Challenges in Fabry disease: the combination of two individually amenable GLA variants may be nonamenable to migalastat.

Fabry disease is a rare lysosomal storage disorder caused by mutations in the GLA gene, resulting in reduced or absent α-Gal A activity. Migalastat is an oral chaperone therapy for Fabry patients with amenable GLA variants. We previously reported a case of a 60-year-old male patient with a classic phenotype of Fabry disease, presenting with two GLA variants: p.R356Q and p.G360R. Herein, we report that, although these two missense variants are individually classified as amenable to migalastat in the validated in vitro human embryonic kidney-293 cell-based assay, their combination precludes the patient to be treated with this oral chaperone. This case illustrates how therapeutic decisions may be challenging and how a good genotypic characterization of Fabry patients is critical for the selection of the correct therapeutic strategy.

Fabry disease is a rare genetic disease that is part of a group of conditions called lysosomal storage diseases. It is characterized by an abnormal accumulation of glycosphingolipids, a subclass of glycolipids which are important components of the body's cell membranes. This accumulation is caused by a reduction in, or absence of, enzyme α-Gal A activity, which normally breaks glycosphingolipids down into smaller units, avoiding their accumulation. The absence or reduction in the α-Gal A enzyme activity is caused by mutations (changes in the normal DNA sequence) in the GLA gene. Migalastat is an oral treatment for Fabry patients with GLA mutations that respond to this treatment. We report a case of a 60-year-old male patient with Fabry disease, presenting with two GLA mutations (p.R356Q and p.G360R). Although these mutations are individually amenable to migalastat, their combination and interaction in the same chromosome precludes response to this treatment. This case illustrates how therapeutic decisions for treating Fabry disease can be challenging depending on the mutations causing the disease and how genetic material is decisive for therapy selection.

Premature acute coronary syndrome: understanding the early onset.

INTRODUCTION: Acute coronary syndrome (ACS) is less frequent in young adults, but it has become a significant health problem, associated with the increasing prevalence of modifiable risk factors. OBJECTIVES: To characterize patients admitted with premature ACS, comparing with those with nonpremature ACS. METHODS: We performed a retrospective study encompassing patients of the Portuguese Registry (ProACS), comparing two groups: one composed of men less than 55 and women less than 65 years old; and other with men ≥55 and women ≥65 years old at the ACS admission. The primary endpoint was the composite of in-hospital mortality, stroke and myocardial reinfarction (re-MI). RESULTS: A total of 29 870 patients were enrolled and 25% had premature ACS, with a mean age of 50 ± 7 years old. They had a larger prevalence of smoking habits, obesity and dyslipidemia. ST-segment elevation MI (STEMI) was the main admission diagnosis in young patients and coronary angiogram mainly revealed one vessel disease in this subgroup. They had a lower Killip-Kimball (KK) class and mostly preserved left ventricular ejection fraction (LVEF). Composite endpoint was more frequent in nonpremature ACS patients. Nonpremature age, presentation with syncope or cardiac arrest, KK class >1, multivessel disease and LVEF <40% were independent predictors of the primary endpoint ( P < 0.001). Younger patients had lower rates of in-hospital all-cause mortality, re-MI and stroke. One-year all-cause mortality and 1-year cardiovascular and non-cardiovascular readmissions were also lower. CONCLUSIONS: Premature ACS affects 25% of the ACS population, mostly presenting with STEMI, but generally associated with better clinical evolution. Nevertheless, prevention measures are essential to correct modifiable cardiovascular risk factors and reduce coronary events.

Generation and cardiac differentiation of a human induced pluripotent stem cell line UALGi002-A from a female patient with Left-Ventricular Noncompaction Cardiomyopathy.

Left Ventricular Noncompaction Cardiomyopathy (LVNC) is characterized by abnormal number and prominence of trabeculations of the left ventricle of the heart. Although LVNC has been associated with mutations in several genes encoding for transcriptional regulators, ion channels, sarcomeric and mitochondrial proteins, approximately 60% of LVNC patients do not present these genetic alterations. Here, we describe an induced pluripotent stem cell (hiPSC) line (UALGi002-A) originated from a LVNC female patient (LVNC-hiPSC) who does not present any previously known mutations associated to LVNC. The LVNC-hiPSC exhibited full pluripotency and differentiation potential and retained a normal karyotype after reprogramming. Moreover, the LVNC-hiPSC differentiated into contracting cardiomyocytes. This cellular model will be useful to study the molecular, genetic and functional aspects of LVNC in vitro.

Giant Left Ventricular (Pseudo?) Aneurysm Complicating Anterior Myocardial Infarction.

The differential diagnosis of true aneurysms and pseudoaneurysms is challenging, and multimodality cardiac imaging is often necessary. We report a case in which the limitations of these techniques are exposed, showing that post-operative evaluation of tissue layers remains the gold standard in establishing this diagnosis. (Level of Difficulty: Beginner.).

Generation of a human induced pluripotent stem cell line (UALGi001-A) from a patient with Left-Ventricular Noncompaction Cardiomyopathy.

Left Ventricular Noncompaction Cardiomyopathy (LVNC) is characterized by excessive trabeculation of the left ventricle. To date, mutations in more than 40 genes have been associated with LVNC, however the exact mechanisms underlying the disease remain unknown. Here, we describe an induced pluripotent stem cell (iPSC) line (UALGi001-A) from a LVNC patient (LVNC-iPSC) that does not present mutations in the genes most commonly associated with the disease (van Waning et al., 2019). The LVNC-iPSC exhibited full pluripotency and differentiation potential, and retained a normal karyotype after reprogramming. This in vitro cellular model will be useful to study the molecular, genetic and functional aspects of LVNC.

Specific Therapy for Transthyretin Cardiac Amyloidosis: A Systematic Literature Review and Evidence-Based Recommendations.

Background The emergence of specific therapies for transthyretin cardiac amyloidosis (CA) warrants the need for a systematic review of the literature. Methods and Results A systematic review of the literature was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search was performed on MEDLINE, PubMed, and Embase databases on November 29, 2019. Studies were selected based on the following predefined eligibility criteria: English-language randomized controlled trials (RCTs), non-RCTs, or observational studies, which included adult patients with variant/wild-type transthyretin-CA, assessed specific therapies for transthyretin-CA, and reported cardiovascular outcomes. Relevant data were extracted to a predefined template. Quality assessment was based on National Institute for Health and Care Excellence recommendations (RCTs) or a checklist by Downs and Black (non-RCTs). From 1203 records, 24 publications were selected, describing 4 RCTs (6 publications) and 16 non-RCTs (18 publications). Tafamidis was shown to significantly improve all-cause mortality and cardiovascular hospitalizations and reduce worsening in 6-minute walk test, Kansas City Cardiomyopathy Questionnaire-Overall Summary score, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) in variant/wild-type transthyretin-CA. Patisiran showed promising results in a subgroup analysis of patients with variant transthyretin-CA, which have to be confirmed in RCTs. Inotersen showed conflicting results on cardiac imaging parameters. The one study on AG10 had only a 1-month duration and cardiovascular end points were exploratory and limited to cardiac biomarkers. Limited evidence from noncomparative single-arm small non-RCTs existed for diflunisal, epigallocatechin-3-gallate (green tea extract), and doxycycline+tauroursodeoxycholic acid/ursodeoxycholic acid. Conclusions This systematic review of the literature supports the use of tafamidis in wild-type and variant transthyretin-CA. Novel therapeutic targets including transthyretin gene silencers are currently under investigation.

Clinical Features and Natural History of PRKAG2 Variant Cardiac Glycogenosis.

BACKGROUND: PRKAG2 gene variants cause a syndrome characterized by cardiomyopathy, conduction disease, and ventricular pre-excitation. Only a small number of cases have been reported to date, and the natural history of the disease is poorly understood. OBJECTIVES: The aim of this study was to describe phenotype and natural history of PRKAG2 variants in a large multicenter European cohort. METHODS: Clinical, electrocardiographic, and echocardiographic data from 90 subjects with PRKAG2 variants (53% men; median age 33 years; interquartile range [IQR]: 15 to 50 years) recruited from 27 centers were retrospectively studied. RESULTS: At first evaluation, 93% of patients were in New York Heart Association functional class I or II. Maximum left ventricular wall thickness was 18 ± 8 mm, and left ventricular ejection fraction was 61 ± 12%. Left ventricular hypertrophy (LVH) was present in 60 subjects (67%) at baseline. Thirty patients (33%) had ventricular pre-excitation or had undergone accessory pathway ablation; 17 (19%) had pacemakers (median age at implantation 36 years; IQR: 27 to 46 years), and 16 (18%) had atrial fibrillation (median age 43 years; IQR: 31 to 54 years). After a median follow-up period of 6 years (IQR: 2.3 to 13.9 years), 71% of subjects had LVH, 29% had AF, 21% required de novo pacemakers (median age at implantation 37 years; IQR: 29 to 48 years), 14% required admission for heart failure, 8% experienced sudden cardiac death or equivalent, 4% required heart transplantation, and 13% died. CONCLUSIONS: PRKAG2 syndrome is a progressive cardiomyopathy characterized by high rates of atrial fibrillation, conduction disease, advanced heart failure, and life-threatening arrhythmias. Classical features of pre-excitation and severe LVH are not uniformly present, and diagnosis should be considered in patients with LVH who develop atrial fibrillation or require permanent pacemakers at a young age.

p.G360R Is a Pathogenic GLA Gene Mutation Responsible for a Classic Phenotype of Fabry Disease.

The authors report the case of a classic phenotype of Fabry disease in a 60-year-old male patient presenting with left ventricular hypertrophy and stroke. Genetic analysis revealed 2 GLA-gene variants, i.e., p.R356Q and p.G360R. This clinical case highlights that the finding of 2 or more GLA gene variants in a Fabry patient should lead to a careful evaluation in order to determine their exact role in the condition. This case also provides the first clinical evidence that the p.G360R mutation is pathogenic and responsible for a classic phenotype of Fabry disease. The clinical improvement following the initiation of enzyme replacement therapy reinforces the importance of Fabry disease awareness and diagnosis in patients exhibiting red flags, such as left ventricular hypertrophy and stroke.

Short- and medium-term prognosis of Takotsubo syndrome in a Portuguese population.

INTRODUCTION: Takotsubo syndrome (TTS) is characterized by transient left ventricular (LV) systolic dysfunction. AIM: To characterize a Portuguese population with TTS and to determine their short- and medium-term prognosis. METHODS: We conducted a multicenter study in Portuguese hospitals that included all patients diagnosed with TTS, initially retrospectively and subsequently prospectively. Short- and medium-term clinical complications and mortality were assessed. Independent predictors of in-hospital complications and prognostic factors were determined. RESULTS: A total of 234 patients (210 female, age 68±12 years) were included. During hospitalization, 32.9% of patients had complications: acute heart failure (24.4%), atrial fibrillation (9.0%), ventricular arrhythmias (2.6%), complete atrioventricular block (2.1%), stroke/transient ischemic attack (1.7%), and LV thrombus (1.3%). Chronic kidney disease (CKD) (p=0.02), coronary artery disease (CAD) (p=0.027), lower LV ejection fraction (LVEF) on admission (p=0.003), and dyspnea at presentation (p=0.019) were predictors of in-hospital complications. In-hospital mortality was 2.2%. At the mean follow-up of 33±33 months, all-cause mortality was 4.4%, cardiovascular mortality was 0.9% and TTS recurrence was 4.4%. Prolonged QTc interval on admission was associated with complications in follow-up (p=0.001). CONCLUSION: TTS has a good short- and medium-term prognosis. However, the rate of in-hospital complications is high and should not be overlooked. Dyspnea at presentation, CKD, CAD and lower LVEF on admission were independent predictors of in-hospital complications. Prolonged QTc on admission was associated with complications in follow-up.

Surgical aortic valve replacement improves the quality of life of octogenarians with severe aortic stenosis. / A cirurgia de substituição valvular aórtica melhora a qualidade de vida dos octogenários com estenose aórtica severa.

INTRODUCTION: Aortic stenosis (AS) is the most common valvular disease in the elderly, affecting around 8.1% by the age of 85, with a negative impact on quality of life. OBJECTIVE: To determine the impact of surgical aortic valve replacement (SAVR) on quality of life in octogenarians. METHODS: In a single-center retrospective study of octogenarians undergoing isolated SAVR for symptomatic AS between 2011 and 2015, quality of life was assessed using the Medical Outcomes Study Short Form (SF-36) at baseline and at three, six and 12 months after surgery. Scores for the eight domains and two components of the SF-36 were compared at baseline and in the postoperative period by one-way analysis of variance. RESULTS: Over a five-year period, 163 octogenarians underwent SAVR, of whom 3.1% died in the hospital. Deceased patients and those who did not complete the SF-36 were excluded. A total of 81 patients were included, mean age 83±2 years, 63% female, 60.5% in NYHA class II or higher and 19.7% with left ventricular systolic dysfunction. The mean logistic EuroSCORE was 10.7±5.1%. In the hospital, 1.2% suffered stroke, 1.2% received a permanent implantable pacemaker and 23.5% presented atrial fibrillation. In the assessment of quality of life, improvement was seen in all SF-36 domains (p<0.002) and in the physical component (p<0.001) at three, six and 12 months compared to baseline. The mental component also showed improvement, which was significant at six months (p=0.011). CONCLUSION: SAVR improved the physical and mental health status of octogenarians with severe AS. This improvement was evident at three months and consistent at six and 12 months.

CRUSADE: Is it still a good score to predict bleeding in acute coronary syndrome? / Score CRUSADE ­ Será ainda um bom score para prever a hemorragia na síndrome coronária aguda?

INTRODUCTION: Major bleeding is a serious complication of acute coronary syndrome (ACS) and is associated with a worse prognosis. The CRUSADE bleeding score is used to stratify the risk of major bleeding in ACS. OBJECTIVE: To assess the predictive ability of the CRUSADE score in a contemporary ACS population. METHODS: In a single-center retrospective study of 2818 patients admitted with ACS, the CRUSADE score was calculated for each patient and its discrimination and goodness of fit were assessed by the area under the receiver operating characteristic curve (AUC) and by the Hosmer-Lemeshow test, respectively. Predictors of in-hospital major bleeding (IHMB) were determined. RESULTS: The IHMB rate was 1.8%, significantly lower than predicted by the CRUSADE score (7.1%, p<0.001). The incidence of IHMB was 0.5% in the very low risk category (rate predicted by the score 3.1%), 1.5% in the low risk category (5.5%), 1.6% in the moderate risk category (8.6%), 5.5% in the high risk category (11.9%), and 4.4% in the very high risk category (19.5%). The predictive ability of the CRUSADE score for IHMB was only moderate (AUC 0.73). The in-hospital mortality rate was 4.0%. Advanced age (p=0.027), femoral vascular access (p=0.004), higher heart rate (p=0.047) and ticagrelor use (p=0.027) were independent predictors of IHMB. CONCLUSIONS: The CRUSADE score, although presenting some discriminatory power, significantly overestimated the IHMB rate, especially in patients at higher risk. These results question whether the CRUSADE score should continue to be used in the stratification of ACS.

Changes in referral protocols for cardiac surgery: do financial considerations come at a cost?

INTRODUCTION AND OBJECTIVES: The aim of this study was to determine whether changes to referral protocols for cardiac surgery have had an impact on waiting times, hospitalizations and mortality during the waiting period and during the first year of follow-up after surgery. METHODS: In this retrospective study of patients referred for cardiac surgery between January 1, 2008 and September 30, 2014, the study population was divided into two groups: those referred before (group A, January 1, 2008 to August 31, 2011) and after (group B, September 1, 2011 to September 30, 2014) the change in referral protocols. A telephone follow-up was conducted. RESULTS: There were 864 patients referred for cardiac surgery, 557 in group A and 307 in group B. Patient characteristics were similar between groups. The mean waiting time for surgery was 10.6±18.5 days and 55.7±79.9 days in groups A and B, respectively (p=0.00). During the waiting period two patients (0.4%) were hospitalized in group A and 28 (9.1%) in group B (p=0:00); mortality was, respectively, 0% and 2.3% (p=0.00). During one-year follow-up 12.8% of group A patients and 16% of group B patients were hospitalized. Cardiovascular mortality in this period was around 5% in both groups (p>0.05). CONCLUSION: Changes to referral protocols for cardiac surgery had an impact on waiting times, on the number of hospitalizations and on mortality in this period.

Holt-Oram syndrome: a case report.

Holt-Oram syndrome is clinically characterized by morphological abnormalities of the upper limbs and congenital cardiac defects. Although the disease is congenital, the diagnosis may only be made later in life. It is a rare autosomal dominant disorder, caused by a mutation in the TBX5 gene located on chromosome 12, but sporadic cases have also been reported. We describe the case of a 75-year-old man with known morphological alterations of the upper limbs since birth and congenital cardiac defect (atrial septal defect), who later in life also manifested with advanced atrioventricular block.