Functional analysis of two novel TBX5 variants present in individuals with Holt-Oram syndrome with different clinical manifestations.

Holt-Oram syndrome (HOS) is a rare disorder characterized by cardiac and upper-limb defects. Pathogenic variants in TBX5-a gene encoding a transcription factor important for heart and skeletal development-are the only known cause of HOS. Here, we present the identification and functional analysis of two novel TBX5 pathogenic variants found in two individuals with HOS presenting distinct phenotypes. The individual with the c.905delA variant has a severe cardiac phenotype but mild skeletal defects, unlike the individual with the c.246_249delGATG variant who has no cardiac problems but severe upper limbs malformations, including phocomelia. Both frameshift variants, c.246_249delGATG and c.905delA, generate mRNAs harbouring premature stop codons which, if not degraded by nonsense mediated decay, will lead to the production of shorter TBX5 proteins, p.Gln302Argfs*92 and p.Met83Phefs*6, respectively. Immunocytochemistry results suggest that both mutated proteins are produced and furthermore, like the wild-type protein, p.Gln302Argfs*92 mutant appears to be mainly localized in the nucleus, in contrast with p.Met83Phefs*6 mutant that displays a higher level of cytoplasmic localization. In addition, luciferase activity analysis revealed that none of the TBX5 mutants are capable of transactivating the NPPA promoter. In conclusion, our results provide evidence that both pathogenic variants cause a severe TBX5 loss-of-function, dramatically reducing its biological activity. The absence of cardiac problems in the individual with the p.Met83Phefs*6 variant supports the existence of other mechanisms/genes underlying the pathogenesis of HOS and/or the existence of an age-related delay in the development of a more serious cardiac phenotype. Further studies are required to understand the differential effects observed in the phenotypes of both individuals.

Mechanical Prosthetic Heart Valve Thrombosis in a Patient Receiving Rivaroxaban.

Direct oral anticoagulants are not approved for use in patients with mechanical valves. When used to replace vitamin K antagonists, they may cause catastrophic consequences. The authors describe the case of a patient who, after discontinuation of warfarin and introduction of rivaroxaban, developed thrombosis of his mechanical mitral prosthesis.

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.

Transthyretin amyloid cardiomyopathy in severe aortic stenosis submitted to valve replacement: a multicenter study.

Aim: To evaluate the prevalence of TTR amyloid cardiomyopathy (ATTR-CM) in severe aortic stenosis (SAS) patients, and to determine the independent predictors of major adverse events (MAE).Patients & methods: 91 SAS patients >65 years with an interventricular septum thickness ≥12.5 mm were referred for aortic valve replacement (AVR). 99mTc-DPD scintigraphy was applied to diagnose ATTR-CM, in the absence of monoclonal protein.Results: ATTR-CM was found in 11%. 78% of patients underwent AVR, but only 2 had ATTR-CM. There were no significant differences in the composite of all cause-mortality or cardiovascular hospitalizations. Lower left ventricle ejection fraction and not performing AVR were independent predictors of MAE.Conclusion: Not performing AVR was an independent predictor of MAE, regardless the ATTR-CM diagnosis.

Our study aimed to evaluate the number of people with severe narrowing of the aortic valve (SAS) and damage to the heart muscle caused to the deposition of filamentous structures composed of TTR (ATTR-CM), and to determine the independent predictors of severe undesirable medical occurrences (MAE). 91 patients >65 years with SAS and increased thickness of the heart muscle were referred to perform an aortic valve prosthesis implantation (AVR). A nuclear medicine exam was used to diagnose ATTR-CM, after excluding the deposition of filamentous structures composed of blood proteins in the heart muscle. ATTR-CM was found in 11%. 78% of patients underwent AVR, but only two had ATTR-CM. There were no significant differences in both death rate from all causes or hospitalizations from cardiovascular causes. A lower percentage of blood pumped out of the heart in each beat and not performing AVR independently predicted the occurrence of MAE in SAS patients, regardless the ATTR-CM diagnosis.

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.

[The impact of direct access to primary angioplasty on reducing the mortality associated with anterior ST-segment elevation myocardial infarction: the experience of the Algarve region of Portugal]. / Impacto da via verde coronária e da angioplastia primária na redução da mortalidade associada ao enfarte com elevação do segmento ST anterior. A experiência algarvia.

INTRODUCTION: There are few published data on mortality in anterior ST-segment elevation myocardial infarction (STEMI) in Portugal, particularly in centers with direct access to primary angioplasty. We present the experience of a center with direct access to primary angioplasty in the management of patients admitted with anterior STEMI. METHODS: We performed a retrospective study of 120 patients admitted with anterior STEMI in 2008 to Faro Hospital (Algarve region, Portugal). RESULTS: Significant coronary artery stenosis was found in 99 patients (82.5%). These patients were predominantly male (79%), and had a mean age of 63 years. Primary angioplasty was performed in the majority of patients within 6 hours of symptom onset and median ECG-to-balloon time was 89 minutes. Primary angioplasty was successful in 98% of patients and complete revascularization was achieved in 83%. Radial access was used in 82% of cases. In-hospital and 30-day mortality was 3%. CONCLUSION: Direct access to primary angioplasty was associated with low mortality in patients admitted with anterior STEMI.

[Fulminant myocarditis]. / Miocardite fulminante - a propósito de um caso clínico.

A 46-year-old woman was admitted due to diplopia because of ophthalmoplegia, which improved with corticosteroid therapy. Eight days later, she was admitted with fulminant myocarditis in cardiogenic shock, with severe left ventricular dysfunction and frequent episodes of nonsustained ventricular tachycardia. As there was no clinical improvement, an endomyocardial biopsy was performed that revealed inflammatory infiltrate, vasculitis, and PCR positive for cytomegalovirus, Epstein-Barr virus, parvovirus B19 and enterovirus. Left ventricular function recovered with heart failure treatment and corticosteroids. Three months later, after progressive withdrawal of prednisolone, there was recurrence of myocarditis and left ventricular dysfunction, which was successfully treated by restarting corticosteroid therapy. One month later she was readmitted with fulminant myocarditis which again responded to steroids. She intermittently presented cutaneous purpura lesions. At this time the provisional diagnosis was vasculitis and she started monthly cycles of cyclophosphamide. Before the second cycle she was admitted with pneumonia and ventricular dysfunction and died.

Implementation of a pre-hospital network favoring primary angioplasty in STEMI to reduce mortality: the Algarve Project.

OBJECTIVE: To analyze the impact of reperfusion by either primary percutaneous coronary intervention (PPCI) or fibrinolysis, and mortality rates of a pre-hospital fast-track network for treating patients with ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: A pre-hospital network for STEMI patients, designated the Green Lane for Acute Myocardial Infarction (GL-AMI), has been implemented in the southern region of Portugal --the Algarve Project. We performed an observational study based on a prospective registry of 1338 patients admitted to Faro Hospital between 2004 and 2009, classified in two groups according to the method of admission: emergency department group (EDG) and GL-AMI group (GLG). More patients from GLG were reperfused (p < 0.0001). PPCI was the preferred method of reperfusion, 73.1% in GLG and 45.3% in EDG. Time delays were significantly shorter in GLG, except for pre-hospital delay: pre-hospital delay (p = 0.11); door-to-needle (p < 0.0001); door-to-balloon (p < 0.0001); and delay between symptoms and reperfusion (p < 0.0001). In-hospital mortality (4.3% vs 9.2%, p = 0.0007) and 6-month mortality (6.3% vs 13.8%, p < 0.0001) were significantly lower in GLG. CONCLUSIONS: The Algarve Project significantly reduced the time delay between onset of symptoms and reperfusion, significantly increased the rate of reperfusion, and significantly reduced in-hospital and six-month mortality.

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.

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.).

Female gender: an independent factor in ST-elevation myocardial infarction.

INTRODUCTION: Cardiovascular disease is the leading cause of death in women. In ST-elevation myocardial infarction (STEMI) in particular, the question has been raised whether specific characteristics of women confer a worse prognosis. OBJECTIVE: To evaluate the differences in STEMI patients between the genders in cardiovascular risk profile, clinical presentation, therapeutic approach and in-hospital and 6-month mortality rates. METHODS: We analyzed 1578 patients admitted consecutively with STEMI during a 7-year period (from January 13, 2002 to December 31, 2008). The patients were divided into two groups according to gender, and compared in terms of baseline clinical and demographic characteristics, pre-hospital and in-hospital delay, clinical presentation on admission, reperfusion therapy, severity of coronary disease and in-hospital and 6-month mortality. RESULTS: Of the 1578 patients, 26% were female. Women were older (by 8 years), and had a higher cardiovascular risk profile. On admission, their clinical presentation was more severe, with a higher frequency of anterior myocardial infarction and acute heart failure symptoms. Women had longer ischemic times and lower rates of reperfusion therapy. Mortality in women was significantly higher than in men, both in-hospital (17.5 vs. 5.3%) and at 6 months (23.5% vs. 8.2%). After adjustment in multivariate analysis, mortality in women remained higher. CONCLUSIONS: The adverse demographic and clinical profile could partially explain the worse prognosis of STEMI in women. This, together with longer pre-hospital delays, led to underuse of reperfusion therapy. Even so, female gender by itself had a negative and independent influence on mortality in STEMI patients.

EGSYS score for the prediction of cardiac etiology in syncope: Is it useful in an outpatient setting? / Score EGSYS para predição de etiologia cardíaca na síncope: tem utilidade no contexto de consulta?

INTRODUCTION: The EGSYS score uses clinical variables to predict which patients may have cardiac (CS) or non-cardiac syncope (NCS) and has been validated in the emergency department setting. This study aims to determine whether the score has the same applicability in an outpatient setting. METHODS: In this retrospective study of all patients observed in the outpatient setting of a hospital with a syncope unit between January 2015 and December 2016, the EGSYS score was calculated for each patient, and its sensitivity and specificity were determined for the prediction of CS in patients with score ≥3. RESULTS: A total of 224 patients, mean age 64.3±21.7 years, 116 (51.8%) male, were analyzed. In the 163 (72.7%) patients with confirmed syncope, CS was diagnosed in 27 (16.6%) and NCS in 136 (83.4%). The EGSYS score was ≥3 in 40 (20.0%) patients with NCS and in 13 (48.1%) with CS. A positive score had a sensitivity of 48.2% (95% CI: 28.7-68.1), a specificity of 77.9% (95% CI: 70.0-84.6), and a positive and negative predictive value of 30.2% (95% CI: 20.8-41.8) and 88.3% (95% CI: 83.9-91.7), respectively. CONCLUSION: The EGSYS score has limited usefulness in an outpatient setting, where observed patients have already been been medically assessed. Given its high specificity and negative predictive value, it may be useful to reassure low-risk patients and family members.

P2Y12 inhibitor loading dose before catheterization in ST-segment elevation myocardial infarction: Is this the best strategy? / Dose de carga do inibidor P2Y12 antes do laboratório de hemodinâmica no enfarte agudo do miocárdio com supradesnivelamento do segmento ST ­ Será mesmo a melhor estratégia?

INTRODUCTION AND OBJECTIVES: In ST-segment elevation myocardial infarction (STEMI) the benefit of dual antiplatelet therapy is unequivocal, but the optimal time to administer the loading dose (LD) of a P2Y12 inhibitor is the subject of debate and disagreement. The main aim of this study was characterize current practice in Portugal and to assess the prognostic impact of P2Y12 inhibitor LD administration strategy, before versus during or after primary percutaneous coronary intervention (PCI). METHODS: This multicenter retrospective study based on the Portuguese National Registry on Acute Coronary Syndromes included patients with STEMI and PCI performed between October 1, 2010 and September 19, 2017. Two groups were established: LD before PCI (LD-PRE) and LD during or after PCI (LD-CATH). RESULTS: A total of 4123 patients were included, 66.3% in the LD-PRE group and 32.4% in the LD-CATH group. Prehospital use of a P2Y12 inhibitor was a predictor of the composite bleeding endpoint (major bleeding, need for transfusion or hemoglobin [Hb] drop >2g/dl), Hb drop >2g/dl and reinfarction. There were no differences between groups in major adverse events (MAE) (in-hospital mortality, reinfarction and stroke) or in-hospital mortality. CONCLUSIONS: Prehospital use of a P2Y12 inhibitor was associated with an increased risk of bleeding, predicting the composite bleeding outcome and Hb drop >2g/dl, with no differences in mortality or MAE, calling into question the benefit of this strategy.

One aneurysm and two pseudoaneurysms, same patient.

Ventricular pseudoaneurysms are rare pathological entities that mainly arise in the context of myocardial infarction or post-cardiac surgery. The clinical presentation is usually non-specific, and at times patients are asymptomatic. Mortality is high even with timely surgical intervention.The authors present a case of postoperative recurrence of a left ventricular pseudoaneurysm superimposed on an ischaemic true aneurysm.

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.

Congenital left ventricular apical aneurysm presenting as ventricular tachycardia.

The authors present the case of a 34-year-old male patient seen in our department due to palpitations. On the electrocardiogram monomorphic ventricular tachycardia (VT) was documented, treated successfully with amiodarone. The subsequent study revealed a normal echocardiogram and an apical aneurysm of the left ventricle on magnetic resonance imaging, confirmed by computed tomography coronary angiography that also excluded coronary disease. He underwent an electrophysiological study to determine the origin of the VT and to perform catheter ablation using electroanatomical mapping. VT was induced and radiofrequency applications were performed in the left ventricular aneurysm area. VT was no longer inducible, with acute success. Despite this it was decided to implant a subcutaneous implantable cardioverter-defibrillator (ICD). Eight months after the ablation the patient was admitted again due to VT, treated by the ICD.

Cardiogenic shock: Inotropes and vasopressors. / Choque cardiogénico ­ fármacos inotrópicos e vasopressores.

Cardiogenic shock is characterized by a decrease in myocardial contractility, and presents a high mortality rate. Inotropic and vasopressor agents have been recommended and used for several years in the treatment of patients in shock, but they remain controversial. Despite its beneficial effect on myocardial contractility, the side effects of inotropic therapy (arrhythmias and increased myocardial oxygen consumption) may be associated with increased mortality. The pharmacodynamics of different inotropic agents suggest benefits in specific situations, but these differences have not been reflected in reduced mortality in most studies, making it difficult to formulate recommendations. This review integrates data from different studies on the use of inotropes and vasopressors in patients with cardiogenic shock, proposing a therapeutic scheme for the pharmacological treatment of patients in cardiogenic shock according to the patient's hemodynamic profile.

Failure to deliver a shock in a dual-chamber implantable cardioverter-defibrillator: a case report.

INTRODUCTION: Inappropriate implantable cardioverter-defibrillator (ICD) therapies due to supraventricular tachyarrhythmia (SVT) are a common problem. The authors report this case to warn of a possible detection problem and subsequent failure of deliver appropriate therapy in patients with atrial fibrillation (AF) and a dual-chamber ICD using the PARAD+ algorithm. To our knowledge this is the first reported case of failure to deliver a shock in a dual-chamber ICD due to the PARAD+ algorithm. CASE REPORT: The authors present a case of a 68-year-old Caucasian man with permanent AF and a dual-chamber Sorin Paradym ICD with the PARAD+ algorithm, who presented an episode of sustained ventricular tachycardia (VT). The ICD did not store the event and did not delivery a therapy, although the heart rate curve was consistent with an episode of VT. No evidence of system dysfunction was found. CONCLUSION: Due to simultaneous occurrence of VT and AF rhythms and alternation in rhythm classification by the PARAD+ algorithm the number of cycles needed to diagnose VT was not achieved and no therapy was delivered. In patients with permanent or long-term persistent AF with a dual-chamber ICD using the PARAD+ algorithm, discrimination should be based only on the ventricular channel. In patients with paroxysmal or persistent recurrent AF the risk of not delivering VT therapy must be weighed against the risk of inappropriate therapy.

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.