Association of variants in MYH7, MYBPC3 and TNNT2 with sudden cardiac death-related risk factors in Brazilian patients with hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy (LVH) and is one of the major causes of sudden cardiac death (SCD). An exon-targeted gene sequencing strategy was used to investigate the association of functional variants in sarcomeric genes (MYBPC3, MYH7 and TNNT2) with severe LVH and other SCD-related risk factors in Brazilian HCM patients. Clinical data of 55 HCM patients attending a Cardiology Hospital (Sao Paulo city, Brazil) were recorded. Severe LVH, aborted SCD, family history of SCD, syncope, non-sustained ventricular tachycardia and abnormal blood pressure in response to exercise were evaluated as SCD risk factors. Blood samples were obtained for genomic DNA extraction and the exons and untranslated regions of the MYH7, MYBPC3 and TNNT2 were sequenced using Nextera® and MiSEq® reagents. Variants were identified and annotated using in silico tools, and further classified as pathogenic or benign according to the American College of Medical Genetics and Genomics guidelines. Variants with functional effects were identified in MYBPC3 (n = 9), MYH7 (n = 6) and TNNT2 (n = 4). The benign variants MYBPC3 p.Val158Met and TNNT2 p.Lys263Arg were associated with severe LVH (p < 0.05), and the MYH7 p.Val320Met (pathogenic) was associated with family history of SCD (p = 0.037). Increased risk for severe LVH was found in carriers of MYBPC3 Met158 (c.472 A allele, OR = 13.5, 95% CI = 1.80-101.12, p = 0.011) or combined variants (MYBPC3, MYH7 and TNNT2: OR = 12.39, 95% CI = 2.14-60.39, p = 0.004). Carriers of TNNT2 p.Lys263Arg and combined variants had higher values of septum thickness than non-carriers (p < 0.05). Molecular modeling analysis showed that MYBPC3 158Met reduces the interaction of cardiac myosin-binding protein C (cMyBP-C) RASK domain (amino acids Arg215-Ala216-Ser217-Lys218) with tropomyosin. In conclusion, the variants MYBPC3 p.Val158Met, TNNT2 p.Lys263Arg and MYH7 p.Val320Met individually or combined contribute to the risk of sudden cardiac death and other outcomes of hypertrophic cardiomyopathy.

Association of variants in MYH7, MYBPC3 and TNNT2 with sudden cardiac death-related risk factors in Brazilian patients with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy (LVH) and is one of the major causes of sudden cardiac death (SCD). An exon-targeted gene sequencing strategy was used to investigate the association of functional variants in sarcomeric genes (MYBPC3, MYH7 and TNNT2) with severe LVH and other SCD-related risk factors in Brazilian HCM patients. Clinical data of 55 HCM patients attending a Cardiology Hospital (Sao Paulo city, Brazil) were recorded. Severe LVH, aborted SCD, family history of SCD, syncope, non-sustained ventricular tachycardia and abnormal blood pressure in response to exercise were evaluated as SCD risk factors. Blood samples were obtained for genomic DNA extraction and the exons and untranslated regions of the MYH7, MYBPC3 and TNNT2 were sequenced using Nextera® and MiSEq® reagents. Variants were identified and annotated using in silico tools, and further classified as pathogenic or benign according to the American College of Medical Genetics and Genomics guidelines. Variants with functional effects were identified in MYBPC3 (n = 9), MYH7 (n = 6) and TNNT2 (n = 4). The benign variants MYBPC3 p.Val158Met and TNNT2 p.Lys263Arg were associated with severe LVH (p < 0.05), and the MYH7 p.Val320Met (pathogenic) was associated with family history of SCD (p = 0.037). Increased risk for severe LVH was found in carriers of MYBPC3 Met158 (c.472 A allele, OR = 13.5, 95% CI = 1.80-101.12, p = 0.011) or combined variants (MYBPC3, MYH7 and TNNT2: OR = 12.39, 95% CI = 2.14-60.39, p = 0.004). Carriers of TNNT2 p.Lys263Arg and combined variants had higher values of septum thickness than non-carriers (p < 0.05). Molecular modeling analysis showed that MYBPC3 158Met reduces the interaction of cardiac myosin-binding protein C (cMyBP-C) RASK domain (amino acids Arg215-Ala216-Ser217-Lys218) with tropomyosin. In conclusion, the variants MYBPC3 p.Val158Met, TNNT2 p.Lys263Arg and MYH7 p.Val320Met individually or combined contribute to the risk of sudden cardiac death and other outcomes of hypertrophic cardiomyopathy.

Persistência de via cava superior esquerda e implante de marca-passo bicameral / Persistence of left superior vena cava and bicameral pacemaker implantation

INTRODUÇÃO: A persistência da veia cava superior esquerda é uma anomalia congénita numa porcentagem de 0,1-0,3% dos indivíduos com o coração normal e no aproximado 3% nos pacientes com cardiopatia congénita. RELATO DE CASO: D.R.S., 53 anos, sexo masculino, com diagnóstico de Miocardiopatía Chagásica, Bloqueio sinoatrial e pausas (a máxima de 3 segundos) sintomáticas. Realizou-se estudo de holter que demonstrou frequência mínima 28, media 53 e máxima 122bpm, com pausas de 2,5 segundos e 7 pausas de >3 segundos sendo um delas na vigília. O Ecocardiograma transtorácico mostrou hipocinesia de parede inferior e demais paredes com hipocontratibilidade miocárdica difusa, com fração de ejeção de 52%, com refluxos valvulares discretos, presencia de persistência de veia cava superior esquerda com drenagem habitual para seio coronário que encontra-se dilatado. Após avaliação do caso foi indicado implante de marca-passos bicameral, durante o procedimento foi injetado contraste e observado a persistência de dita anatomia. Foram colocados os eletrodos no ventrículo direito e outro através da valva tricúspide é implantado na parede lateral do átrio direito. Após um mês é realizada telemetria e observou-se marca-passo normofuncionante e sem relato de sintomas. DISCUSSÃO E CONCLUSÃO: No advenimento dos métodos de imagem cardíaca disponíveis na atualidade como a venografiade contraste , ecocardiograma transesofagico, ressonância magnética , tomografia multicorte são os metodos diagnostico e terapêutica resultam em sucesso na pratica clínica. Em este caso não houve alteração clinica ou hemodinâmica após o implante de marca-passo.

Evaluation of super-responders to cardiac resynchronization therapy in the presence of left bundle branch block and absence of scar in the posterolateral wall of the left ventricle.

Patients with heart failure (HF) undergoing cardiac resynchronization therapy (CRT) who exhibit above-expected improvement are known as super-responders. We assessed the rate of super-responders in a population with left bundle branch block (LBBB) > 150 ms in the absence of scar tissue in the left ventricular posterolateral wall as well as prognostic variables. In this prospective observational cohort study (n=20) an electrocardiogram (ECG) was performed pre- and post-CRT. The classic and Strauss LBBB criteria were adopted (> 150 ms). The percent (%) reduction of the QRS was calculated after implantation. All patients responded to the Minnesota Living with Heart Failure questionnaire and underwent an echocardiogram to measure left ventricular ejection function (LVEF), left atrium (LA) diameter, left ventricular end-systolic volume (LVEDV), left ventricular end-diastolic volume (LVESV), and left ventricular end-diastolic diameter (LVEDD) pre- and 6 months post-CRT. Cardiac magnetic resonance imaging (MRI) measured the presence of scar tissue in the posterolateral LV wall and the total scar burden (% LV mass). Fisher's exact test and the Mann-Whitney test were performed to evaluate possible prognostic variables. The mean age was 58.20±8.79 years old, 60% female, with a mean LVEF of 28.15±5.10%, ECG with LBBB mean QRS of 162.15±7.86 ms, LBBB > 150 ms with Strauss standard in 90% of cases, and 90% with non-ischemic cardiomyopathy. Twelve cases (60%) of super-responders (reduction > 30% LVESV after 6 months) were observed. Super-responders did not present a difference in response in sex (12 vs 8 P=0.67), age (58.67 vs 57.7 P=087), Minnesota quality of life (55.50 vs 67.70 P=0.2), % initial QRS reduction (21.16 vs 18.69 P=0.21), LVEF (29.25 vs 26.5 P=0.38), LVEDD (66.33 vs 67.67 P=0.83), LVEDV (211.16 vs 228.53 P=0.75), LVESV (145.83 vs 167.00 P=0.75), or LA diameter (41.58 vs 43.63 P=0.45). The presence of LBBB > 150 ms, using the Strauss standard (90%) and the absence of scar in the posterolateral wall may account for these positive results. Super-responders benefit the most from CRT, and the results of this study can contribute to a better selection of CRT candidates.

Relation of fractionated atrial potentials with the vagal innervation evaluated by extracardiac vagal stimulation during cardioneuroablation

BACKGROUND: Vagal hyperactivity is directly related to several clinical conditions as reflex/functional bradyarrhythmias and vagal atrial fibrillation (AF). Cardioneuroablation provides therapeutic vagal denervation through endocardial radiofrequency ablation for these cases. The main challenges are neuromyocardium interface identification and the denervation control and validation. The finding that the AF-Nest (AFN) ablation eliminates the atropine response and decreases RR variability suggests that they are related to the vagal innervation. METHOD: Prospective, controlled, longitudinal, nonrandomized study enrolling 62 patients in 2 groups: AFN group (AFN group 32 patients) with functional or reflex bradyarrhythmias or vagal AF treated with AFN ablation and a control group (30 patients) with anomalous bundles, ventricular premature beats, atrial flutter, atrioventricular nodal reentry, and atrial tachycardia, treated with conventional ablation (non-AFN ablation). In AFN group, ablation delivered at AFN detected by fragmentation/fractionation of the endocardial electrograms and by 3-dimensional anatomic location of the ganglionated plexus. Vagal response was evaluated before, during, and postablation by 5 s noncontact vagal stimulation at the jugular foramen, through the internal jugular veins (extracardiac vagal stimulation [ECVS]), analyzing 15 s mean heart rate, longest RR, pauses, and atrioventricular block. All patients had current guidelines arrhythmia ablation indication. RESULTS: Preablation ECVS induced sinus pauses, asystole, and transient atrioventricular block in both groups showing a strong vagal response (P=0.96). Postablation ECVS in the AFN group showed complete abolishment of the cardiac vagal response in all cases (pre/postablation ECVS=P<0.0001), demonstrating robust vagal denervation. However, in the control group, vagal response remained practically unchanged postablation (P=0.35), showing that non-AFN ablation promotes no significant denervation. CONCLUSIONS: AFN ablation causes significant vagal denervation. Non-AFN ablation causes no significant vagal denervation. These results suggest that AFNs are intrinsically related to vagal innervation. ECVS was fundamental to stepwise vagal denervation validation during cardioneuroablation. Visual Overview A visual overview is available for this article.

Evaluation of super-responders to cardiac resynchronization therapy in the presence of left bundle branch block and absence of scar in the posterolateral wall of the left ventricle

Abstract: Patients with heart failure (HF) undergoing cardiac resynchronization therapy (CRT) who exhibit above-expected improvement are known as super-responders. We assessed the rate of super-responders in a population with left bundle branch block (LBBB) > 150 ms in the absence of scar tissue in the left ventricular posterolateral wall as well as prognostic variables. In this prospective observational cohort study (n=20) an electrocardiogram (ECG) was performed pre- and post-CRT. The classic and Strauss LBBB criteria were adopted (> 150 ms). The percent (%) reduction of the QRS was calculated after implantation. All patients responded to the Minnesota Living with Heart Failure questionnaire and underwent an echocardiogram to measure left ventricular ejection function (LVEF), left atrium (LA) diameter, left ventricular end-systolic volume (LVEDV), left ventricular end-diastolic volume (LVESV), and left ventricular end-diastolic diameter (LVEDD) pre- and 6 months post-CRT. Cardiac magnetic resonance imaging (MRI) measured the presence of scar tissue in the posterolateral LV wall and the total scar burden (% LV mass). Fisher's exact test and the Mann-Whitney test were performed to evaluate possible prognostic variables. The mean age was 58.20±8.79 years old, 60% female, with a mean LVEF of 28.15±5.10%, ECG with LBBB mean QRS of 162.15±7.86 ms, LBBB > 150 ms with Strauss standard in 90% of cases, and 90% with non-ischemic cardiomyopathy. Twelve cases (60%) of super-responders (reduction > 30% LVESV after 6 months) were observed. Super-responders did not present a difference in response in sex (12 vs 8 P=0.67), age (58.67 vs 57.7 P=087), Minnesota quality of life (55.50 vs 67.70 P=0.2), % initial QRS reduction (21.16 vs 18.69 P=0.21), LVEF (29.25 vs 26.5 P=0.38), LVEDD (66.33 vs 67.67 P=0.83), LVEDV (211.16 vs 228.53 P=0.75), LVESV (145.83 vs 167.00 P=0.75), or LA diameter (41.58 vs 43.63 P=0.45). The presence of LBBB > 150 ms, using the Strauss standard (90%) and the absence of scar in the posterolateral wall may account for these positive results. Super-responders benefit the most from CRT, and the results of this study can contribute to a better selection of CRT candidates.

Relation of Fractionated Atrial Potentials With the Vagal Innervation Evaluated by Extracardiac Vagal Stimulation During Cardioneuroablation.

BACKGROUND: Vagal hyperactivity is directly related to several clinical conditions as reflex/functional bradyarrhythmias and vagal atrial fibrillation (AF). Cardioneuroablation provides therapeutic vagal denervation through endocardial radiofrequency ablation for these cases. The main challenges are neuromyocardium interface identification and the denervation control and validation. The finding that the AF-Nest (AFN) ablation eliminates the atropine response and decreases RR variability suggests that they are related to the vagal innervation. METHOD: Prospective, controlled, longitudinal, nonrandomized study enrolling 62 patients in 2 groups: AFN group (AFN group 32 patients) with functional or reflex bradyarrhythmias or vagal AF treated with AFN ablation and a control group (30 patients) with anomalous bundles, ventricular premature beats, atrial flutter, atrioventricular nodal reentry, and atrial tachycardia, treated with conventional ablation (non-AFN ablation). In AFN group, ablation delivered at AFN detected by fragmentation/fractionation of the endocardial electrograms and by 3-dimensional anatomic location of the ganglionated plexus. Vagal response was evaluated before, during, and postablation by 5 s noncontact vagal stimulation at the jugular foramen, through the internal jugular veins (extracardiac vagal stimulation [ECVS]), analyzing 15 s mean heart rate, longest RR, pauses, and atrioventricular block. All patients had current guidelines arrhythmia ablation indication. RESULTS: Preablation ECVS induced sinus pauses, asystole, and transient atrioventricular block in both groups showing a strong vagal response (P=0.96). Postablation ECVS in the AFN group showed complete abolishment of the cardiac vagal response in all cases (pre/postablation ECVS=P<0.0001), demonstrating robust vagal denervation. However, in the control group, vagal response remained practically unchanged postablation (P=0.35), showing that non-AFN ablation promotes no significant denervation. CONCLUSIONS: AFN ablation causes significant vagal denervation. Non-AFN ablation causes no significant vagal denervation. These results suggest that AFNs are intrinsically related to vagal innervation. ECVS was fundamental to stepwise vagal denervation validation during cardioneuroablation. Visual Overview A visual overview is available for this article.

Implante de ressincronizador com eletrodo de ventrículo esquerdo em veia cardíaca média do seio coronário e eletrodo do ventrículo direito em posição não habitual / Resynchronizer implantation with left ventricular lead in the middle coronary sinus cardiac vein and right ventricular lead in unusual position

INTRODUÇÃO: A terapia de ressincronização cardíaca através da estimulação biventricular é um tratamento coadjuvante à terapia medicamentosa otimizada, em pacientes com insuficiência cardíaca congestiva (ICC) refratária, causada por disfunção ventricular esquerda crônica e distúrbios de condução intraventricular, promovendo melhora da função cardíaca e da qualidade de vida. RELATO DE CASO: M.S.,49 anos, sexo masculino, com diagnóstico de Hipertensão Arterial Sistêmica e Miocardiopatia Dilatada (fração de ejeção do ventrículo esquerdo ­ FEVE -de 20%), apresentando dispnéia aos moderados esforços. Realizada cintilografia com estresse farmacológico demonstrando hipocaptação persistente moderada e discreta transitoriedade na parede anterosseptal do ventrículo esquerdo além de déficit acentuado da função ventricular e ventrículo esquerdo(VE) com volumes aumentados; eletrocardiograma (ECG)apresentando bloqueio de ramo esquerdo (BRE) com QRS 160ms.Realizado estudo eletrofisiológico com intervalos P-A 60 ms, A-H 105 ms, potencial H 15ms, H-V 55ms, ponto de Wenckebach anterógrado 380 ms, duração do complexo QRS 200 ms - estimulação ventricular programada com três extra-estímulos decrescentes no ápice e na via de saída do VD não provocou arritmias ventriculares sustentadas. Em 22/01/2018 foi optado por implante de ressincronizador cardíaco, sendo colocado o eletrodo do VE através do seio coronário em veia cardíaca média e o eletrodo do ventrículo direito (VD), na via de saída do VD. Logo após foi realizado ECG cujo QRS reduziu em aproximadamente 100 ms. Após 4 meses foi realizado novo ecocardiograma transtorácico que evidenciou FEVE de 28% e presença de dissincronia mais acentuada em septo, parede lateral e médio-basal da parede inferior. Novo ECG apresentando ritmo de marca-passo com QRS de aproximadamente 100 ms e eixo desviado para direita +120 graus. O paciente evolui com melhora dos sintomas (NYHA I).Após um ano de seguimento, paciente assintomático, sendo realizado novo ECG com ritmo de marca-passo e morfologia de BRE, com QRS de 80 ms e eixo -45 graus. O paciente portador de marca-passo ressincronizador em topografia diferente do habitual apresentando excelente resposta clínica e eletrocardiográfica. DISCUSSÃO E CONCLUSÃO: A terapia de ressincronização cardíaca vem se tornando um tratamento de rotina em pacientes previamente selecionados, no caso apresentado o paciente portador de ressincronizador em topografia diferente do habitual apresentou uma boa resposta á terapêutica. (AU)

Video Caso Clínico: Estimulación Vagal Directa Como Maniobra Electrofisiológica Alternativa en el Diagnóstico de Taquicardia Durante Estudio Electrofisiológico / Case Report: Direct Vagal Stimulation as Alternative Electrophysiological Procedure in the Diagnosis of Tachycardias During Electrophysiological Study

INTRODUCCIÓN: El síndrome de Wolff Parkinson White se caracteriza por la conexión anómala entre la aurícula y el ventrículo durante el paso del estímulo sinusal, generalmente causada por una vía accesoria que conecta el músculo auricular con el músculo ventricular llamado haz de Kent, caracterizándose por la presencia de síntomas como: palpitaciones, sincope o muerte súbita y sumado a la presencia de onda delta, intervalo PR corto, QRS ancho y alteraciones de la repolarización ventricular en el electrocardiograma. El estudio electrofisiológico tiene como objetivo confirmar la presencia, localización y características de este haz anómalo y posteriormente, con seguridad, proceder a la ablación por radiofrecuencia eliminando esta vía accesoria, siendo considerado un procedimiento curativo en el caso del síndrome de Wolff Parkinson White. Durante el estudio se realiza estimulaciones eléctricas en los sitios específicos, tanto de la aurícula como del ventrículo, además se utiliza medicación intravenosa como la adenosina que actúa bloqueando al nódulo aurículoventricular y así observar el paso residual de la estimulación sinusal normal y/o el paso retrogrado del estímulo ventricular hacia la aurícula a través del haz de Kent, permitiendo de esta forma analizar las características de las conexiones aurículoventriculares previo a la ablación. La posibilidad de realizar una estimulación vagal selectiva de alta frecuencia y baja amplitud a nivel infraorbitario, descrita por Pachón et al [1], a través de la vena yugular interna y el consecuente bloqueo aurículoventricular transitorio que esta ocasiona, permite realizar el estudio sin necesidad de utilizar otras maniobras electrofisiológicas o medicación endovenosa

BACKGROUND: Wolff Parkinson White Syndrome is characterized by the bypass of the electrical signal through an abnormal pathway, different from the atrioventricular node that connects the atrial and ventricular muscles (Bundle of Kent). It presents with palpitations, syncope or can even cause sudden death. Electrocardiogram findings consist on Delta waves, shortened PR interval, widened QRS complex and altering of the ventricular repolarization. In the presence of Ventricular pre-excitation (Wolff Parkinson White Syndrome), the electrophysiological testing is key to confirm the presence, site and features of this accessory pathway. Later, with the certainty of the diagnosis proceed to perform the Radiofrequency Ablation, the definitive treatment to eliminate this abnormal pathway. This test is usually done with the use of electrophysiological maneuvers, stimulating key sites in the atria and the ventricle, with the help of intravenous drugs like Adenosine. The objective is to block the AV node to look how the remnants of the normal electrical signal move through the abnormal pathway, thus letting the physician analyze the characteristics previously mentioned of this pathway. After the ablation, these maneuvers are repeated to confirm the complete elimination of the accessory pathway that has direct relation with the prognostic. Based on the possibility of high frequency and low amplitude selective vagal stimulation described by Pachón et al [1], at infraorbital level through the internal jugular vein and the resulting transitory atrioventricular block. It is possible to study the abnormal pathway without the need of electrophysiological maneuvers or the use of IV drugs, either pre or post ablation.

Estimulação cardíaca artificial septal, apical e bifocal: estudo comparativo por meio da ecocardiografia transesofágica intraoperatória / Septal, apical and bifocal artificial cardiac pacing: a comparative study using intraoperative transesophageal echocardiography

INTRODUÇÃO: A estimulação cardíaca convencional, apical de VD, produz um QRS largo com morfologia de BRE, o qual ocasiona dissincronismo mecânico ventricular. Este dissincronismo pode agravar ou provocar um quadro de IC. Dentro deste contexto, temos procurado novos sítios e novas formas de estimulação, em busca de um QRS mais estreito e uma contração ventricular menos dissincrônica. O posicionamento de 1 eletrodo septal ou de 2 eletrodos dando origem à estimulação Bifocal do VD tem se mostrando mais benéfico quando comparado à estimulação convencional apical do VD, em evolução a médio e longo prazo. Contudo, essas 3 formas de estimulação: septal, apical e bifocal de VD ainda não haviam sido comparadas através da ecocardiografia moderna para avaliação do dissincronismo e os efeitos imediatos dessas estimulações durante o implante. MÉTODOS: Pacientes em FA permanente, com FE entre 35% e 55% e bradicardia com necessidade de estimulação cardíaca, foram submetidos a implante de MP bifocal do VD (septal alta e apical). Durante o intraoperatório, após cada modo de estimulação, foram realizadas medidas eletrocardiográficas e avaliação do dissincronismo pelo Eco Transesofágico...(AU)

Differential effects of ganglionic plexi ablation in apatient with neurally mediated syncope and intermittent atrioventricular block: acommentary

The treatment of functional bradyarrhythmias by means of endocardial radiofrequency (RF) catheter ablation of the autonomic nervous system began with the original publication in EP-Europace in 2005and it is known as ‘cardioneuro ablation’ (CNA).1,2 The reproducibility and good long-term results have largely been observed justifyingits rapid worldwide expansion having deserved a specific section atHeart Rhythm Society Annual Sessions in 2015 and 2016. The maingoal of CNA is the parasympathetic denervation of the heart to allowthe treatment of bradyarrhythmias symptomatic reflex (neurocardiogenicsyncope) and/or functional (sinus node dysfunction andfunctional atrioventricular (AV) block). Currently, it has been observed very good results in same types of functional brady-tachy syndrome. It is essentially based on a very specific cardiac neural distribution...

Choques no portador de desfibrilador cardíaco implantado: com manejar e prevenir? / Shocks in the implanted cardiac defibrillator carrier: with handle and prevent?

O cardiodesfibrilador implantável (CDI) consagrou- se como importante arma do arsenal terapêutico da cardiologia contemporânea. Contribui de modo inequívoco para o avanço no tratamento da morte súbita cardíaca. Esta, frequente e traumática para a sociedade, somente pode ser tratada de forma adequada com impacto na redução de mortalidade em portadores de arritmias ventriculares a partir do advento desse dispositivo...