SciELO - Scientific Electronic Library Online

vol.81 issue2Circulation of Echinococcus granulosus in Los Antiguos, Santa CruzCollaborative registry of pulmonary hypertension in Argentina (RECOPILAR). Final analysis author indexsubject indexarticles search
Home Pagealphabetic serial listing  

Services on Demand




  • Have no cited articlesCited by SciELO

Related links

  • Have no similar articlesSimilars in SciELO


Medicina (Buenos Aires)

Print version ISSN 0025-7680On-line version ISSN 1669-9106

Medicina (B. Aires) vol.81 no.2 Ciudad Autónoma de Buenos Aires June 2021



Major cardiovascular adverse events in Fabry disease patients receiving agalsidase alfa

Eventos cardiovasculares mayores en pacientes con enfermedad de Fabry tratados con agalsidasa alfa

Gustavo Ferrari1 

Ricardo Reisin2 

Isaac Kisinovsky3 

Pablo Neumann4 

Laura Dragonetti5 

Guillermo Cáceres6 

Martin Choua7 

Paula Rozenfeld8 

Cintia Marchesoni2 

Verónica Finn1 

1 Departamento de Cardiología, Hospital Británico, Buenos Aires

2 Departamento de Neurología, Hospital Británico, Buenos Aires

3 Departamento de Hematología, Sanatorio Urquiza, Quilmes

4 Departamento de Nefrología, Clínica Ipensa, La Plata

5 Departamento de Imágenes, Hospital Alemán, Buenos Aires

6 Hospital Comunitario, Pinamar

7 Centro Fabry, San Miguel de Tucumán

8 Departamento de Ciencias Biológicas, Universidad Nacional de La Plata, Buenos Aires, Argentina


Cardiovascular mortality (CVM) has become the major contributor to overall Fabry disease (FD) mortality in the enzyme replacement therapy (ERT) era. Our objectives were to describe causes and potential predictors of mortality in FD adult patients in Argentina, and to assess risk of major adverse cardio vascular events (MACE) in the ERT era. We retrospectively studied 93 consecutive patients treated with alpha-galactosidase A (median follow up: 9.5 years from start of ERT). Mean age at ERT starting was 35±16.3 years. Prevalence of cardiomyopathy and renal disease reached 47% and 41%, respectively. Eleven subjects (11.8%, 95%CI: 5-18%) died during follow up (1.24/100 patient-years). Mean overall survival was 71 years (95%CI: 66-75 years). Seven cases were considered as CVM; main causes were sudden death and stroke. Risk of MACE was 14% (95%CI: 6.9-21.1%; 1.47 events/100 patient-years from start of ERT). All but 2 subjects had at least one comorbid cardiovascular risk factor; however, 86% of patients remained free of MACE during follow-up. CVM remained low and our study was underpowered for detection of predictors of mortality, but it is worth noting that age at diagnosis and ERT starting, left ventricular mass index and renal disease trended to correlate with CVM. Prevalence of hypertension, diabetes and dyslipidemia were lower in FD patients when compared to population level data. As in the Argentinean general population, CVM was the leading cause of mortality among this cohort of consecutive FD patients treated with agalsidase alfa.

Key words: Anderson-Fabry disease; Cardiomyopathy; Cardiovascular mortality; Enzyme replacement therapy; Agalsidase alfa; Argentina


La mortalidad cardiovascular (MCV) se ha convertido en el principal contribuyente a la mortalidad general por enfermedad de Fabry (EF) en la era de la terapia de reemplazo enzimático (TRE). Nuestros objetivos fueron describir las causas y posibles predictores de mortalidad en pacientes adultos con EF en la Argentina, y evaluar el riesgo de eventos cardiovasculares mayores (MACE) en la actual era de TRE. Se estudiaron 93 pacientes consecutivos tratados con agalsidasa-alfa por una mediana de 9.5 años tras iniciar TRE. La edad al inicio de TRE fue 35 ± 16.3 años. La prevalencia de cardiomiopatía y enfermedad renal alcanzó 47% y 41%, respectivamente. Once sujetos (11.8%; IC95%: 5-18%) murieron durante el seguimiento (1.24/100 pacientes/año). La supervivencia global fue 71 años (IC95%: 66-75 años). Siete casos fueron considerados como MCV; las principales causas fueron muerte súbita e ictus. El riesgo de MACE fue 14% (IC95%: 6.9-21.1%; 1.47 eventos/100 pacientes/año desde la ERT). Todos menos 2 sujetos tenían al menos un factor de riesgo cardiovascular, pero el 86% permaneció libre de MACE. Los eventos de MCV fueron escasos. El estudio tuvo reducido poder estadístico para detectar predictores de mortalidad, pero la edad al diagnóstico y al iniciar la TRE, índice de masa ventricular izquierda y enfermedad renal tendieron a correlacionarse con MCV. La prevalencia de hipertensión, diabetes y dislipidemia fue menor en comparación con la población general. Como ocurre con la población general en Argentina, los eventos cardiovasculares fueron la principal causa de muerte en esta cohorte de pacientes consecutivos con EF tratados con agalsidasa-alfa.

Palabras clave: Enfermedad de Anderson-Fabry; Miocardiopatía; Mortalidad cardiovascular; Terapia de reemplazo enzimático; Agalsidasa alfa; Argentina


Current knowledge

• Fabry disease (FD) progression has been linked to ma jor adverse cardiovascular events (MACE) that limit life expectancy of untreated patients.

What this article adds

• Long-term FD treatment with agalsidase alfa is associ ated with a low number of deaths and major cardiovas cular events in Argentina.

• Even though prevalence of cardiomyopathy and renal disease reached 47% and 41%, respectively, among FD patients, mean overall survival was 71 years (95%CI: 66- 75 years) and 86% of patients remained free of MACE during 9.5 years of follow-up.

• Overall prevalence of vascular risk factors in FD was lower than in the general population.

• Age at FD diagnosis and enzyme replacement therapy starting, left ventricular mass index and renal disease trended to correlate with cardiovascular mortality among FD patients.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the gene encoding for alfa-galactosidase A. FD is characterized by progressive lysosomal accumulation of glycosphingolipids in multiple systems and organs including peripheral and autonomic nerves, gastrointestinal tract, skin, heart, kidneys and brain, with a myriad of progressive signs and symptoms including left ventricular hypertrophy (LVH), proteinuria, decreased renal function, neuropathic pain, hypohidrosis, exercise intolerance, gastrointestinal symptoms, stroke, angiokeratoma and corneal dystrophy (cornea verticil lata)1-4. Symptoms usually begin in childhood and ado lescence, especially for classical FD phenotype (mainly characterized by gastrointestinal symptoms, anhidrosis, acroparesthesias and kidney dysfunction); however, mis diagnosis is common5.The long delay between symptoms onset and the definitive diagnosis is probably related with poor recognition of FD’s manifestations5.

FD progression has been linked to end-stage renal disease and major adverse cardiovascular events (MACE) that limit life expectancy of untreated males and females (20 and 10 year reduction, respectively) as compared to the general population2. Natural history of FD has changed after the introduction of enzyme replacement therapy (ERT). In adult subjects, agalsidase alfa is administrated at 0.2 mg/kg body weight every other week by intravenous infusion6, mostly in a home-based schedule.

Data from the Fabry Outcome Survey (FOS), which collects information on the natural history of FD and the long-term efficacy and safety of ERT, suggest that the importance of renal disease as a cause of death in patients with FD is decreasing, while the importance of cardiac disease is highlighted7. Improvement in sup portive care, greater accessibility to dialysis facilities and improved treatment of hypertension have all probably contributed to the lower mortality due to renal disease among FD patients7. ERT has been linked to a slower decline or even stabilization of renal function in patients with relative lesser degrees of renal impairment7. As car diac disease is now the most commonly reported cause of death in FD patients, its treatment has become strikingly important, as ERT improve cardiac structure and function in this population7. Likewise, main causes of death among affected relatives of patients in FOS (mostly before 2001 when ERT was made available) were renal failure in males (42%) and cerebrovascular disease in females (25%)7. By contrast, cardiac disease was the main cause of death in both male (34%) and female (57%) patients during the 2001 to 2007 period7.

As well as in the rest of the world, FD is underdiag nosed in Argentina, because of its low prevalence and its infrequent consideration among differential diagnosis by the medical community8. Data about mortality and MACE in FD patients are lacking in Argentina. As cardiovascular mortality (CVM) has become the major contributor to over all FD mortality in ERT era, our aims were to assess the risk of MACE during long-term follow up in ERT-treated patients in Argentina and to describe causes and potential predictors of mortality in our patients’ cohort.

Materials and methods

An observational, longitudinal cohort study was performed in 93 consecutive patients with FD treated with agalsidase alfa between June 2001 and June 2015. Data were retrospectively retrieved in AADELFA (Asociación Argentina de Estudio y Tratamiento de Fabry y Otras Enfermedades Lisosomales) expert centers in eight Argentinean provinces and centrally analyzed in Hospital Británico in Buenos Aires, Argentina.

Inclusion criteria were confirmed FD by deficient enzyme activity in leukocytes and pathogenic mutation in GLA gene in males and demonstration of pathogenic mutation by genetic test in females; age ≥ 15 years; and patients receiving ERT with agalsidase alfa as recommended in Argentinean guide lines9. Patients without at least one documented follow up visit after 12 months of ERT initiation were excluded. Follow up cohort time was based on review of medical records and actual assessment visits from the moment of ERT initiation until the last documented assessment or death.

Mutation analysis of GLA gene (NM_000169.2) was done using DNA isolated from EDTA blood samples. Polymerase chain reaction amplification of each exon and adjacent intron- exon boundaries by the use of specific primers was carried out. The amplicons were purified and then sequenced in both directions in a DNA sequencing device (Applied Biosystems, California, USA). Interpretation and classification of GLA vari ants were based upon American College of Medical Genetics criteria10 and recent expert consensus11. All patients included in this study presented with pathogenic variants in GLA.

CVM was defined as sudden death (unexpected death within 1 hour of onset of new symptoms, including nocturnal deaths with no history of worsening symptoms); death due to heart failure, myocardial infarction, stroke or other cardio vascular cause (cardiological procedures, peripheral artery disease and pulmonary embolism).

MACEs have been inconsistently defined in the literature12. In this study, MACE were widely defined a composite criterion including cardiovascular death, non-lethal stroke, non-lethal myocardial infarction and coronary revascularization13.

Cardiovascular death and non-cardiovascular deaths were adjudicated based on review of medical records by a clinical endpoint committee formed by expert medical specialists in cardiology, neurology, nephrology and hematology, all with broad experience in FD.

Renal disease was defined by the presence of proteinuria (> 150 mg/24 hours), decreased estimated glomerular filtra tion rate (less than 60 ml/minute/1.73 m2), dialysis or renal transplant at inclusion. Coronary artery disease was defined as history of acute coronary syndrome, coronary angioplasty or coronary artery bypass surgery.

FD cardiomyopathy was defined as presence of left ventric ular mass index (LVMI) calculated by the Deveraux formula14 > 115 g/m2 in males and > 95 g/m2 in females or left ventricular systolic dysfunction (ejection fraction < 50%) assessed by echocardiogram (biplane Simpson’s method). All echocardio grams were centrally performed in Hospital Británico.

The study was approved by the institutional ethics commit tee of Hospital Británico and was performed according to good pharmacoepidemiology practice guidelines15 and local country regulations for observational clinical research (Resolution 1480/2011 from the Argentinean Ministry of Health)16, in com pliance with the Declaration of Helsinki. Given the retrospec tive data collection and the anonymization of included data, the Institutional Revision Committee has exempted the inves tigators from needing informed consents from participants.

Continuous variables were summarized as mean and standard deviation or median and quartiles, depending on distribution. Categorical variables were summarized using percentages and 95% confidence intervals (CI) were calculated. We compared the subgroup of patients without MACE during follow up versus those with MACE by univariate analysis. We used parametric or non-parametric test (depending on the dis tribution of quantitative variables) and Chi square or Fisher’s exact test, as applicable for categorical variables.

Mean cardiovascular survival time and overall survival time were determined by Kaplan Meier survival analysis; all patients were followed until death by any cause or until the last documented clinical evaluation visit that was the censoring moment for patients that did not die during follow up.

Potential predictors of mortality and MACE were evalu ated through logistic regression analysis; including eventual variables with p < 0.2 in the univariate analysis for logistic regression testing and posteriorly removing covariates with two-sided p > 0.10. Statistical significance was considered at p < 0.05. Data were tabulated using Microsoft Excel® 2013 and were analyzed using Stata Statistical Software (Release 12, College Station, TX: StataCorp LP)


Ninety-three consecutive patients with FD treated with agalsidase alfa were included in this cohort study. Median follow up was 9.5 years (first and third quartile [Q1-Q3]: 6.5-12 years) from start of ERT.

Our patient population was characterized by a median age at start of ERT of 31 years (Q1-Q3: 23-48), mean 35 ± 16.3 years; 52 were females (56%). General data and prevalence of cardiovascular disease risk factors are summarized in Table 1.

Table 1 General and clinical characteristics in the studied patients (n = 93) 

Overall prevalence of FD cardiomyopathy was 47% (95% CI: 37-57), while coronary artery disease was documented in 8% of subjects (4 patients had prior myo cardial infarction, 4 coronary artery bypass surgery and/ or percutaneous angioplasty). Renal disease was present in 41% (95% CI: 34-54), including 11% of patients with dialysis or renal transplant.

All included patients presented pathogenic mutations in GLA gene. A total of 17 mutations were identified in our group. Phenotype was classical type in 80% of patients. Mutations frequencies are detailed in Table 2. Relative distribution of the most frequent mutations was similar in male and female patients (data not shown).

Table 2 GLA mutations frequencies in the studied population 

Eleven subjects died during follow up (11.8%, 95% CI: 5-18), equivalent to 1.24 per 100 patient-years. Median age was 53 years (Q1-Q3: 42-58) for these subgroup (male: 63%, versus 41.4 % for non-deceased patients; p = 0.28). Deceased patients were marginally older (p < 0.045) than non-deceased subjects (40 years). Mean overall survival calculated by Kaplan Meier curves from date of birth was 71 years (95% CI: 66-75). No signifi cant differences were reported in the age at diagnosis, database inclusion or ERT starting among deceased and non-deceased subjects.

Seven of the eleven cases were considered as CVM: sudden death in 4/7, stroke in 2/7 (one ischemic and one hemorrhagic), and heart failure in 1/7. No mortality events were related to medical procedures, peripheral artery disease and pulmonary embolism. All patients that died due to cardiovascular causes had the classical phenotype. No aborted episodes of sudden death due to successful cardiac resuscitation or appropriate internal cardioverter defibrillator shock were described during the follow up period. Detailed data about these patients subset are available in Table 3.

Table 3 Selected characteristics of FD patients with cardiovascular mortality 

Non-CVM was observed in 4/11 patients, caused by renal transplant complications, metastatic cervical carci noma, accident and suicide due to depression.

Risk of MACE was observed in 13/93 patients (14%, 95% CI: 6.9-21.1), equivalent to 1.47 events per 100 patient-years according to median follow up from start of ERT. The two patients with no lethal MACE were women with history of hypertension and dyslipidemia; both of them experienced myocardial infarction (one of them with ST elevation). MACE patients were significantly older (me dian age: 54, Q1-Q3: 46-59) than subjects without MACE (median age: 37, Q1-Q3: 30-49; p < 0.01, Mann-Whitney U Test). Male patients represented 54% of this subgroup. Eleven out of 13 MACE subjects had at least one comor bid conventional cardiovascular risk factor; the other two patients suffered from renal failure, attributed to FD.

Due to lack of statistical power (limited number of mortality and MACE events), it was not possible to identify predictors of CVM. However, the subgroup of patients with CVM during follow up was characterized by a trend to older age at diagnosis and at start of ERT (p = 0.06 for both comparisons). A non-significant trend of higher prevalence rates of atrial fibrillation, coronary artery disease, renal disease, and a non-significant trend of increased LVMI were also observed (data not shown).

A subset of 44 (47%) patients had at least one cardiac magnetic resonance imaging (MRI), including 4/7 patients with cardiovascular death. Late gadolinium enhancement (LGE) was present in the 4 deceased patients with CVM (100%) and in 38% of the patients without CVM.


Our research describes the epidemiology of MACE and causes of mortality among a large cohort of con secutive FD patients treated with agalsidase alfa in Argentina.

CVM was approximately 1% per year of median follow up from ERT initiation and represented the main cause of overall mortality. Sudden death and stroke were the two principal causes of cardiovascular death in our series. In previous reports, life expectancy in cohorts of FD patients (both untreated and treated with ERT) reaches between 50-57 years in males and 64-72 years in females7,17-21. However, results from those studies should be interpreted with caution, considering their heterogeneity in terms of inclusion criteria, participation of patients from different re gions and differences in age at diagnosis or starting ERT. Besides, some studies do not include consecutive patients with complete follow up and both prevalence of cardiac and renal involvement and proportion of patients treated with ERT vary among the different cohorts. Moreover, FD patients from Latin America were not usually included in previous studies; therefore, local epidemiological informa tion is scarce, despite the fact that 10% of FD patients live in this region22. By contrast, our study included consecu tive patients with complete follow up over a decade from starting of ERT with no patient was lost and showed a high prevalence of cardiomyopathy and renal disease (includ ing dialysis and/or renal transplantation). Our population was at higher risk for morbidity and mortality, compared with previous reports that described lower mortality rates, but with less severe renal and cardiac affection23.

Recent data from the FOS showed that treatment with agalsidase alfa has a positive effect on mortality, with a median survival time of 77.5 years in 360 treated male patients, versus 60 years in historic control patients with a similar FD severity in the era prior to ERT24. By contrast, in a study including 40 patients with genetically proven FD (mean age 40 ± 9 years; 31 male) treated prospectively with agalsidase beta during a median follow-up of 6 years, 15 “hard” events were informed in 13 patients (including 6 sudden deaths and 4 strokes)25. The event rate was not different between the agalsidase beta treated group and an untreated matched-control group of the Fabry Registry. Our overall estimated survival of 71 years is only slightly lower than in previous studies using agalsidase alfa, which may be attributable to epidemiological differences; however, no evaluation was done in this study.

Cardiovascular deaths events in our cohort remained small and our study was underpowered for detection of predictors of mortality. However, it is worth noting that sev eral variables (age at diagnosis and starting of ERT, LVMI, and renal disease) have shown at least a positive trend of relationship with CVM, as previously observed7,17-21,23. It is interesting to note that a subset of our cohort had cardiac MRI, showing a prevalence rate of LGE reaching 100% in patients with cardiovascular death. However, this finding may be affected by selection bias since we only obtained cardiac MRI in 44% of participants.

Among our ERT-treated FD patients, risk of MACE was equivalent to 1.47 events per 100 patient-years from start of ERT, with 86% of our patients remained free of MACE during the follow-up period. All MACE patients had at least one comorbid conventional cardiovascular risk factor, including renal failure26. Interestingly, prevalence of hypertension (28%), diabetes (8%) and dyslipidemia (16%) were lower in our FD cohort in comparison with general adult population in Argentina (36%, 10% and 30%, respectively)27-29. This is most likely due to strict control of cardiovascular risk factors in every patient of our group upon FD diagnosis.

Importance of renal failure in the epidemiology of MACE in this population is highlighted. Dialysis or renal transplant may represent the first relevant clinical event in the natural history of patients with FD. In the Fabry Disease Registry, 55% of deceased patients experienced a first renal event (dialysis or transplant) versus 8% of liv ing patients17. In FD patients, renal involvement has been linked to cardiovascular disease progression including LVMI, sudden death, arrhythmia and pacing device inser tion30,31. Chronic kidney disease is a known independent risk factor for coronary artery disease, the leading cause of morbidity and mortality in patients with chronic renal disease32. In our cohort, all patients with MACE had at least one CV risk factor, including renal failure.

FD cardiomyopathy is characterized by diffuse vacuol ization of myocytes, endotheliocytes and smooth muscle cells due to glycosphingolipid accumulation. Additionally, extracellular glycosphingolipids accumulate due to death of severely affected cells with later myocardial fibrosis33. Cascade of myocardial changes in FD involves a broad range of pathological mechanisms, including toxic me tabolites, cytokine activation, autophagy and fibrosis34-37. These deleterious mechanisms may be potentiated in FD patients with concomitant chronic kidney disease and coronary artery disease, leading to primary or secondary arrhythmic death due to acute coronary events30,33.

In addition, stroke (one ischemic and one hemor rhagic) was the second cause of cardiovascular death in our study. FD is characterized by stroke at young ages, basilar dolichoectasia and white matter hyperintensities1-3. According to previous research, a relevant proportion of young FD patients may present evidence of small ves sel disease on brain magnetic resonance imaging, even without a history of stroke38. We found a trend towards larger prevalence of atrial fibrillation in deceased patients, which may be a contributor to potential cardioembolic stroke. This merits further research, since early detection and treatment with adequate anticoagulation therapy may potentially impact the incidence of stroke39.

Our study has several limitations, including its retro spective observational design, and low number of deaths that underpower a potential in-depth analysis of potential mortality predictors. The lack of a control group is a rel evant limitation, but ethical consideration regarding the indication of a treatment with proven efficacy needs to be taken into account. However, FD patients have been historically considered a subgroup with early mortality; by contrast, the mortality rates in our cohort seem similar to general Argentinean population data.

We consider our evidence, combined with that of other similar cohorts, adds relevant clinical data to the better understanding of the natural history of high risk in treated FD patients. This is especially important in a context of scarce data for FD patients from Latin America.

Besides, cardiac MRI was obtained only from a subset of our cohort, considering the growing, but yet reduced availability, of this imaging method in Argentina40. We recognize that, in addition to the diagnostic contribution of cardiac MRI in terms of different patterns of fibrosis, increasing evidence is accumulating regarding the role of LGE in defining prognosis and treatment in FD patients41. However, echocardiography remains the cornerstone for first evaluation and follow-up in FD patients41; all echocar diographic examinations of our cohort were obtained in a centrally laboratory, reducing risks of operator-linked bias.

In conclusion, long-term FD treatment with agalsidase alfa was associated with a low number of deaths and MACE. CVM (mainly due to sudden death and stroke) was the leading cause of death. Overall prevalence of vascular risk factors was lower than in the general populations, most likely to early preventive measures implemented and their benefits in our population. Potential impact of these modifiable factors in FD patients’ morbidity and mortal ity warrants a high degree of awareness for prevention, detection and treatment.


This work was supported by Shire Human Genetic Therapies SA in Argentina.


1. Mehta A, Beck M, Eyskens F, et al. Fabry disease: a review of current management strategies. QJM 2010; 103: 641-59. [ Links ]

2. Germain DP. Fabry disease. Orphanet J Rare Dis 2010; 5: 30. [ Links ]

3. Mehta A, Ricci R, Widmer U, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest 2004; 34: 236- 42. [ Links ]

4. AADELFA (Asociación Argentina de estudio de enfermedad de Fabry y otras enfermedades lisosomales). Evaluation of patients with Fabry disease in Argentina. Medicina (B Aires) 2010; 70: 37-43. [ Links ]

5. Marchesoni CL, Roa N, Pardal AM, et al. Misdiagnosis in Fabry disease. J Pediatr. 2010; 156: 828-31. [ Links ]

6. Ortiz A, Germain DP, Desnick RJ, et al. Fabry disease revisited: Management and treatment recommendations for adult patients. Mol Genet Metab 2018; 123: 416-427. [ Links ]

7. Mehta A, Clarke JT, Giugliani R, et al. Natural course of Fabry disease: changing pattern of causes of death in FOS - Fabry Outcome Survey. J Med Genet 2009; 46: 548-52. [ Links ]

8. Rozenfeld PA. Fabry disease in Argentina. Acta Bioquím Clín Latinoam 2016; 50: 17-25. [ Links ]

9. Consenso de Médicos de AADELFA y GADYTEF. Guía para el diagnóstico, seguimiento y tratamiento de la En fermedad de Fabry. Medicina (B Aires) 2013; 73: 482-94. [ Links ]

10. Richards S, Aziz N, Bale S, et al. Standards and guide lines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17: 405-24. [ Links ]

11. Smid BE, van der Tol L, Cecchi F, et al. Uncertain diag nosis of Fabry disease: consensus recommendation on diagnosis in adults with left ventricular hypertrophy and genetic variants of unknown significance. Int J Cardiol 2014; 177: 400-8. [ Links ]

12. Poudel I, Tejpal C, Rashid H, Jahan N. Major adverse car diovascular events: An inevitable outcome of ST-elevation myocardial infarction? A Literature Review. Cureus 2019; 11: e5280. [ Links ]

13. Vaccaro O, Masulli M, Nicolucci A, et al. Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA. IT): a randomised, multicentre trial. Lancet Diabetes Endocrinol 2017; 5: 887-97. [ Links ]

14. Devereux RB, Alonso DR, Lutas EM, et al. Echocardio graphic assessment of left ventricular hypertrophy: com parison to necropsy findings. Am J Cardiol 1986; 57: 450-8. [ Links ]

15. Epstein M; International Society of Pharmacoepidemiology. Guidelines for good pharmacoepidemiology practices (GPP). Pharmacoepidemiol Drug Saf 2005; 14: 589-95. [ Links ]

16. Ministerio de Salud de la Nación. Resolución 1480/2011. In: In: ; accessed June 2020. [ Links ]

17. Waldek S, Patel MR, Banikazemi M, Lemay R, Lee P. Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry Registry. Genet Med 2009; 11: 790-6. [ Links ]

18. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 98 hemizygous males. J Med Genet 2001; 38: 750-60. [ Links ]

19. MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet 2001; 38: 769 -75. [ Links ]

20. Branton MH, Schiffmann R, Sabnis SG, et al. Natural his tory of Fabry renal disease: influence of alpha-galactosi dase A activity and genetic mutations on clinical course. Medicine (Baltimore) 2002; 81: 122-38. [ Links ]

21. Vedder AC, Linthorst GE, van Breemen MJ, et al. The Dutch Fabry cohort: diversity of clinical manifestations and Gb3 levels. J Inherit Metab Dis 2007; 30: 68-78. [ Links ]

22. Villalobos J, Politei JM, Martins AM, et al. Fabry disease in Latin America: data from the Fabry registry. JIMD Rep 2013; 8: 91-9. [ Links ]

23. Patel V, O’Mahony C, Hughes D, et al. Clinical and ge netic predictors of major cardiac events in patients with Anderson-Fabry Disease. Heart 2015; 101: 961-6. [ Links ]

24. Beck M, Hughes D, Kampmann C, et al. Long-term effec tiveness of agalsidase alfa enzyme replacement in Fabry disease: A Fabry Outcome Survey analysis. Mol Genet Metab Rep 2015; 3: 21-7. [ Links ]

25. Weidemann F, Niemann M, Störk S, et al. Long-term outcome of enzyme-replacement therapy in advanced Fabry disease: evidence for disease progression towards serious complications. J Intern Med 2013; 274: 331-41. [ Links ]

26. Fort J. Chronic renal failure: a cardiovascular risk factor. Kidney Int Suppl 2005; (99): S25-9. 11/j.1523-1755.2005.09906.x27. [ Links ]

27. Delucchi AM, Majul CR, Vicario A, Cerezo GH, Fábregues G. National Registry of Hypertension. Epidemiological characteristics of hypertension in Argentina. The RE NATA 2 Study. Rev Argent Cardiol 2017; 85: 340-6. [ Links ]

28. World Health Organization. Country profiles. In: In: ; accessed June 2020. [ Links ]

29. Ministerio de Salud de la Nación (Argentina). Tercera Encuesta Nacional de Factores de Riesgo para Enferme dades No Transmisibles. 2013. In: In: ; accessed June 2020. [ Links ]

30. Talbot AS, Lewis NT, Nicholls KM. Cardiovascular out comes in Fabry disease are linked to severity of chronic kidney disease. Heart 2015; 101: 287-93. [ Links ]

31. Patel MR, Cecchi F, Cizmarik M, et al. Cardiovascular events in patients with Fabry disease natural history data from the Fabry registry. J Am Coll Cardiol 2011; 57: 1093-9. [ Links ]

32. Cai Q, Mukku VK, Ahmad M. Coronary artery disease in patients with chronic kidney disease: a clinical update. Curr Cardiol Rev 2013; 9: 331-9. [ Links ]

33. Pieroni M, Chimenti C, De Cobelli F. Fabry’s disease cardiomyopathy: echocardiographic detection of endomyocardial glycosphingolipid compartmentalization. J Am Coll Cardiol 2006; 47: 1663-71. [ Links ]

34. Dimitrow PP. Heart in Fabry Disease. Journal of Rare Cardiovascular Diseases 2012; 1: 3-6. [ Links ]

35. Moon JC, Sachdev B, Elkington AG, et al. Gadolinium enhanced cardiovascular magnetic resonance in An derson-Fabry disease. Evidence for a disease specific abnormality of the myocardial interstitium. Eur Heart J 2003; 24: 2151-5. [ Links ]

36. Krämer J, Niemann M, Störk S, et al. Relation of burden of myocardial fibrosis to malignant ventricular arrhythmias and outcomes in Fabry disease. Am J Cardiol 2014; 114: 895-900. [ Links ]

37. Weidemann F, Breunig F, Beer M, et al. The variation of morphological and functional cardiac manifestation inFabry disease: potential implications for the time course of the disease. Eur Heart J 2005; 26: 1221-7. [ Links ]

38. Reisin RC, Romero C, Marchesoni C, et al. Brain MRI find ings in patients with Fabry disease. J Neurol Sci 2011; 305: 41-4. [ Links ]

39. Mehta A, Beck M, Elliott P, et al. Enzyme replacement therapy with agalsidase alfa in patients with Fabry’s disease: an analysis of registry data. Lancet 2009; 374: 1986-96. [ Links ]

40. De Stefano L. Sociedad Argentina de Cardiología: seis preguntas sobre resonancia magnética cardíaca. In: In: ; accessed June 2020. [ Links ]

41. Militaru S, Ginghina C, Popescu BA, Saftoiu A, Linhart A, Jurcut R. Multimodality imaging in Fabry cardiomyopathy: from early diagnosis to therapeutic targets. Eur Heart J Cardiovasc Imaging 2018; 19: 1313-22. [ Links ]

Received: June 17, 2020; Accepted: October 15, 2020

*Dirección postal: Gustavo Ferrari, Departamento de Cardiología, Hospital Británico, Perdriel 74, 1280 Buenos Aires, Argentina e-mail:

Creative Commons License This is an open-access article distributed under the terms of the Creative Commons Attribution License