A novel rare variant in SCN1Bb linked to Brugada syndrome and SIDS by combined modulation of Na(v)1.5 and K(v)4.3 channel currents.

BACKGROUND Cardiac sodium channel β-subunit mutations have been associated with several inherited cardiac arrhythmia syndromes. OBJECTIVE To identify and characterize variations in SCN1Bb associated with Brugada syndrome (BrS) and sudden infant death syndrome (SIDS). METHODS All known exons and intron borders of the BrS-susceptibility genes were amplified and sequenced in both directions. Wild type (WT) and mutant genes were expressed in TSA201 cells and studied using co-immunoprecipitation and whole-cell patch-clamp techniques. RESULTS Patient 1 was a 44-year-old man with an ajmaline-induced type 1 ST-segment elevation in V1 and V2 supporting the diagnosis of BrS. Patient 2 was a 62-year-old woman displaying a coved-type BrS electrocardiogram who developed cardiac arrest during fever. Patient 3 was a 4-month-old female SIDS case. A R214Q variant was detected in exon 3A of SCN1Bb (Na(v)1B) in all three probands, but not in any other gene previously associated with BrS or SIDS. R214Q was identified in 4 of 807 ethnically-matched healthy controls (0.50%). Co-expression of SCN5A/WT + SCN1Bb/R214Q resulted in peak sodium channel current (I(Na)) 56.5% smaller compared to SCN5A/WT + SCN1Bb/WT (n = 11-12, P<0.05). Co-expression of KCND3/WT + SCN1Bb/R214Q induced a Kv4.3 current (transient outward potassium current, I(to)) 70.6% greater compared with KCND3/WT + SCN1Bb/WT (n = 10-11, P<0.01). Co-immunoprecipitation indicated structural association between Na(v)β1B and Na(v)1.5 and K(v)4.3. CONCLUSION Our results suggest that R214Q variation in SCN1Bb is a functional polymorphism that may serve as a modifier of the substrate responsible for BrS or SIDS phenotypes via a combined loss of function of sodium channel current and gain of function of transient outward potassium current.

Electrocardiographic changes during stress test in a patient with "Brugada syndrome".

We report a 28 year old man with the Brugada syndrome characterised by an electrocardiographic pattern of a right bundle branch block and an ST segment elevation in the right precordial leads as well as syncope. During an exercise test, we observed a normalization of the ST segment in V2+ while in the postexercise phase, the ST segment elevation in the right leads was established. This is the first case reported of the Brugada syndrome in Mexico, with spontaneous changes on the EKG masked during exercise and apparent during postexercise phase.

Left atrial remodeling, early repolarization pattern, and inflammatory cytokines in professional soccer players

OBJECTIVES: Although regular physical exercise clearly reduces cardiovascular morbidity risk, long-term endurance sports practice has been recognized as a risk factor for atrial fibrillation (AF). However, the mechanisms how endurance sports can lead to AF are not yet clear. The aim of our present study was to investigate the influence of long-term endurance training on vagal tone, atrial size, and inflammatory profile in professional elite soccer players. METHODS: A total of 25 professional major league soccer players (mean age 24+/-4 years) and 20 sedentary controls (mean age 26+/-3 years) were included in the study and consecutively examined. All subjects underwent a sports cardiology check-up with physical examination, electrocardiography, echocardiography, exercise testing on a bicycle ergometer, and laboratory analysis [standard laboratory and cytokine profile: interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, IL-8, IL-10]. RESULTS: Athletes were divided into two groups according to presence or absence of an early repolarization (ER) pattern, defined as a ST-segment elevation at the J-point (STE) >/=0.1mm in 2 leads. Athletes with an ER pattern showed significantly lower heart rate and an increased E/e' ratio compared to athletes without an ER pattern. STE significantly correlated with E/e' ratio as well as with left atrial (LA) volume. The pro-inflammatory cytokines IL-6, IL-8, TNF-alpha as well as the anti-inflammatory cytokine IL-10 were significantly elevated in all soccer players. However, athletes with an ER pattern had significantly higher IL-6 plasma levels than athletes without ER pattern. Furthermore, athletes with "high" level IL-6 had significantly larger LA volumes than players with "low" level IL-6. CONCLUSIONS: Athletes with an ER pattern had significantly higher E/e' ratios, reflecting higher atrial filling pressures, higher LA volume, and higher IL-6 plasma levels. All these factors may contribute to atrial remodeling over time and thus increase the risk of AF in long-term endurance sports.

Efficacy and safety of a novel bioabsorbable polymer-coated, everolimus-eluting coronary stent: the EVOLVE II Randomized Trial.

BACKGROUND Drug eluting stents with durable polymers may be associated with hypersensitivity, delayed healing, and incomplete endothelialization, which may contribute to late/very late stent thrombosis and the need for prolonged dual antiplatelet therapy. Bioabsorbable polymers may facilitate stent healing, thus enhancing clinical safety. The SYNERGY stent is a thin-strut, platinum chromium metal alloy platform with an ultrathin bioabsorbable Poly(D,L-lactide-co-glycolide) abluminal everolimus-eluting polymer. We performed a multicenter, randomized controlled trial for regulatory approval to determine noninferiority of the SYNERGY stent to the durable polymer PROMUS Element Plus everolimus-eluting stent. METHODS AND RESULTS Patients (n=1684) scheduled to undergo percutaneous coronary intervention for non-ST-segment-elevation acute coronary syndrome or stable coronary artery disease were randomized to receive either the SYNERGY stent or the PROMUS Element Plus stent. The primary end point of 12-month target lesion failure was observed in 6.7% of SYNERGY and 6.5% PROMUS Element Plus treated subjects by intention-to-treat (P=0.83 for difference; P=0.0005 for noninferiority), and 6.4% in both the groups by per-protocol analysis (P=0.0003 for noninferiority). Clinically indicated revascularization of the target lesion or definite/probable stent thrombosis were observed in 2.6% versus 1.7% (P=0.21) and 0.4% versus 0.6% (P=0.50) of SYNERGY versus PROMUS Element Plus-treated subjects, respectively. CONCLUSIONS In this randomized trial, the SYNERGY bioabsorbable polymer everolimus-eluting stent was noninferior to the PROMUS Element Plus everolimus-eluting stent with respect to 1-year target lesion failure. These data support the relative safety and efficacy of SYNERGY in a broad range of patients undergoing percutaneous coronary intervention. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01665053.

Complex genetic background in a large family with Brugada syndrome.

The Brugada syndrome (BrS) is an inherited arrhythmia characterized by ST-segment elevation in V1-V3 leads and negative T wave on standard ECG. BrS patients are at risk of sudden cardiac death (SCD) due to ventricular tachyarrhythmia. At least 17 genes have been proposed to be linked to BrS, although recent findings suggested a polygenic background. Mutations in SCN5A, the gene coding for the cardiac sodium channel Nav1.5, have been found in 15-30% of index cases. Here, we present the results of clinical, genetic, and expression studies of a large Iranian family with BrS carrying a novel genetic variant (p.P1506S) in SCN5A. By performing whole-cell patch-clamp experiments using HEK293 cells expressing wild-type (WT) or p.P1506S Nav1.5 channels, hyperpolarizing shift of the availability curve, depolarizing shift of the activation curve, and hastening of the fast inactivation process were observed. These mutant-induced alterations lead to a loss of function of Nav1.5 and thus suggest that the p.P1506S variant is pathogenic. In addition, cascade familial screening found a family member with BrS who did not carry the p.P1506S mutation. Additional next generation sequencing analyses revealed the p.R25W mutation in KCNH2 gene in SCN5A-negative BrS patients. These findings illustrate the complex genetic background of BrS found in this family and the possible pathogenic role of a new SCN5A genetic variant.

Multicenter double blind trial of autologous bone marrow mononuclear cell transplantation through intracoronary injection post acute myocardium infarction - MiHeart/AMI study

Background: Myocardial infarction remains as a major cause of mortality worldwide and a high rate of survivors develop heart failure as a sequel, resulting in a high morbidity and elevated expenditures for health system resources. We have designed a multicenter trial to test for the efficacy of autologous bone marrow (ABM) mononuclear cell (MC) transplantation in this subgroup of patients. The main hypothesis to be tested is that treated patients will have a significantly higher ejection fraction (EF) improvement after 6 months than controls. Methods: A sample of 300 patients admitted with ST elevation acute myocardial infarction (STEMI) and left ventricle (LV) systolic dysfunction, and submitted to successful mechanical or chemical recanalization of the infarct-related coronary artery will be selected for inclusion and randomized to either treated or control group in a double blind manner. The former group will receive 100 x 106 MC suspended in saline with 5% autologous serum in the culprit vessel, while the latter will receive placebo (saline with 5% autologous serum). Implications: Many phase I/II clinical trials using cell therapy for STEMI have been reported, demonstrating that cell transplantation is safe and may lead to better preserved LV function. Patients with high risk to develop systolic dysfunction have the potential to benefit more. Larger randomized, double blind and controlled trials to test for the efficacy of cell therapies in patients with high risk for developing heart failure are required.

Safety and efficacy of angioplasty with intracoronary stenting in patients with unstable coronary syndromes. Comparison with stable coronary syndromes

OBJECTIVE: To assess safety and efficacy of coronary angioplasty with stent implantation in unstable coronary syndromes. METHODS: Retrospective analysis of in-hospital and late evolution of 74 patients with unstable coronary syndromes (unstable angina or infarction without elevation of the ST segment) undergoing coronary angioplasty with stent placement. These 74 patients were compared with 31 patients with stable coronary syndromes (stable angina or stable silent ischemia) undergoing the same procedure. RESULTS: No death and no need for revascularization of the culprit artery occurred in the in-hospital phase. The incidences of acute non-Q-wave myocardial infarction were 1.4% and 3.2% (p=0.6) in the unstable and stable coronary syndrome groups, respectively. In the late follow-up (11.2±7.5 months), the incidences of these events combined were 5.7% in the unstable coronary syndrome group and 6.9% (p=0.8) in the stable coronary syndrome group. In the multivariate analysis, the only variable with a tendency to significance as an event predictor was diabetes mellitus (p=0.07; OR=5.2; 95% CI=0.9-29.9). CONCLUSION: The in-hospital and late evolutions of patients with unstable coronary syndrome undergoing angioplasty with intracoronary stent implantation are similar to those of the stable coronary syndrome group, suggesting that this procedure is safe and efficacious when performed in unstable coronary syndrome patients.

Association of early repolarization with risk of cardiac mortality in the general population

Early repolarization, which is characterized by an elevation of the J-point on 12-lead electrocardiography, is a common finding that has been considered as benign for decades. However, in the last years, it has been related with vulnerability to idiopathic ventricular fibrillation and with cardiac mortality in the general population. Recently, 4 potential ECG predictors that could differentiate the benign from the malignant form of early repolarization have been suggested. Any previous study about early repolarization has been done in Spain. Aim. To ascertain whether the presence of early repolarization pattern in a resting electrocardiogram is associated with a major risk of cardiac death in a Spanish general population and to determine whether the presence of potential predictors of malignancy in a resting electrocardiogram increases the risk of cardiac mortality in patients with early repolarization pattern. Methods. We will analyse the presence of early repolarization and the occurrence of cardiac mortality in a retrospective cohort study of 4,279 participants aged 25 to 74 years in the province of Girona. This cohort has been followed during a mean of 9.8 years. Early repolarization will be stratified according to the degree of J-point elevation (≥0.1 mV or ≥0.2 mV), the morphology of the J-wave (slurring, notching or any of these two), the ST-segment pattern (ascending or descending) and the localization (inferior leads, lateral leads, or both). Association of early repolarization with cardiac death will be assessed by adjusted Cox-proportional hazards models

Troponina I y factores de riesgo como predictores enfermedad ateroesclerótica coronaria en pacientes con IAM sin elevación del ST en Bogotá 2010-2013

RESUMEN Introducción: La enfermedad cardiovascular es una de las principales causas de morbilidad y mortalidad tanto en hombres como en mujeres a nivel mundial (1). En Colombia para el 2010, se presentaron 26.334 muertes por infarto agudo de miocardio, siendo la primera causa de defunción a nivel nacional (2). Objetivo: Determinar factores de riesgo asociados a troponina I de alta sensibilidad como predictores de enfermedad coronaria ateroesclerótica en pacientes con infarto agudo de miocardio sin elevación del ST, con alteración vascular coronaria ateroesclerótica demostrada por coronoangiografía en una población de pacientes ingresados a la unidad coronaria de una clínica privada de III nivel de la ciudad de Bogotá durante los años 2010 al 2013. Metodología: Se propuso un estudio retrospectivo observacional analítico, tipo casos y controles, en una población con diagnóstico de infarto agudo de miocardio sin elevación ST que consultó a un servicio de urgencias de una clínica privada de Bogotá, en la cual se quiso evaluar la predictividad de la troponina I ultrasensible para el diagnóstico de enfermedad coronaria ateroesclerótica comprobada por coronoangiografía, y los factores de riesgo asociados que pudieran aumentar dicha predictividad. Resultados: De los 918 pacientes diagnosticados con infarto agudo de miocardio sin elevación del ST, estratificados según presencia de enfermedad coronaria ateroesclerótica comprobada por coronoangiografía, se encontró que la troponina I presentó una sensibilidad de 89% y una especificidad de 18% para el diagnóstico de enfermedad coronaria sin elevación del ST al ingreso a urgencias en un paciente diagnosticado clínicamente con IAM sin elevación del ST. En cuanto al valor predictivo positivo este fue de 77% y el valor predictivo negativo fue de 35%. En el modelo propuesto, si un paciente presentara edad avanzada (65 años), troponina I ultrasensible positiva, diabetes mellitus, dislipidemia, tabaquismo, enfermedad coronaria previa, enfermedad artero-oclusiva, historia de stent previo, revascularización previa, este paciente presentaría un riesgo de tener enfermedad ateroesclerótica coronaria de 99.83%; mientras que si un paciente presentara edad avanzada (65 años), troponina I ultrasensible positiva, diabetes mellitus, dislipidemia, tabaquismo, enfermedad artero-oclusiva, este paciente presentaría un riesgo de tener enfermedad ateroesclerótica coronaria de 96.81%. Adicionalmente, el modelo propuesto presenta una probabilidad pronostica de 0,828, evaluado por curva ROC. Conclusión: La predictividad de la troponina I para enfermedad coronaria ateroesclerótica fue aceptable. Sin embargo esta aumenta cuando se suma a factores de riesgo como ser hombre, edad avanzada, diabetes, tabaquismo, enfermedad coronaria previa, enfermedad arterial oclusiva previa, STENT previo, PCI previo y revascularización previa.

Effects of anti-ischaemic drug therapy in silent myocardial ischaemia type I: the Swiss Interventional Study on Silent Ischaemia type I (SWISSI I): a randomized, controlled pilot study

AIMS: To determine the effect of anti-ischaemic drug therapy on long-term outcomes of asymptomatic patients without coronary artery disease (CAD) history but silent exercise ST-depression. METHODS AND RESULTS: In a randomized multicentre trial, 263 of 522 asymptomatic subjects without CAD but at least one CAD risk factor in whom silent ischaemia by exercise ECG was confirmed by stress imaging were asked to participate. The 54 (21%) consenting patients were randomized to anti-anginal drug therapy in addition to risk factor control (MED, n = 26) or risk factor control-only (RFC, n = 28). They were followed yearly for 11.2 +/- 2.2 years. During 483 patient-years, cardiac death, non-fatal myocardial infarction, or acute coronary syndrome requiring hospitalization or revascularization occurred in 3 (12%) of MED vs. 17 (61%) of RFC patients (P < 0.001). In addition, MED patients had consistently lower rates of exercise-induced ischaemia during follow-up, and left ventricular ejection fraction remained unchanged (-0.7%, P = 0.597) in contrast to RFC patients in whom it decreased over time (-6.0%, P = 0.006). CONCLUSION: Anti-ischaemic drug therapy and aspirin seem to reduce cardiac events in subjects with asymptomatic ischaemia type I. In such patients, exercise-induced ST-segment depression should be verified by stress imaging; if silent ischaemia is documented, anti-ischaemic drug therapy and aspirin should be considered.

Effects of coronary sinus occlusion on myocardial ischaemia in humans: role of coronary collateral function

OBJECTIVE This study tested the hypotheses that intermittent coronary sinus occlusion (iCSO) reduces myocardial ischaemia, and that the amount of ischaemia reduction is related to coronary collateral function. DESIGN Prospective case-control study with intraindividual comparison of myocardial ischaemia during two 2-min coronary artery balloon occlusions with and without simultaneous iCSO by a balloon-tipped catheter. SETTING University Hospital. PATIENTS 35 patients with chronic stable coronary artery disease. INTERVENTION 2-min iCSO. MAIN OUTCOME MEASURES Myocardial ischaemia as assessed by intracoronary (i.c.) ECG ST shift at 2 min of coronary artery balloon occlusion. Collateral flow index (CFI) without iCSO, that is, the ratio between mean distal coronary occlusive (Poccl) and mean aortic pressure (Pao) both minus central venous pressure. RESULTS I.c. ECG ST segment shift (elevation in all) at the end of the procedure with iCSO versus without iCSO was 1.33±1.25 mV versus 1.85±1.45 mV, p<0.0001. Regression analysis showed that the degree of i.c. ECG ST shift reduction during iCSO was related to CFI, best fitting a Lorentzian function (r(2)=0.61). Ischaemia reduction with iCSO was greatest at a CFI of 0.05-0.20, whereas in the low and high CFI range the effect of iCSO was absent. CONCLUSIONS ICSO reduces myocardial ischaemia in patients with chronic coronary artery disease. Ischaemia reduction by iCSO depends on coronary collateral function. A minimal degree of collateral function is necessary to render iCSO effective. ICSO cannot manifest an effect when collateral function prevents ischaemia in the first place.

Intrapericardial Ranolazine Prolongs Atrial Refractory Period and Markedly Reduces Atrial Fibrillation Inducibility in the Intact Porcine Heart

Introduction: Extensive experimental studies and clinical evidence (Metabolic Efficiency with Ranzolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction-36 [MERLIN TIMI-36] trial) indicate potential antiarrhythmic efficacy of the antianginal agent ranolazine. Delivery of agents into the pericardial space allows high local concentrations to be maintained in close proximity to myocardial tissue while systemic effects are minimized. Methods and Results: The effects of intrapericardial (IPC) administration of ranolazine (50-mg bolus) on right atrial and right ventricular effective refractory periods (ERP), atrial fibrillation threshold, and ventricular fibrillation threshold were determined in 17 closed-chest anesthetized pigs. IPC ranolazine increased atrial ERP in a time-dependent manner from 129 +/- 5.14 to 186 +/- 9.78 ms (P < 0.01, N = 7) but did not significantly affect ventricular ERP (from 188.3 +/- 4.6 to 201 +/- 4.3 ms (NS, N = 6). IPC ranolazine increased atrial fibrillation threshold from 4.8 +/- 0.8 to 28 +/- 2.3 mA (P < 0.03, N = 6) and ventricular fibrillation threshold (from 24 +/- 3.56 baseline to 29.33 +/- 2.04 mA at 10-20 minutes, P < 0.03, N = 6). No significant change in mean arterial pressure was observed (from 92.8 +/- 7.1 to 74.8 +/- 7.5 mm Hg, P < 0.125, N = 5, at 7 minutes). Conclusions: IPC ranolazine exhibits striking atrial antiarrhythmic actions as evidenced by increases in refractoriness and in fibrillation inducibility without significantly altering mean arterial blood pressure. Ranolazine`s effects on the atria appear to be more potent than those on the ventricles.

Using postoperative cardiac troponin-I (cTi) levels to detect myocardial ischaemia in patients undergoing vascular surgery

Background, Cardiac complications occur commonly in vascular surgery patients. Diagnosis of cardiac complications is difficult because of the inaccuracies associated with traditional cardiac enzyme measurements. CTi, a highly sensitive and specific marker of myocardial injury, may be able to detect cardiac complications with greater ease and accuracy. Methods. The study prospectively examined 100 consecutive patients who underwent major vascular surgery between 6/7/98 and 31/12/98 at the Royal Brisbane Hospital. Daily measurements of cTi, creatine kinase (CK), creatine kinase MB (CKMB), CKMB index, renal function and haemoglobin were taken for three postoperative days. One postoperative electrocardiograph (ECC) was taken. An extensive cardiac history was taken. Intraoperative and postoperative events were recorded. Findings. There were 100 patients, 18 patients (18%) had a cTi elevation. On the basis of classical diagnostic criteria, 15 patients (15%) suffered one or more cardiac complication (either myocardial infarction, congestive cardiac failure, unstable angina or atrial fibrillation), One patient (1%) who had a cTi elevation died. CTI elevation occurred in five patients (5%) who were not diagnosed with cardiac complications based on traditional criteria. Despite not meeting specific diagnostic criteria for cardiac complications, all patients showed signs and symptoms that could be attributed to myocardial ischaemia, Every patient who developed congestive cardiac failure or atrial fibrillation had a cTi elevation. A Chi-square analysis revealed a significant association between cTi elevation and postoperative cardiac complications. Four variables contributed small but significant amounts of unique variance to the prediction of peak cTi on linear regression analysis. These were peak CKMB index, postoperative congestive cardiac failure, postoperative chest pain and postoperative cardiac complications. Conclusions. Routine cTi monitoring of postoperative vascular patients would be an effective and inexpensive way to detect patients with cardiac complications. The relationship between postoperative cTi elevation and significant coronary artery disease remains to be shown, (C) 2001 The international Society for Cardiovascular Surgery. Published by Elsevier Science Ltd. All rights reserved.

Intervenção coronária percutânea no enfarte agudo do miocárdio: influência no prognóstico dos doentes

Mestrado em Tecnologia de Diagnóstico e Intervenção Cardiovascular. Área de especialização: Intervenção Cardiovascular.

Avaliação de realce tardio do miocárdio por tomografia computorizada

A distinção entre miocárdio atordoado e danificado tem sido uma preocupação relevante, no cenário de um enfarte agudo do miocárdio (EAM). A avaliação da viabilidade do miocárdio, pós-enfarte, é de importância vital, no contexto clínico, principalmente numa fase inicial. Actualmente a Ressonância Magnética Cardíaca é o exame de referência para a avaliação de viabilidade do miocárdio. No entanto, é um exame com elevado custo e de difícil acesso. Estudos preliminares demonstraram potencial na utilização de imagens por Tomografia Computorizada para avaliação da área de enfarte, quer em estudos animais quer em humanos. É objectivo desta tese verificar a utilidade de um protocolo de avaliação de viabilidade do miocárdio, com base em imagens de realce tardio (RT) por Tomografia Computorizada, após um procedimento de intervenção coronária percutânea, no contexto de enfarte agudo do miocárdio com elevação do segmento ST (STEMI). Pretende-se igualmente contribuir para a análise da imagem médica do miocárdio, proporcionando métodos de quantificação do RT e software de suporte à decisão médica nesta modalidade de imagem substancialmente recente. São avaliados vários processos para a quantificação do volume de RT, incluindo um método inovador baseado na detecção automática do miocárdio normal. _E ainda proposto um algoritmo para detecção automática do grau de transmuralidade, por segmento do miocárdio, e comparado o seu grau de eficiência face ao diagnóstico médico dos mesmos exames. Apesar do reduzido número de exames utilizado para validação das técnicas descritas nesta tese, os resultados são bastante promissores e podem constituir uma mais-valia no auxilio à gestão do paciente com EAM.