Predictors of Fabry disease in patients with hypertrophic cardiomyopathy: How to guide the diagnostic strategy?

BACKGROUND: Fabry disease (FD) is a treatable cause of hypertrophic cardiomyopathy (HCM). We aimed to determine the independent predictors of FD and to define a clinically useful strategy to discriminate FD among HCM. METHODS: Multicenter study including 780 patients with the ESC definition of HCM. FD screening was performed by enzymatic assay in males and genetic testing in females. Multivariate regression analysis identified independent predictors of FD in HCM. A discriminant function analysis defined a score based on the weighted combination of these predictors. RESULTS: FD was found in 37 of 780 patients with HCM (4.7%): 31 with p.F113L mutation due to a founder effect; and 6 with other variants (p.C94S; p.M96V; p.G183V; p.E203X; p.M290I; p.R356Q/p.G360R). FD prevalence in HCM adjusted for the founder effect was 0.9%. Symmetric HCM (OR 3.464, CI95% 1.151-10.430), basal inferolateral late gadolinium enhancement (LGE) (OR 10.677, CI95% 3.633-31.380), bifascicular block (OR 10.909, CI95% 2.377-50.059) and ST-segment depression (OR 4.401, CI95% 1.431-13.533) were independent predictors of FD in HCM. The score ID FABRY-HCM [-0.729 + (2.781xBifascicular block) + (0.590xST depression) + (0.831xSymmetric HCM) + (2.130xbasal inferolateral LGE)] had a negative predictive value of 95.8% for FD, with a cut-off of 1.0, meaning that, in the absence of both bifascicular block and basal inferolateral LGE, FD is a less probable cause of HCM, being more appropriate to perform HCM gene panel than targeted FD screening. CONCLUSION: FD prevalence in HCM was 0.9%. Bifascicular block and basal inferolateral LGE were the most powerful predictors of FD in HCM. In their absence, HCM gene panel is the most appropriate step in etiological study of HCM.

Ischaemia alters the effects of cardiomyocyte-derived extracellular vesicles on macrophage activation.

Myocardial ischaemia is associated with an exacerbated inflammatory response, as well as with a deregulation of intercellular communication systems. Macrophages have been implicated in the maintenance of heart homeostasis and in the progression and resolution of the ischaemic injury. Nevertheless, the mechanisms underlying the crosstalk between cardiomyocytes and macrophages remain largely underexplored. Extracellular vesicles (EVs) have emerged as key players of cell-cell communication in cardiac health and disease. Hence, the main objective of this study was to characterize the impact of cardiomyocyte-derived EVs upon macrophage activation. Results obtained demonstrate that EVs released by H9c2 cells induced a pro-inflammatory profile in macrophages, via p38MAPK activation and increased expression of iNOS, IL-1ß and IL-6, being these effects less pronounced with ischaemic EVs. EVs derived from neonatal cardiomyocytes, maintained either in control or ischaemia, induced a similar pattern of p38MAPK activation, expression of iNOS, IL-1ß, IL-6, IL-10 and TNFα. Importantly, adhesion of macrophages to fibronectin was enhanced by EVs released by cardiomyocytes under ischaemia, whereas phagocytic capacity and adhesion to cardiomyocytes were higher in macrophages incubated with control EVs. Additionally, serum-circulating EVs isolated from human controls or acute myocardial infarction patients induce macrophage activation. According to our model, in basal conditions, cardiomyocyte-derived EVs maintain a macrophage profile that ensure heart homeostasis, whereas during ischaemia, this crosstalk is affected, likely impacting healing and post-infarction remodelling.

Myocardial infarction affects Cx43 content of extracellular vesicles secreted by cardiomyocytes.

Ischemic heart disease has been associated with an impairment on intercellular communication mediated by both gap junctions and extracellular vesicles. We have previously shown that connexin 43 (Cx43), the main ventricular gap junction protein, assembles into channels at the extracellular vesicle surface, mediating the release of vesicle content into target cells. Here, using a comprehensive strategy that included cell-based approaches, animal models and human patients, we demonstrate that myocardial ischemia impairs the secretion of Cx43 into circulating, intracardiac and cardiomyocyte-derived vesicles. In addition, we show that ubiquitin signals Cx43 release in basal conditions but appears to be dispensable during ischemia, suggesting an interplay between ischemia-induced Cx43 degradation and secretion. Overall, this study constitutes a step forward for the characterization of the signals and molecular players underlying vesicle protein sorting, with strong implications on long-range intercellular communication, paving the way towards the development of innovative diagnostic and therapeutic strategies for cardiovascular disorders.

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.

Screening for Fabry disease in patients with left ventricular noncompaction.

INTRODUCTION AND AIM: It is unclear whether left ventricular noncompaction (LVNC) is a distinct cardiomyopathy or a morphologic manifestation of different cardiomyopathies. We previously reported a case of LVNC in a Fabry disease (FD) patient, but it remains to be clarified whether LVNC is a cardiac manifestation of FD, a coincidental finding or an overdiagnosis, which has major therapeutic implications. This study aims to determine the prevalence of FD among patients with LVNC. METHODS: We performed a retrospective study including all patients diagnosed with LVNC in eight hospital centers. Diagnosis of LVNC was based on at least one echocardiographic or cardiac magnetic resonance criterion. FD screening was performed by combined enzyme and genetic testing. RESULTS: The study included 78 patients diagnosed with LVNC based on the Jenni (84.6%), Stöllberger (46.2%), Chin (21.8%), Petersen (83.8%) and Jacquier (16.2%) criteria. Left ventricular systolic dysfunction was present in 48.7%. Heart failure was found in 60.3%, ventricular dysrhythmias in 21.6% and embolic events in 11.5%. FD screening found no additional cases among patients with LVNC, besides the previously described case. CONCLUSION: No additional FD cases were found among patients with LVNC, which argues against the hypothesis that LVNC is a cardiac manifestation of FD.

Prevention of Sudden Cardiac Death in Hypertrophic Cardiomyopathy: What has Changed in The Guidelines?

BACKGROUND: The new European Society of Cardiology guidelines for hypertrophic cardiomyopathy (HCM) define the estimation of sudden cardiac death (SCD) risk as an integral part of clinical management. An implantable cardioverter defibrillator (ICD) is recommended (class IIa) when the risk is ≥ 6%. OBJECTIVES: To compare the SCD risk stratification according to the 2011 and 2014 recommendations for ICD implantation in patients with HCM. METHODS: Retrospective study including 105 patients diagnosed with HCM. The indication for ICD was assessed using the 2011 and 2014 guidelines. Statistical analysis was performed using SPSS software version 19.0.0.2®. The tests performed were bilateral, considering the significance level of 5% (p < 0.05). RESULTS: Regarding primary prevention, according to the 2011 ACCF/AHA recommendations, 39.0% of the patients had indication for ICD implantation (level of evidence IIa). Using the 2014 guidelines, only 12.4% of the patients had an indication for ICD implantation. Comparing the two risk stratification models for patients with HCM, we detected a significant reduction in the number of indications for ICD implantation (p < 0.001). Of the 41 patients classified as IIa according to the 2011 recommendations, 68.3% received a different classification according to the 2014 guidelines. CONCLUSION: Significant differences were found when comparing the SCD risk stratification for ICD implantation in the two guidelines. The current SCD risk score seems to identify many low-risk patients who are not candidates for ICD implantation. The use of this new score results in a significant reduction in the number of ICD implanted.

Registry of left atrial appendage closure and initial experience with intracardiac echocardiography. / Registo de encerramento percutâneo do apêndice auricular esquerdo e experiência inicial com ecografia intracardíaca.

INTRODUCTION: Percutaneous closure of the left atrial appendage (LAA) is a promising therapy in patients with atrial fibrillation with high risk for stroke and contraindication for oral anticoagulation (OAC). Intracardiac echocardiography (ICE) may make this percutaneous procedure feasible in patients in whom transesophageal echocardiography (TEE) is inadvisable. Our aim was to assess the efficacy and safety of LAA closure and the feasibility of ICE compared to TEE to guide the procedure. METHODS: In this cohort study of patients who underwent LAA closure between May 2010 and January 2017, clinical and imaging assessment was performed before and after the procedure. RESULTS: In 82 patients (mean age 74±8 years, 64.4% male) the contraindications for OAC were severe bleeding or anemia (65%), high bleeding risk (14%), labile INR (16%), or recurrent embolic events (5%). The procedural success rate was 96.3%. The procedure was guided by TEE or ICE, and no statistically significant differences were observed between the two techniques. During follow-up, one patient had an ischemic stroke at 12 months, two had bleeding complications at six months, and there were four non-cardiovascular deaths. Embolic and bleeding events were less frequent than expected from the observed CHA2DS2VASc (0.6% vs. 6.3%; p<0.001) and HAS-BLED (1.2% vs. 4.1%; p<0.001) risk scores. CONCLUSIONS: In this population percutaneous LAA closure was shown to be safe and effective given the lower frequency of events than estimated by the CHA2DS2VASc and HAS-BLED scores. The clinical and imaging results of procedures guided by ICE in the left atrium were not inferior to those guided by TEE.

Inotropes and cardiorenal syndrome in acute heart failure - A retrospective comparative analysis.

INTRODUCTION: Cardiorenal syndrome (CRS) is common in acute heart failure (AHF), and is associated with dire prognosis. Levosimendan, a positive inotrope that also has diuretic effects, may improve patients' renal profile. Published results are conflicting. OBJECTIVES: We aimed to assess the incidence of CRS in AHF patients according to the inotrope used and to determine its predictors in order to identify patients who could benefit from the most renoprotective inotrope. METHODS: In a retrospective study, 108 consecutive patients with AHF who required inotropes were divided into two groups according to the inotrope used (levosimendan vs. dobutamine). The primary endpoint was CRS incidence. Follow-up for mortality and readmission for AHF was conducted. RESULTS: Seventy-one percent of the study population were treated with levosimendan and the remainder with dobutamine. No differences were found in heart failure etiology or chronic kidney disease. At admission, the dobutamine group had lower blood pressure; there were no differences in estimated glomerular filtration rate or cystatin C levels. The levosimendan group had lower left ventricular ejection fraction. CRS incidence was higher in the dobutamine group, and they more often had incomplete recovery of renal function at discharge. In multivariate analysis, cystatin C levels predicted CRS. The dobutamine group had higher in-hospital mortality, of which CRS and the inotrope used were predictors. CONCLUSIONS: Levosimendan appears to have some renoprotective effect, as it was associated with a lower incidence of CRS and better recovery of renal function at discharge. Identification of patients at increased risk of renal dysfunction by assessing cystatin C may enable more tailored therapy, minimizing the incidence of CRS and its negative impact on outcome in AHF.

Does percutaneous left atrial appendage closure affect left atrial performance? / O fechamento percutâneo do apêndice atrial esquerdo afeta o desempenho do átrio esquerdo?

Background: Percutaneous left atrial appendage (LAA) occlusion may be an alternative therapy for atrial fibrillation (AF) patients with contraindication for anti-coagulation therapy. However, the influence of LAA occlusion on left atrial (LA) performance has not been studied. Objective: Our aim was to evaluate the influence of percutaneous LAA occlusion device on LA function by transthoracic echocardiography plus speckle-tracking echocardiography (STE).Methods: We included 16 patients undergoing percutaneous LAA closure with adequate echocardiographic window for the study of LA mechanics. Transthoracic echocardiography was performed before and after the procedure. LA volumes were calculated using the biplane method, and LA mechanics were assessed using STE. The analysis focused on the LA reservoir phase strain and strain rate.Results: Seventy-five percent of patients had permanent atrial fibrillation. Embolic and bleeding risk scores used were CHA2DS2-VASc [median of 4-5] and HAS-BLED [median of 2-3]. Major bleeding (62%) was the most common indication for the procedure. Percutaneous LAA closure was performed successfully in all patients, without major complications. No differences were found in maximum LA volume (44 ± 11 vs. 46 ± 13 mL/m2; p = 0.54), minimum LA volume (32 ± 8 vs. 37 ± 14 mL/m2; p = 0.09) or LA emptying fraction (26 ± 17 vs. 21 ± 14%; p = 0.33) before and after the procedure. Similarly, no differences were noted in left atrial strain (13.7 ± 11.1 vs. 13.0 ± 8.8%; p = 0.63) or strain rate (1.06 ± 0.26 vs. 1.13 ± 0.34 s-1; p = 0.38) in the reservoir phase. Conclusions: Our data suggest that percutaneous LAA closure does not affect LA reservoir function

Prevention of Sudden Cardiac Death in Hypertrophic Cardiomyopathy: What has Changed in The Guidelines? / Prevenção de Morte Súbita Cardíaca em Doentes com Miocardiopatia Hipertrófica: O Que Mudou nas Guidelines?

Abstract Background: The new European Society of Cardiology guidelines for hypertrophic cardiomyopathy (HCM) define the estimation of sudden cardiac death (SCD) risk as an integral part of clinical management. An implantable cardioverter defibrillator (ICD) is recommended (class IIa) when the risk is ≥ 6%. Objectives: To compare the SCD risk stratification according to the 2011 and 2014 recommendations for ICD implantation in patients with HCM. Methods: Retrospective study including 105 patients diagnosed with HCM. The indication for ICD was assessed using the 2011 and 2014 guidelines. Statistical analysis was performed using SPSS software version 19.0.0.2®. The tests performed were bilateral, considering the significance level of 5% (p < 0.05). Results: Regarding primary prevention, according to the 2011 ACCF/AHA recommendations, 39.0% of the patients had indication for ICD implantation (level of evidence IIa). Using the 2014 guidelines, only 12.4% of the patients had an indication for ICD implantation. Comparing the two risk stratification models for patients with HCM, we detected a significant reduction in the number of indications for ICD implantation (p < 0.001). Of the 41 patients classified as IIa according to the 2011 recommendations, 68.3% received a different classification according to the 2014 guidelines. Conclusion: Significant differences were found when comparing the SCD risk stratification for ICD implantation in the two guidelines. The current SCD risk score seems to identify many low-risk patients who are not candidates for ICD implantation. The use of this new score results in a significant reduction in the number of ICD implanted.

Resumo Fundamento: As recomendações de miocardiopatia hipertrófica (MCH) da Sociedade Europeia de Cardiologia aconselham a estimativa do risco de morte súbita cardíaca (MSC) como parte da avaliação clínica e decisão de implantação de cardioversor desfibrilador implantável (CDI). Objetivo: Comparar a estratificação de risco de MSC de acordo com as recomendações de 2011 e 2014. Métodos: Estudo retrospectivo de 105 pacientes com diagnóstico de MCH. Avaliou-se a recomendação para implantação de CDI conforme as recomendações de 2011 e 2014. A análise estatística foi realizada usando o software SPSS versão 19.0.0.2®. Os testes realizados foram bilaterais, sendo considerado o nível de significância de 5% (p< 0,05). Resultados: Conforme as recomendações ACCF/AHA 2011, 39,0% dos pacientes tinham indicação para implantação de CDI (nível de evidência classe IIa). Conforme as recomendações de 2014, apenas 12,4% dos pacientes apresentam indicação classe IIa para implantação de CDI. Comparando os dois modelos de estratificação de risco de MSC em MCH, verificou-se uma redução significativa na proporção de pacientes com indicação para implantação de CDI (p < 0,001). Do total de 41 pacientes classificados como IIa segundo as recomendações de 2011, 68,3% deles recebeu uma classificação diferente em 2014. Conclusão: No estudo foram encontradas diferenças significativas quando comparados os métodos de estratificação de risco de MSC para implantação de CDI. O escore de risco atual parece identificar muitos pacientes de baixo risco, que não são candidatos à implantação de CDI. A utilização desse novo escore resulta numa redução significativa do número de CDI implantados.