0.03 vs. 1.26±0.04, P =0.010; total: 1.29±0.02 vs. 1.27±0.02, P=0.044). Total Df showed significant correlations with: (i) T1 value (r=-0.569; P<0.001); (ii) LV mass (r=0.664, P<0.001); (iii) trabecular mass (r=0.676; P <0.001); (iv) Mainz Severity Score Index (r=0.638; P<0.001).

Conclusion: Fabry cardiomyopathy is characterized by a progressive increase in Df of endocardial trabeculae together with shortening of T1 values. Myocardial trabeculation is increased before the presence of detectable sphingolipid storage, thus representing an early sign of cardiac involvement.
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http://dx.doi.org/10.1093/ehjci/jeaa354DOI Listing
January 2021

Prognostic Value of Nonischemic Ringlike Left Ventricular Scar in Patients With Apparently Idiopathic Nonsustained Ventricular Arrhythmias.

Circulation 2021 Apr 6;143(14):1359-1373. Epub 2021 Jan 6.

Cardiac Electrophysiology, Cardiovascular Division (D.M., S.A.C., I.L., A.E., J.J.L., S.D., R.D., F.C.G., D.J.C., D.S.F., F.E.M., P.S.), Hospital of the University of Pennsylvania, Philadelphia.

Background: Left ventricular (LV) scar on late gadolinium enhancement (LGE) cardiac magnetic resonance has been correlated with life-threatening arrhythmic events in patients with apparently idiopathic ventricular arrhythmias (VAs). We investigated the prognostic significance of a specific LV-LGE phenotype characterized by a ringlike pattern of fibrosis.

Methods: A total of 686 patients with apparently idiopathic nonsustained VA underwent contrast-enhanced cardiac magnetic resonance. A ringlike pattern of LV scar was defined as LV subepicardial/midmyocardial LGE involving at least 3 contiguous segments in the same short-axis slice. The end point of the study was time to the composite outcome of all-cause death, resuscitated cardiac arrest because of ventricular fibrillation or hemodynamically unstable ventricular tachycardia and appropriate implantable cardioverter defibrillator therapy.

Results: A total of 28 patients (4%) had a ringlike pattern of scar (group A), 78 (11%) had a non-ringlike pattern (group B), and 580 (85%) had normal cardiac magnetic resonance with no LGE (group C). Group A patients were younger compared with groups B and C (median age, 40 vs 52 vs 45 years; <0.01), more frequently men (96% vs 82% vs 55%; <0.01), with a higher prevalence of family history of sudden cardiac death or cardiomyopathy (39% vs 14% vs 6%; <0.01) and more frequent history of unexplained syncope (18% vs 9% vs 3%; <0.01). All patients in group A showed VA with a right bundle-branch block morphology versus 69% in group B and 21% in group C (<0.01). Multifocal VAs were observed in 46% of group A patients compared with 26% of group B and 4% of group C (<0.01). After a median follow-up of 61 months (range, 34-84 months), the composite outcome occurred in 14 patients (50.0%) in group A versus 15 (19.0%) in group B and 2 (0.3%) in group C (<0.01). After multivariable adjustment, the presence of LGE with ringlike pattern remained independently associated with increased risk of the composite end point (hazard ratio, 68.98 [95% CI, 14.67-324.39], <0.01).

Conclusions: In patients with apparently idiopathic nonsustained VA, nonischemic LV scar with a ringlike pattern is associated with malignant arrhythmic events.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047640DOI Listing
April 2021

Interpretation of elevated high-sensitivity cardiac troponin I in elite soccer players previously infected by severe acute respiratory syndrome coronavirus 2.

Int J Cardiol 2021 03 23;326:248-251. Epub 2020 Nov 23.

Cardiovascular and Thoracic Department, IRCCS Ospedale Policlinico San Martino, Genova, Italia - Italian IRCCS Cardiovascular Network; Università di Genova, Dipartimento di Medicina Interna e Specialità Mediche (DIMI), Genova, Italy. Electronic address:

Objectives: To clarify the meaning of elevated cardiac troponin in elite soccer athletes previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and screened for cardiovascular involvement in the wake of competitive sport resumption.

Methods: We designed a retrospective cohort study with the collaboration of two Italian Serie A teams. Soccer players from both rosters (58 athletes) were systematically analysed. For every SARS-CoV-2 positive athlete, the Italian Soccer Federation protocol requested full blood tests including high-sensitivity cardiac troponin I (hs-cTnI), along with a complete cardiovascular examination. We extended the analysis to SARS-CoV-2 negative athletes.

Results: A total of 13/58 players (22.4%) suffered from SARS-CoV-2infection: all had a negative cardiovascular examination and 2/13 (15%) showed increased hs-cTnI values (120.8 pg/ml and 72,6 pg/ml, respectively; upper reference level 39.2 pg/ml), which did not track with inflammatory biomarkers. Regarding the 45/58 (77.6%) non infected athletes, a slight increase in hs-cTnI was observed in 2 (4.5%) subjects (values: 61 pg/ml and 75 pg/ml respectively). All hs-cTnI positive athletes (4/58, 7%) underwent cardiac magnetic resonance (CMR), that excluded any cardiac injury.

Conclusions: In our retrospective study, SARS-CoV-2 infection in elite soccer athletes was not associated to clinical or biomarkers abnormalities. Increased hs-cTnI was rare and not significantly associated with previous SARS-COV2 infection nor with pathological findings at CMR, albeit elevated hs-cTnI was numerically more prevalent in the infected group.
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http://dx.doi.org/10.1016/j.ijcard.2020.11.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682525PMC
March 2021

[Clinical pathway for cardiomyopathies: a genetic testing strategy proposed by ANMCO in Tuscany].

G Ital Cardiol (Rome) 2020 Dec;21(12):926-934

Dipartimento di Cardiologia, Ospedale Versilia, Lucca.

Hereditary cardiomyopathies, hypertrophic cardiomyopathy, dilated cardiomyopathy, arrhythmogenic cardiomyopathy, restrictive cardiomyopathy and left ventricular noncompaction, are clinically and genetically very heterogeneous diseases, and they represent a frequent cause of cardiac arrest and sudden death. To date, over 100 genes are known to be associated with the onset of cardiomyopathies. Genetic testing is performed by next generation sequencing, a technology that has made it possible to analyze hundreds of genes in many patients simultaneously, shortening costs and execution times. However, with the use of this technology, new problems have arisen regarding the indications for access to the test, the interpretation of the data and the clinical implications of the results.This document aims to represent an operational support tool for hospital cardiologists to make the use of genetic testing more accessible and appropriate for their patients with suspected or ascertained hereditary cardiomyopathy.
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http://dx.doi.org/10.1714/3472.34547DOI Listing
December 2020

Evidence of evolution towards left midventricular obstruction in severe Anderson-Fabry cardiomyopathy.

ESC Heart Fail 2021 Feb 19;8(1):725-728. Epub 2020 Nov 19.

Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of the Sacred Heart, Rome, Italy.

Aims: In Fabry cardiomyopathy, left ventricular outflow tract obstruction mimicking hypertrophic cardiomyopathy is a very rare finding, with few cases reported and successfully treated with cardiac surgery. In our population of patients with Fabry disease and severe left ventricular hypertrophy (LVH) at the time of diagnosis, we observed an evolution towards a midventricular obstructive phenotype.

Methods And Results: We present a case series of three classically affected Fabry male patients with significant diagnostic delay and severe cardiac involvement (maximal wall thickness >20 mm) at first evaluation. All patients developed midventricular obstructive form over time despite prompt initiation and optimal compliance to enzyme replacement therapy. The extension and distribution of the LVH, involving the papillary muscles, was the main mechanism of obstruction, unlike the asymmetric septal basal hypertrophy and the mitral valve abnormalities commonly seen as substrate of left ventricular outflow tract obstruction in hypertrophic cardiomyopathy.

Conclusions: Fabry cardiomyopathy can evolve over time towards a midventricular obstructive form due to massive LVH in classically affected men with significant diagnostic delay and severe LVH before enzyme replacement therapy initiation. This newly described cardiac phenotype could represent an adverse outcome of the disease.
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http://dx.doi.org/10.1002/ehf2.13101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835588PMC
February 2021

Randomized Controlled Trial of Acotec Drug-Eluting Balloon Versus Plain Balloon for Below-the-Knee Angioplasty.

JACC Cardiovasc Interv 2020 10 16;13(19):2277-2286. Epub 2020 Sep 16.

Cardiovascular Department, San Donato Hospital, Arezzo, Italy.

Objectives: The aim of this study was to investigate the efficacy and safety of the Litos drug-coated balloon (DCB) versus plain old balloon angioplasty (POBA) for reduction of late lumen loss (LLL) in patients with critical limb ischemia undergoing below-the-knee (BTK) intervention.

Background: Restenosis after balloon angioplasty of BTK arteries approximates 70%. Previous studies of DCBs in BTK arteries produced conflicting results.

Methods: ACOART-BTK (Evaluation of the Use of ACOTEC Drug-Eluting Balloon Litos® in Below-the-Knee Arteries to Treat Critical Limb Ischemia) is a randomized controlled single-center study. Inclusion criteria were critical limb ischemia (Rutherford class ≥4) and significant stenosis or occlusion >40 mm of at least 1 BTK vessel with distal runoff successfully treated with angioplasty. Six-month angiographic LLL was the primary endpoint. Occlusive restenosis at 6 months and clinically driven target lesion revascularization at 12 months were secondary endpoints.

Results: From January 2016 through January 2019, 105 patients with 129 BTK lesions were enrolled in the study. Mean lesion length was 168 ± 109 mm in the DCB group and 187 ± 113 mm in the POBA group (p = 0.30). Almost 70% of lesions were occluded at baseline in both groups. On 6-month angiography, mean LLL was 0.51 ± 0.60 mm in the DCB group and 1.31 ± 0.72 mm in the POBA group (p < 0.001); rates of occlusive restenosis were 8.6% and 48.4%, respectively (p < 0.001). Twelve-month clinically driven target lesion revascularization occurred in 6 of 62 DCB-treated lesions (10%) versus 27 of 66 POBA-treated lesions (41%) (p < 0.001). Complete healing at 12 months was observed in 42 of 47 DCB-treated limbs (89.4) versus 35 of 47 POBA-treated limbs (74.5%) (p = 0.05); no major amputations occurred.

Conclusions: Litos DCBs strikingly reduced LLL, vessel reocclusion, and clinically driven target lesion revascularization compared with POBA in BTK angioplasty.
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http://dx.doi.org/10.1016/j.jcin.2020.06.045DOI Listing
October 2020

Impact of COVID-19 pandemic on patients with Fabry disease: An Italian experience.

Mol Genet Metab 2020 Sep - Oct;131(1-2):124-125. Epub 2020 Jul 28.

Department of Public Health, Nephrology, University Federico II of Naples, Italy.

We conducted an observational study to assess the impact of COVID-19 emergency on management and outcomes of patients with Fabry disease referring to our Center in Naples, Italy. No patient of the 129 included reported suspected symptoms; 3 isolated themselves in auto-quarantine for flu-like symptoms. All treated patients regularly continued their therapies; 8 missed one infusion: 3 for self-isolation with 2 relatives, and 3 refused to receive nurse at home. All elective procedures were deferred and telemedicine was adopted.
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http://dx.doi.org/10.1016/j.ymgme.2020.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386205PMC
January 2021

Prevalence, causes and predictors of cardiovascular hospitalization in patients with hypertrophic cardiomyopathy.

Int J Cardiol 2020 Nov 29;318:94-100. Epub 2020 Jul 29.

Cardiomyopathy Unit, Cardiothoracic and Vascular Department, Careggi University Hospital, Largo Brambilla 3, 50134, Florence, Italy.

Background: Despite numerous studies assessing the natural history of patients with hypertrophic cardiomyopathy (HCM), there is lack of data regarding the burden of hospitalization. Aim of this study was to describe prevalence, causes and predictors of cardiovascular hospitalization in patients with HCM.

Methods: We retrospectively included 253 patients with HCM undergoing first evaluation at our center. Enrolment criteria included cardiac magnetic resonance imaging (CMRI) at baseline and > 1-year follow-up. All hospital admissions were recorded during follow-up and adjudicated as acute vs elective and cardiovascular (CV) vs non-cardiovascular (non-CV).

Results: During 6.4 ± 4.0 years there were 187 hospitalizations in 92 patients (36%, at a rate of 5.7%/year). Most were CV-related (158/187,84.5%; 4.8%/year) while non-CV admissions were 29/187 (15.5%, 0.88%/year). There was a slight predominance of elective (n = 96, 58%, 2.8%/year) vs acute (n = 62, 41.8%, 2.0%/year) CV hospitalizations. Independent predictors of CV hospitalization were baseline symptoms (NYHA class II vs I: HR 2.06; 95% CI 1.24-3.43, NYHA III-IV vs I: HR 3.05; 95% CI 1.40-6.65, p = .004), indexed left atrial (LA) volume (HR 1.03; 95% CI 1.01-1.04, p < .001), and lower indexed right ventricular end-diastolic volume iRVEDV) at cardiac magnetic resonance (HR 0.99; 95% CI 0.97-0.99, p = .03).

Conclusions: In little over 6 years, CV hospitalization was required in over one-in-three of our HCM patients, often unplanned and due to acute disease-related complications. Symptomatic status, larger LA volume and reduced iRVEDV at baseline were independently associated with CV admissions. Strategies aimed at preventing hospitalizations are an important target to reduce the burden of disease in HCM patients.
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http://dx.doi.org/10.1016/j.ijcard.2020.07.036DOI Listing
November 2020

Electroanatomic mapping-guided endomyocardial biopsy in patients with apparently idiopathic ventricular arrhythmias.

Pacing Clin Electrophysiol 2020 09 13;43(9):1028-1038. Epub 2020 Aug 13.

Cardiovascular Department, San Donato Hospital, Arezzo, Italy.

The management of ventricular arrhythmias (VA) in the presence of an apparently normal heart represents a major clinical challenge and a main field of clinical research. In the past years, new imaging techniques and the spreading of new generation genetic testing have improved our knowledge of the pathogenesis of apparently idiopathic VA. However, in the absence of specific recommendations, the type and the number of noninvasive and invasive studies necessary to rule out a possible underlying cause of VA or sudden cardiac death remain extremely variable. Therefore, in many patients the underlying cardiac disease is not recognized, and a possible specific therapeutic approach cannot be initiated. Endomyocardial biopsy (EMB) can provide a significant contribution to the identification of myocardial disorders causing VA but has never been definitively included in the routine diagnostic work-up of these patients due to the possible sampling error particularly in disorders with a focal or patchy distribution. Three-dimensional electroanatomic mapping (EAM) may guide EMB allowing to draw myocardial samples from abnormal voltage, areas of the ventricular wall, thus reducing sampling error and increasing the sensitivity of EMB. The systematic association of EAM with EMB represents a crucial approach to characterize the pathological substrate of electroanatomic abnormalities and VA and to further clarify the arrhythmogenic mechanisms of acquired and also inherited arrhythmic disorders.
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http://dx.doi.org/10.1111/pace.14014DOI Listing
September 2020

An expert consensus document on the management of cardiovascular manifestations of Fabry disease.

Eur J Heart Fail 2020 07 14;22(7):1076-1096. Epub 2020 Aug 14.

Institute of Cardiovascular Science, University College London and Barts Heart Centre, London, UK.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by pathogenic variants in the α-galactosidase A (GLA) gene that leads to reduced or undetectable α-galactosidase A enzyme activity and progressive accumulation of globotriaosylceramide and its deacylated form globotriaosylsphingosine in cells throughout the body. FD can be multisystemic with neurological, renal, cutaneous and cardiac involvement or be limited to the heart. Cardiac involvement is characterized by progressive cardiac hypertrophy, fibrosis, arrhythmias, heart failure and sudden cardiac death. The cardiac management of FD requires specific measures including enzyme replacement therapy or small pharmacological chaperones in patients carrying amenable pathogenic GLA gene variants and more general management of cardiac symptoms and complications. In this paper, we summarize current knowledge of FD-related heart disease and expert consensus recommendations for its management.
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http://dx.doi.org/10.1002/ejhf.1960DOI Listing
July 2020

Risk Stratification of Patients With Apparently Idiopathic Premature Ventricular Contractions: A Multicenter International CMR Registry.

JACC Clin Electrophysiol 2020 06 18;6(6):722-735. Epub 2019 Dec 18.

Department of Cardiovascular Medicine, Flinders Medical Centre, Bedford Park, Adelaide, Australia; Cardiac Imaging Unit, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester, United Kingdom. Electronic address:

Objectives: This study investigated the prevalence and prognostic significance of concealed myocardial abnormalities identified by cardiac magnetic resonance (CMR) imaging in patients with apparently idiopathic premature ventricular contractions (PVCs).

Background: The role of CMR imaging in patients with frequent PVCs and otherwise negative diagnostic workup is uncertain.

Methods: This was a multicenter, international study that included 518 patients (age 44 ± 15 years; 57% men) with frequent (>1,000/24 h) PVCs and negative routine diagnostic workup. Patients underwent a comprehensive CMR protocol including late gadolinium enhancement imaging for detection of necrosis and/or fibrosis. The study endpoint was a composite of sudden cardiac death, resuscitated cardiac arrest, and nonfatal episodes of ventricular fibrillation or sustained ventricular tachycardia that required appropriate implantable cardioverter-defibrillator therapy.

Results: Myocardial abnormalities were found in 85 (16%) patients. Male gender (odds ratio [OR]: 4.28; 95% confidence interval [CI]: 2.06 to 8.93; p = 0.01), family history of sudden cardiac death and/or cardiomyopathy (OR: 3.61; 95% CI: 1.33 to 9.82; p = 0.01), multifocal PVCs (OR: 11.12; 95% CI: 4.35 to 28.46; p < 0.01), and non-left bundle branch block inferior axis morphology (OR: 14.11; 95% CI: 7.35 to 27.07; p < 0.01) were all significantly related to the presence of myocardial abnormalities. After a median follow-up of 67 months, the composite endpoint occurred in 26 (5%) patients. Subjects with myocardial abnormalities on CMR had a higher incidence of the composite outcome (n = 25; 29%) compared with those without abnormalities (n = 1; 0.2%; p < 0.01).

Conclusions: CMR can identify concealed myocardial abnormalities in 16% of patients with apparently idiopathic frequent PVCs. Presence of myocardial abnormalities on CMR predict worse clinical outcomes.
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http://dx.doi.org/10.1016/j.jacep.2019.10.015DOI Listing
June 2020

An autoantibody profile detects Brugada syndrome and identifies abnormally expressed myocardial proteins.

Eur Heart J 2020 08;41(30):2878-2890

Department of Pediatrics, The Labatt Family Heart Centre and Translational Medicine, The Hospital for Sick Children & Research Institute and the University of Toronto, Room 1725D, 555 University Avenue, Toronto, ON M5G 1X8, Canada.

Aims: Brugada syndrome (BrS) is characterized by a unique electrocardiogram (ECG) pattern and life-threatening arrhythmias. However, the Type 1 Brugada ECG pattern is often transient, and a genetic cause is only identified in <25% of patients. We sought to identify an additional biomarker for this rare condition. As myocardial inflammation may be present in BrS, we evaluated whether myocardial autoantibodies can be detected in these patients.

Methods And Results: For antibody (Ab) discovery, normal human ventricular myocardial proteins were solubilized and separated by isoelectric focusing (IEF) and molecular weight on two-dimensional (2D) gels and used to discover Abs by plating with sera from patients with BrS and control subjects. Target proteins were identified by mass spectrometry (MS). Brugada syndrome subjects were defined based on a consensus clinical scoring system. We assessed discovery and validation cohorts by 2D gels, western blots, and ELISA. We performed immunohistochemistry on myocardium from BrS subjects (vs. control). All (3/3) 2D gels exposed to sera from BrS patients demonstrated specific Abs to four proteins, confirmed by MS to be α-cardiac actin, α-skeletal actin, keratin, and connexin-43, vs. 0/8 control subjects. All (18/18) BrS subjects from our validation cohorts demonstrated the same Abs, confirmed by western blots, vs. 0/24 additional controls. ELISA optical densities for all Abs were elevated in all BrS subjects compared to controls. In myocardium obtained from BrS subjects, each protein, as well as SCN5A, demonstrated abnormal protein expression in aggregates.

Conclusion: A biomarker profile of autoantibodies against four cardiac proteins, namely α-cardiac actin, α-skeletal actin, keratin, and connexin-43, can be identified from sera of BrS patients and is highly sensitive and specific, irrespective of genetic cause for BrS. The four involved proteins, along with the SCN5A-encoded Nav1.5 alpha subunit are expressed abnormally in the myocardium of patients with BrS.
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http://dx.doi.org/10.1093/eurheartj/ehaa383DOI Listing
August 2020

Long-Term Arrhythmic Risk Assessment in Biopsy-Proven Myocarditis.

JACC Clin Electrophysiol 2020 05 26;6(5):574-582. Epub 2020 Feb 26.

Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; Institute of Cardiology, Università Cattolica del Sacro Cuore, Rome, Italy.

Objectives: This study sought to assess long-term arrhythmic risk in patients with myocarditis who received an implantable cardioverter-defibrillator (ICD).

Background: The arrhythmic risk of patients with myocarditis overtime remains poorly known.

Methods: The study enrolled 56 patients with biopsy-proven myocarditis who received an ICD for either primary (57%) or secondary prevention (43%) according to current guidelines. Clinical characteristics, biopsy findings, electrophysiological data from endocardial 3-dimensional electroanatomic voltage mapping, and device interrogation data were analyzed to detect arrhythmic events overtime. Coronary angiography excluded significant coronary artery disease in all patients.

Results: At a mean follow-up of 74 ± 60 months (median 65 months), 25 (45%) patients had major ventricular arrhythmias treated by ICD intervention (76% being terminated by ICD shock and 24% by antitachyarrhythmia burst pacing). At multivariable analysis, the presence of sustained ventricular tachycardia on admission (hazard ratio: 13.0; 95% confidence interval: 2.0 to 35.0; p = 0.032) and the extension of the areas of low potentials at the bipolar endocardial mapping (hazard ratio: 1.19; 95% confidence interval: 1.04 to 1.37; p = 0.013) were the only independent predictors of appropriate ICD interventions. A cutoff value of 10% of abnormal bipolar area at electroanatomical ventricular mapping discriminated patients with appropriate ICD interventions with a sensitivity of 89% and a specificity of 85%.

Conclusions: The study demonstrates that the prevalence of life-threatening ventricular arrhythmias in patients with myocarditis receiving an ICD according to current guidelines is high and the arrhythmic risk persists late overtime. Electroanatomical ventricular mapping may be a useful tool to identify patients at greater arrhythmic risk.
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http://dx.doi.org/10.1016/j.jacep.2019.12.010DOI Listing
May 2020

Prognostic significance of right ventricular hypertrophy and systolic function in Anderson-Fabry disease.

ESC Heart Fail 2020 08 20;7(4):1605-1614. Epub 2020 May 20.

Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, Rome, 00168, Italy.

Aims: Right ventricular hypertrophy (RVH) is a common finding in Anderson-Fabry disease (AFD), but the prognostic role of right ventricular (RV) involvement has never been assessed. The aim of our study was to evaluate the prognostic significance of RVH and RV systolic function in AFD.

Methods And Results: Forty-five AFD patients (56% male patients) with extensive baseline evaluation, including assessment of RVH and RV systolic function, were followed-up for an average of 51.2 ± 11.4 months. RV systolic function was assessed by standard and tissue Doppler echocardiography. Cardiovascular events were defined as new-onset atrial fibrillation (AF), sustained ventricular arrhythmias, heart failure, or pacemaker/implantable cardioverter defibrillator implantation; renal events were defined as progression to dialysis and/or renal transplantation or significant worsening of glomerular filtration rate; and cerebrovascular events were defined as transient ischaemic attack or stroke. Fourteen patients (31.1%) presented RVH, while RV systolic function was normal in all cases. During the follow-up period, 13 patients (28.8%, 11 male) experienced 18 major events, including two deaths. Cardiovascular events occurred in eight patients (17.7%). The most common event was pacemaker/implantable cardioverter defibrillator implantation (six patients, 13.3%), followed by AF (three cases, 6.6%). Only one case of worsening New York Heart Association class (from II to III and IV) was observed. Ischaemic stroke occurred in three cases (6.6%). Renal events were recorded in three patients (6.6%). At univariate analysis, several variables were associated with the occurrence of events, including RVH (HR: 7.09, 95% CI: 2.17 to 23.14, P = 0.001) and indexes of RV systolic function (tricuspid annular plane systolic excursion HR: 0.77, 95% CI: 0.62 to 0.96, P = 0.02; and RV tissue Doppler systolic velocity HR: 0.76, 95% CI: 0.61 to 0.93, P = 0.01). At multivariate analysis, proteinuria (HR:8.3, 95% CI: 2.88 to 23.87, P < 0.001) and left ventricular mass index (HR: 1.02, 95% CI: 1.00 to 1.03, P = 0.03) emerged as the only independent predictors of outcome.

Conclusions: RVH and RV systolic function show significant association with clinical events in AFD, but only proteinuria and left ventricular mass index emerged as independent predictors of outcome. Our findings suggest that RV involvement does not influence prognosis in AFD and confirm that renal involvement and left ventricular hypertrophy are the main determinant of major cardiac and non-cardiac events.
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http://dx.doi.org/10.1002/ehf2.12712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373914PMC
August 2020

The GALA project: practical recommendations for the use of migalastat in clinical practice on the basis of a structured survey among Italian experts.

Orphanet J Rare Dis 2020 04 7;15(1):86. Epub 2020 Apr 7.

Department of Public Health, Nephrology Unit, University of Naples "Federico II", Naples, Italy.

Background: Oral migalastat has recently been approved for the treatment of Anderson-Fabry disease (FD) in patients aged ≥16 years with amenable mutations on the basis of two phase III trials, FACETS and ATTRACT. However, with the introduction of migalastat into clinical practice, it is important to correctly identify the patients who may gain the most benefits from this therapy. Due to the relatively recent availability of migalastat, its role in clinical practice still has to be included in guidelines or recommendations. On these bases, a multidisciplinary group of Italian Experts in the treatment of FD has run the GALA project, with the aim to collect the opinions of expert physicians and to propose some starting points for an experience-based use of migalastat.

Results: Overall, although studies and data from longer-term follow-up with migalastat are still emerging, available evidence is consistent in showing that this molecule does represent a suitable therapy for the treatment of FD, in patients aged ≥16 years and with amenable mutations. The use of migalastat as an oral option appears to be overall safe, and experience thus far indicates potential for improving quality of life, controlling GI symptoms, stabilizing renal function and reducing cardiac hypertrophy.

Conclusion: Migalastat can be considered either as a first-line therapy - given its efficacy, extensive tissue penetration, convenient oral regimen, and the current limited therapeutic options available - or in patients on enzyme-replacement therapy (ERT) who experience side effects, with poor compliance to chronic i.v. therapy, or with clinical evidence of progression of the disease.
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http://dx.doi.org/10.1186/s13023-020-1318-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140546PMC
April 2020

The spectrum of myocarditis: from pathology to the clinics.

Virchows Arch 2019 Sep 11;475(3):279-301. Epub 2019 Jul 11.

Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy.

Myocarditis is an inflammatory disease of the myocardium, which may occur in isolation or as part of systemic infectious/immune/autoimmune conditions, characterized by vast aetiologic, clinical and histopathologic heterogeneity. The broad spectrum of myocarditis can be categorized according to the prevalent histopathologic pattern including lymphocytic, lympho-histiocytic, eosinophilic and neutrophilic forms, giant cell myocarditis and myocarditis with granulomata. Diverse histopathologic substrates generally reflect different aetiologies and pathogenetic mechanisms and may be critical to clinical decision-making. Active vasculitis, when present, completes the inflammatory spectrum. Unfortunately, the correlation of histopathologic patterns, clinical presentation and disease course in myocarditis is still largely unresolved, due to limited availability of bioptic samples at specific stages of disease and impracticality of serial sampling. We here review the elements supporting an aetiology-driven diagnostic work-up in myocarditis, emphasizing the importance of integrating pathologic studies with clinical features and information derived from multimodality imaging. Furthermore, we explore myocardial inflammation in genetic cardiomyopathies, its role in driving clinical variability and the potential of transcriptomic and proteomic analysis in our understanding of these complex interrelations.
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http://dx.doi.org/10.1007/s00428-019-02615-8DOI Listing
September 2019

Brugada Syndrome in the Young and in the Adult: A Tale of 2 Diseases?

J Am Coll Cardiol 2019 04;73(14):1766-1768

Cardiovascular Department, San Donato Hospital, Arezzo, Italy.

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http://dx.doi.org/10.1016/j.jacc.2019.01.047DOI Listing
April 2019

Predictors of Clinical Evolution in Prehypertrophic Fabry Disease.

Circ Cardiovasc Imaging 2019 04;12(4):e008424

Multimodality Cardiac Imaging Section (A.C., S.P., M.L.), IRCCS Policlinico San Donato, San Donato Milanese, Milano, Italy.

Background: In prehypertrophic Fabry disease, low myocardial T1 values, reflecting sphingolipid storage, are associated with early structural and ECG changes. The correlations between T1 values and functional parameters have not been explored. Furthermore, the potential prognostic role of T1 in predicting disease worsening is still unknown.

Methods: ECG, 2D echocardiography, cardiopulmonary test, and cardiac magnetic resonance were performed in 44 Fabry patients without left ventricular hypertrophy (35.7±14.5 years, 68.2% females). After a 12-month follow-up, clinical stability was evaluated using Fabry Stabilization Index.

Results: At baseline, T1 values showed a negative correlation with left ventricular mass ( r=-0.79; P<0.0001), maximum wall thickness ( r=-0.79; P<0.0001), Sokolow-Lyon Index ( r=-0.54; P<0.0001), left atrial volume ( r=-0.49; P<0.0002), and Mainz Severity Score Index ( r=-0.61; P<0.0001). No significant differences in systo-diastolic function and exercise capacity were observed comparing normal and low T1 Fabry patients. Arrhythmias were reported in 2 females with low T1 and late gadolinium enhancement. Five patients (40.0±12.4 years, 2 females) showed clinical worsening (Fabry Stabilization Index >20%) at follow-up. Higher left ventricular wall thickness (odds ratio, 2.61; CI, 1.04-6.57; P=0.04), left atrial volume (odds ratio, 1.24; CI, 1.02-1.51; P=0.03), and lower T1 values (odds ratio, 0.98; CI, 0.96-0.99; P=0.03) at baseline were independently associated with clinical worsening at follow-up.

Conclusions: In prehypertrophic Fabry disease, low T1 values correlate with early electrocardiographic, morphological cardiac changes, and worsening of global disease severity but are not associated with functional abnormalities. The presence of low T1 values is a risk factor for disease worsening, thus representing a potential new tool in prognostic stratification and therapeutic approach.
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http://dx.doi.org/10.1161/CIRCIMAGING.118.008424DOI Listing
April 2019

New insights from the application of the FAbry STabilization indEX in a large population of Fabry cases.

Clin Kidney J 2019 Feb 14;12(1):65-70. Epub 2018 Nov 14.

Department of Medicine and Surgery, University of Milano-Bicocca and Nephrology and Dialysis Department, ASST Monza, Italy.

Background: The FAbry STabilization indEX (FASTEX) is an innovative index allowing the assessment of clinical stability over time in Fabry disease patients. This index was developed in a population of 28 male patients with the classical form of Fabry disease.

Objectives: The aim of the study was to test the accuracy of the FASTEX in evaluating Fabry disease stability in 132 male and female patients with classical and non-classical Fabry disease from nine Italian centres and it also aimed to define the sensitivity and specificity of this new tool. In particular, we aimed to investigate the correlation between the FASTEX and clinical judgement in a large-scale cohort of the study population.

Methods: Statistical methods applied to this investigation included the calculation of accuracy, specificity and sensitivity, receiver operating characteristic (ROC) curves and Cohen's κ index related to the FASTEX and clinical judgement.

Results: The patient population included 58 males (43.9%). The mean age of the overall population was 46.3 ± 15. 1 years (range 31.2-61.4). The median interval between the two multidisciplinary evaluations used for FASTEX calculation was 398 days. Since no gold standard method is available to define the overall clinical condition of Fabry patients over time, the results of the FASTEX were compared with clinical judgements given by the physicians involved in this study. In this way, the FASTEX classified 121 of 132 (92%) patients correctly. In particular, the FASTEX correctly identified 93% (41/44) of clinically 'unstable' and 91% (80/88) of clinically 'stable' patients. The area under the curve of the ROC related to the FASTEX index cut-off (20) was equal to 0.967, very close to its theoretical maximum (1), which means that it is an excellent test for classifying patients as 'stable' or 'unstable' compared with clinical judgement. In addition, the FASTEX cut-off >20 provides the most acceptable balance between sensitivity and specificity. The Cohen's κ index value obtained in our study was 0.82, showing a highly statistically significant P-value < 0.01 related to the agreement between the FASTEX and clinical judgement.

Conclusions: The FASTEX is demonstrated here to be a specific and sensitive tool. When applied to a large cohort of Fabry patients, it was shown to be a valid instrument in helping physicians to discriminate objectively the clinical stability of individual Fabry patients.
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http://dx.doi.org/10.1093/ckj/sfy108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425459PMC
February 2019

The effect of enzyme replacement therapy on clinical outcomes in male patients with Fabry disease: A systematic literature review by a European panel of experts.

Mol Genet Metab Rep 2019 Jun 6;19:100454. Epub 2019 Feb 6.

Department of Paediatrics, University of Torino, Torino, Italy.

Background: Enzyme replacement therapy (ERT) with recombinant human α-galactosidase has been available for the treatment of Fabry disease since 2001 in Europe and 2003 in the USA. Treatment outcomes with ERT are dependent on baseline patient characteristics, and published data are derived from heterogeneous study populations.

Methods: We conducted a comprehensive systematic literature review of all original articles on ERT in the treatment of Fabry disease published up until January 2017. This article presents the findings in adult male patients.

Results: Clinical evidence for the efficacy of ERT in adult male patients was available from 166 publications including 36 clinical trial publications. ERT significantly decreases globotriaosylceramide levels in plasma, urine, and in different kidney, heart, and skin cell types, slows the decline in estimated glomerular filtration rate, and reduces/stabilizes left ventricular mass and cardiac wall thickness. ERT also improves nervous system, gastrointestinal, pain, and quality of life outcomes.

Conclusions: ERT is a disease-specific treatment for patients with Fabry disease that may provide clinical benefits on several outcomes and organ systems. Better outcomes may be observed when treatment is started at an early age prior to the development of organ damage such as chronic kidney disease or cardiac fibrosis. Consolidated evidence suggests a dose effect. Data described in male patients, together with female and paediatric data, informs clinical practice and therapeutic goals for individualized treatment.
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http://dx.doi.org/10.1016/j.ymgmr.2019.100454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365982PMC
June 2019

Electroanatomic and Pathologic Right Ventricular Outflow Tract Abnormalities in Patients With Brugada Syndrome.

J Am Coll Cardiol 2018 12;72(22):2747-2757

Cardiovascular Department, San Donato Hospital, Arezzo, Italy.

Background: The prevalence and significance of structural abnormalities in Brugada syndrome (BrS) are still largely debated.

Objectives: The authors investigated the relationship between genetic background, electroanatomic abnormalities, and pathologic substrate in BrS.

Methods: They performed 3-dimensional electroanatomic unipolar and bipolar mapping in 30 patients with BrS. Twenty patients underwent 3-dimensional electroanatomic unipolar and bipolar mapping-guided right ventricular outflow tract (RVOT) endomyocardial biopsy. Programmed ventricular stimulation and genetic analysis were performed in all patients.

Results: Low-voltage areas (LVAs) were observed at unipolar map in 93% of patients and at bipolar map in 50% of cases. Unipolar LVAs were always larger than bipolar LVAs, were always colocalized, and in all cases included RVOT. Disease-causing mutations were detected in 10 (33%) patients. Programmed ventricular stimulation was positive in 16 cases (53%). In 75% of patients, RVOT histology showed pathologic findings with myocardial inflammation in 80% of them. Among patients with abnormal bipolar map submitted to endomyocardial biopsy, 9 (81%) showed evidence of myocardial inflammation. Conversely, bipolar map was abnormal in 83% of patients with myocardial inflammation. Myocardial inflammation was also more prevalent among inducible patients (83% vs. 25% in noninducible; p = 0.032).

Conclusions: BrS is characterized by electroanatomical and structural abnormalities localized to RVOT with a gradient of the pathologic substrate from epicardium to endocardium possibly driven by myocardial inflammation. These findings reclassify BrS as a combination of structural and electrical defects opening the way to new risk stratification and therapeutic strategies.
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http://dx.doi.org/10.1016/j.jacc.2018.09.037DOI Listing
December 2018

Mutations in the GLA Gene and LysoGb3: Is It Really Anderson-Fabry Disease?

Int J Mol Sci 2018 Nov 23;19(12). Epub 2018 Nov 23.

Institute of Biomedicine and Molecular Immunology "A. Monroy", National Research Council, 90146 Palermo, Italy.

Anderson-Fabry disease (FD) is a rare, progressive, multisystem storage disorder caused by the partial or total deficit of the lysosomal enzyme α-galactosidase A (α-Gal A). It is an X-linked, lysosomal enzymopathy due to mutations in the galactosidase alpha gene (GLA), encoding the α-Gal A. To date, more than 900 mutations in this gene have been described. In our laboratories, the study of genetic and enzymatic alterations related to FD was performed in about 17,000 subjects with a symptomatology referable to this disorder. The accumulation of globotriaosylsphingosine (LysoGb3) was determined in blood of positives. Exonic mutations in the GLA gene were detected in 471 patients (207 Probands and 264 relatives): 71.6% of mutations were associated with the classic phenotype, 19.8% were associated with the late-onset phenotype, and 8.6% of genetic variants were of unknown significance (GVUS). The accumulation of LysoGb3 was found in all male patients with a mutation responsible for classic or late-onset FD. LysoGb3 levels were consistent with the type of mutations and the symptomatology of patients. α-Gal A activity in these patients is absent or dramatically reduced. In recent years, confusion about the pathogenicity of some mutations led to an association between non-causative mutations and FD. Our study shows that the identification of FD patients is possible by associating clinical history, GLA gene analysis, α-Gal A assay, and blood accumulation of LysoGB3. In our experience, LysoGB3 can be considered a reliable marker, which is very useful to confirm the diagnosis of Fabry disease.
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http://dx.doi.org/10.3390/ijms19123726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320967PMC
November 2018

European expert consensus statement on therapeutic goals in Fabry disease.

Mol Genet Metab 2018 07 12;124(3):189-203. Epub 2018 Jun 12.

Department of Neurology, University of Erlangen-Nuremberg, Erlangen, Germany.

Background: Fabry disease, an inherited lysosomal storage disorder, causes multi-organ pathology resulting in substantial morbidity and a reduced life expectancy. Although Fabry disease is an X-linked disorder, both genders may be affected, but generally to a lesser extent in females. The disease spectrum ranges from classic early-onset disease to non-classic later-onset phenotypes, with complications occurring in multiple organs or being confined to a single organ system depending on the stage of the disease. The impact of therapy depends upon patient- and disease-specific factors and timing of initiation.

Methods: A European panel of experts collaborated to develop a set of organ-specific therapeutic goals for Fabry disease, based on evidence identified in a recent systematic literature review and consensus opinion.

Results: A series of organ-specific treatment goals were developed. For each organ system, optimal treatment strategies accounted for inter-patient differences in disease severity, natural history, and treatment responses as well as the negative burden of therapy and the importance of multidisciplinary care. The consensus therapeutic goals and proposed patient management algorithm take into account the need for early disease-specific therapy to delay or slow the progression of disease as well as non-specific adjunctive therapies that prevent or treat the effects of organ damage on quality of life and long-term prognosis.

Conclusions: These consensus recommendations help advance Fabry disease management by considering the balance between anticipated clinical benefits and potential therapy-related challenges in order to facilitate individualized treatment, optimize patient care and improve quality of life.
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http://dx.doi.org/10.1016/j.ymgme.2018.06.004DOI Listing
July 2018