Reducing agalsidase beta infusion time in Fabry patients: low incidence of antibody formation and infusion-associated reactions in an Italian multicenter study.

BACKGROUND: Fabry disease is a rare progressive X-linked lysosomal storage disease caused by mutations in the GLA gene that encodes α-galactosidase A. Agalsidase beta is a recombinant enzyme replacement therapy authorized in Europe at a standard dose of 1.0 mg/kg intravenously every other week at an initial infusion rate of ≤ 0.25 mg/min until patient tolerance is established, after which the infusion rate may be increased gradually. However, specific practical guidance regarding the progressive reduction in infusion time is lacking. This study investigated a new and specific protocol for reducing agalsidase beta infusion time in which a stable dosage of 15 mg/h is infused for the first four months, and the infusion rate is increased progressively from 15 to 35 mg/h for the subsequent four infusions. The shortest infusion time is reached after six months and maintained thereafter. The incidence of infusion-associated reactions (IARs) and the development of anti-drug antibodies were analyzed, and the disease burden and the clinical evolution of the disease at 12 months were evaluated. RESULTS: Twenty-five of the 31 patients were naïve to enzyme or chaperone treatment at baseline and six patients had been switched from agalsidase alfa. The reduced infusion time protocol was well tolerated. Only one patient exhibited an IAR, with mild symptoms that resolved with low-dose steroids. Six patients globally seroconverted during treatment (4 with a classic phenotype and 2 with late-onset disease). All but three patients were seronegative at month 12. All patients were stable at the study's end (FAbry STabilization indEX value < 20%); reducing infusion time did not negatively impact clinical outcomes in any patient. The perceived medical assessment showed that the quality of life of all patients improved. CONCLUSIONS: The study demonstrates that reducing agalsidase beta infusion time is possible and safe from both an immunogenic and clinical point of view. The use of a low infusion rate in the first months when the probability of onset of the development of antibodies is higher contributed to very limited seroconversion to antibody-positive status.

The pivotal role of ECG in cardiomyopathies.

Cardiomyopathies are a heterogeneous group of pathologies characterized by structural and functional alterations of the heart. Recent technological advances in cardiovascular imaging offer an opportunity for deep phenotypic and etiological definition. Electrocardiogram (ECG) is the first-line diagnostic tool in the evaluation of both asymptomatic and symptomatic individuals. Some electrocardiographic signs are pathognomonic or fall within validated diagnostic criteria of individual cardiomyopathy such as the inverted T waves in right precordial leads (V1-V3) or beyond in individuals with complete pubertal development in the absence of complete right bundle branch block for the diagnosis of arrhythmogenic cardiomyopathy of the right ventricle (ARVC) or the presence of low voltages typically seen in more than 60% of patients with amyloidosis. Most other electrocardiographic findings such as the presence of depolarization changes including QRS fragmentation, the presence of epsilon wave, the presence of reduced or increased voltages as well as alterations in the repolarization phase including the negative T waves in the lateral leads, or the profound inversion of the T waves or downsloping of the ST tract are more non-specific signs which can however raise the clinical suspicion of cardiomyopathy in order to initiate a diagnostic procedure especially using imaging techniques for diagnostic confirmation. Such electrocardiographic alterations not only have a counterpart in imaging investigations such as evidence of late gadolinium enhancement on magnetic resonance imaging, but may also have an important prognostic value once a definite diagnosis has been made. In addition, the presence of electrical stimulus conduction disturbances or advanced atrioventricular blocks that can be seen especially in conditions such as cardiac amyloidosis or sarcoidosis, or the presence of left bundle branch block or posterior fascicular block in dilated or arrhythmogenic left ventricular cardiomyopathies are recognized as a possible expression of advanced pathology. Similarly, the presence of ventricular arrhythmias with typical patterns such as non-sustained or sustained ventricular tachycardia of LBBB morphology in ARVC or non-sustained or sustained ventricular tachycardia with an RBBB morphology (excluding the "fascicular pattern") in arrhythmogenic left ventricle cardiomyopathy could have a significant impact on the course of each disease. It is therefore clear that a learned and careful interpretation of ECG features can raise suspicion of the presence of a cardiomyopathy, identify diagnostic "red flags" useful for orienting the diagnosis toward specific forms, and provide useful tools for risk stratification. The purpose of this review is to emphasize the important role of the ECG in the diagnostic workup, describing the main ECG findings of different cardiomyopathies.

Effect of Migalastat on cArdiac InvOlvement in FabRry DiseAse: MAIORA study.

BACKGROUND: A small but significant reduction in left ventricular (LV) mass after 18 months of migalastat treatment has been reported in Fabry disease (FD). This study aimed to assess the effect of migalastat on FD cardiac involvement, combining LV morphology and tissue characterisation by cardiac magnetic resonance (CMR) with cardiopulmonary exercise testing (CPET). METHODS: Sixteen treatment-naïve patients with FD (4 women, 46.4±16.2 years) with cardiac involvement (reduced T1 values on CMR and/or LV hypertrophy) underwent ECG, echocardiogram, troponin T and NT-proBNP (N-Terminal prohormone of Brain Natriuretic Peptide) assay, CMR with T1 mapping, and CPET before and after 18 months of migalastat. RESULTS: No change in LV mass was detected at 18 months compared to baseline (95.2 g/m2 (66.0-184.0) vs 99.0 g/m2 (69.0-121.0), p=0.55). Overall, there was an increase in septal T1 of borderline significance (870.0 ms (848-882) vs 860.0 ms (833.0-875.0), p=0.056). Functional capacity showed an increase in oxygen consumption (VO2) at anaerobic threshold (15.50 mL/kg/min (13.70-21.50) vs 14.50 mL/kg/min (11.70-18.95), p=0.02), and a trend towards an increase in percent predicted peak VO2 (72.0 (63.0-80.0) vs 69.0 (53.0-77.0), p=0.056) was observed. The subset of patients who showed an increase in T1 value and a reduction in LV mass (n=7, 1 female, age 40.5 (28.6-76.0)) was younger and at an earlier disease stage compared to the others, and also exhibited greater improvement in exercise tolerance. CONCLUSION: In treatment-naïve FD patients with cardiac involvement, 18-month treatment with migalastat stabilised LV mass and was associated with a trend towards an improvement in exercise tolerance. A tendency to T1 increase was detected by CMR. The subset of patients who had significant benefits from the treatment showed an earlier cardiac disease compared to the others. TRIAL REGISTRATION NUMBER: NCT03838237.

Myocardial infarction with non-obstructive coronary arteries in hypertrophic cardiomyopathy vs Fabry disease.

BACKGROUND: Little is known about prevalence and predictors of myocardial infarction with non-obstructive coronary arteries (MINOCA) in Fabry disease (FD) and hypertrophic cardiomyopathy (HCM). We assessed and compared the prevalence and predictors of MINOCA in a large cohort of HCM and FD patients. METHODS: In this multicenter, retrospective study we enrolled 2870 adult patients with HCM and 267 with FD. The only exclusion criterion was documented obstructive coronary artery disease. MINOCA was defined according to guidelines. For each patient we collected clinical, ECG and echocardiographic data recorded at initial evaluation. RESULTS: Overall, 36 patients had MINOCA during a follow-up period of 4.5 ± 11.2 years. MINOCA occurred in 16 patients with HCM (0.5%) and 20 patients with FD (7.5%; p < 0.001). The difference between the 2 groups was highly significant, also after adjustment for the main clinical, ECG and echocardiographic variables (OR 6.12; 95%CI 2.80-13.3; p < 0.001). In the FD population MINOCA occurred in 17 out of 96 patients with left ventricle hypertrophy (LVH, 17.7%) and in 3 out of 171 patients without LVH (1.7%; OR 12.0; 95%CI 3.43-42.3; p < 0.001). At multivariable analysis, voltage criteria for LVH at ECG (OR 7.3; 95%CI 1.93-27.7; p = 0.003) and maximal LV wall thickness at echocardiography (OR 1.15; 95%CI 1.05-1.27; p = 0.002) maintained an independent association with MINOCA. No major significant differences were found in clinical, ECG and echocardiographic findings between HCM patients with or without MINOCA. CONCLUSIONS: MINOCA was rare in HCM patients, and 6-fold more frequent in FD patients. MINOCA may be considered a red flag for FD and aid in the differential diagnosis from HCM.

Appropriate use criteria for cardiovascular magnetic resonance imaging (CMR): SIC-SIRM position paper part 1 (ischemic and congenital heart diseases, cardio-oncology, cardiac masses and heart transplant).

Cardiac magnetic resonance (CMR) has emerged as new mainstream technique for the evaluation of patients with cardiac diseases, providing unique information to support clinical decision-making. This document has been developed by a joined group of experts of the Italian Society of Cardiology and Italian society of Radiology and aims to produce an updated consensus statement about the current state of technology and clinical applications of CMR. The writing committee consisted of members and experts of both societies who worked jointly to develop a more integrated approach in the field of cardiac radiology. Part 1 of the document will cover ischemic heart disease, congenital heart disease, cardio-oncology, cardiac masses and heart transplant.

Clinical significance of ST depression at exercise stress testing in competitive athletes: usefulness of coronary CT during screening.

BACKGROUND: Congenital coronary anomalies (CCAs) and coronary artery disease (CAD) arouse intense scientific and clinical interest in sports medicine and sports cardiology medical communities because of their potential to trigger sudden cardiac death (SCD) in athletes. Exercise stress testing represent the first instrumental assessment to evaluate electrocardiographic changes during effort. Coronary computed tomography angiography (CCTA) is an advanced accurate noninvasive imaging modality for excluding CAD and abnormalities of origin and course of coronary vessels. The aim of this study is to investigate with CCTA the clinical significance of ST depression suggestive for myocardial ischemia during exercise stress testing in athletes and to determine the prevalence of CAD and/or CCAs. METHODS: Sixty-five consecutive athletes showing electrocardiographic findings positive or equivocal for myocardial ischemia on exercise stress testing during pre-participation screening were investigated with CCTA. RESULTS: Among the 65 athletes investigated, 36 showed Myocardial Bridge (MB), one showed an anomalous coronary origin and seven showed CAD. Among 36 athletes with MB, 4 were associated with mild coronary artery stenosis. Three athletes with CAD needed percutaneous transluminal coronary angioplasty or coronary artery bypass surgery. CONCLUSIONS: In competitive athletes even with excellent workload capacities, in absence of cardiomyopathy, the presence of ischemic electrocardiographic abnormalities could be mainly determined by a coronary congenital or acquired pathology. In this population CCTA is a useful imaging modality of choice for the risk stratification and for the diagnostic process, to allow eligible athletes to compete and to follow-up subjects requiring medical surveillance.