RESUMO
BACKGROUND: Cardiovascular diseases represent the most common non-oncologic cause of death in patients following radiotherapy (RT) in the thoracic region. Radiation-induced heart disease (RIHD) can manifest as various heterogeneous clinical entities. However, the influence of RT on the cardiac conduction system has only recently gained more attention. Arrhythmogenic toxicity, i.e., conduction disorders and arrhythmias, constitutes a significant part of these adverse effects. The cardiac conduction system is not routinely monitored as an organ at risk (OaR). Its specific histological nature and function suggest different sensitivity and response to radiation. The heart is a highly heterogeneous organ, and the routinely monitored dose to the whole heart may not adequately characterize the risk of increased arrhythmogenic toxicity from RT. Cardiac structures, including the conduction system, appear to be additional OaRs for which dose distribution should be monitored. MATERIAL AND METHODS: For the systematic selection of studies, we utilized the PubMed database with keywords derived from the analysis of existing literature. The search was limited to English-language publications, and the selection criteria included relevance to the topic and the quality of methodology. PURPOSE: This article summarizes the impact of RT on the cardiac conduction system. CONCLUSION: Radiotherapy-induced cardiotoxicity significantly affects morbidity and mortality. The heart exhibits heterogeneity in terms of radiosensitivity. Certain cardiac subregions in the dose distribution show a higher correlation with poorer overall survival than routinely monitored doses to the whole heart and derived parameters (the volumes irradiated with the doses of 5 or 30 Gy - V5 or V30, respectively). The most radiosensitive subregions appear to be the base of the heart, including the beginning of the conduction system. Higher doses to the conduction system, especially the sinoatrial (SA) node, are associated with a higher incidence of a wide range of arrhythmias and poorer overall survival. However, dose limits (Dmean and Dmax) for the conduction system have not yet been established. Dosimetric studies have identified cutoff doses to the SA node, exceeding which there is a significant increase in mortality and the occurrence of arrhythmias.
Assuntos
Sistema de Condução Cardíaco , Humanos , Sistema de Condução Cardíaco/efeitos da radiação , Sistema de Condução Cardíaco/fisiopatologia , Radioterapia/efeitos adversos , Órgãos em Risco/efeitos da radiação , Arritmias Cardíacas/etiologia , Lesões por Radiação/etiologiaRESUMO
OBJECTIVES: Sex differences occur in atrial fibrillation (AF), including age at first manifestation, pathophysiology, treatment allocation, complication rates and quality of life. However, optimal doses of cardiovascular pharmacotherapy used in women with AF with or without heart failure (HF) are unclear. We investigated sex-specific associations of beta-blocker and renin-angiotensin system (RAS) inhibitor doses with cardiovascular outcomes in patients with AF or AF with concomitant HF. METHODS: We used data from the prospective Basel Atrial Fibrillation and Swiss Atrial Fibrillation cohorts on patients with AF. The outcome was major adverse cardiovascular events (MACEs), including death, myocardial infarction, stroke, systemic embolisation and HF-related hospitalisation. Predictors of interest were spline (primary analysis) or quartiles (secondary analysis) of beta-blocker or RAS inhibitor dose in per cent of the maximum dose (reference), in interaction with sex. Cox models were adjusted for demographics, comorbidities and comedication. RESULTS: Among 3961 patients (28% women), MACEs occurred in 1113 (28%) patients over a 5-year median follow-up. Distributions of RAS inhibitor and beta-blocker doses were similar in women and men. Cox models revealed no association between beta-blocker dose or RAS inhibitor dose and MACE. In a subgroup of patients with AF and HF, the lowest hazard of MACE was observed in women prescribed 100% of the RAS inhibitor dose. However, there was no association between RAS dose quartiles and MACE. CONCLUSIONS: In this study of patients with AF, doses of beta-blockers and RAS inhibitors did not differ by sex and were not associated with MACE overall.
Assuntos
Antagonistas Adrenérgicos beta , Fibrilação Atrial , Humanos , Fibrilação Atrial/tratamento farmacológico , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/complicações , Feminino , Masculino , Idoso , Estudos Prospectivos , Fatores Sexuais , Antagonistas Adrenérgicos beta/administração & dosagem , Antagonistas Adrenérgicos beta/efeitos adversos , Fatores de Risco , Pessoa de Meia-Idade , Suíça/epidemiologia , Resultado do Tratamento , Seguimentos , Medição de Risco/métodos , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Relação Dose-Resposta a Droga , Fatores de Tempo , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Brugada syndrome is an inheritable arrhythmia condition that is associated with rare, loss-of-function variants in SCN5A. Interpreting the pathogenicity of SCN5A missense variants is challenging, and ≈79% of SCN5A missense variants in ClinVar are currently classified as variants of uncertain significance. Automated patch clamp technology enables high-throughput functional studies of ion channel variants and can provide evidence for variant reclassification. METHODS: An in vitro SCN5A-Brugada syndrome automated patch clamp assay was independently performed at Vanderbilt University Medical Center and Victor Chang Cardiac Research Institute. The assay was calibrated according to ClinGen Sequence Variant Interpretation recommendations using high-confidence variant controls (n=49). Normal and abnormal ranges of function were established based on the distribution of benign variant assay results. Odds of pathogenicity values were derived from the experimental results according to ClinGen Sequence Variant Interpretation recommendations. The calibrated assay was then used to study SCN5A variants of uncertain significance observed in 4 families with Brugada syndrome and other arrhythmia phenotypes associated with SCN5A loss-of-function. RESULTS: Variant channel parameters generated independently at the 2 research sites showed strong correlations, including peak INa density (R2=0.86). The assay accurately distinguished benign controls (24/25 concordant variants) from pathogenic controls (23/24 concordant variants). Odds of pathogenicity values were 0.042 for normal function and 24.0 for abnormal function, corresponding to strong evidence for both American College of Medical Genetics and Genomics/Association for Molecular Pathology benign and pathogenic functional criteria (BS3 and PS3, respectively). Application of the assay to 4 clinical SCN5A variants of uncertain significance revealed loss-of-function for 3/4 variants, enabling reclassification to likely pathogenic. CONCLUSIONS: This validated high-throughput assay provides clinical-grade functional evidence to aid the classification of current and future SCN5A-Brugada syndrome variants of uncertain significance.
Assuntos
Síndrome de Brugada , Canal de Sódio Disparado por Voltagem NAV1.5 , Síndrome de Brugada/genética , Humanos , Canal de Sódio Disparado por Voltagem NAV1.5/genética , Masculino , Feminino , Mutação de Sentido Incorreto , Técnicas de Patch-Clamp , Adulto , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Whether vigorous exercise increases risk of ventricular arrhythmias for individuals diagnosed and treated for congenital long QT syndrome (LQTS) remains unknown. METHODS: The National Institutes of Health-funded LIVE-LQTS study (Lifestyle and Exercise in the Long QT Syndrome) prospectively enrolled individuals 8 to 60 years of age with phenotypic and/or genotypic LQTS from 37 sites in 5 countries from May 2015 to February 2019. Participants (or parents) answered physical activity and clinical events surveys every 6 months for 3 years with follow-up completed in February 2022. Vigorous exercise was defined as ≥6 metabolic equivalents for >60 hours per year. A blinded Clinical Events Committee adjudicated the composite end point of sudden death, sudden cardiac arrest, ventricular arrhythmia treated by an implantable cardioverter defibrillator, and likely arrhythmic syncope. A National Death Index search ascertained vital status for those with incomplete follow-up. A noninferiority hypothesis (boundary of 1.5) between vigorous exercisers and others was tested with multivariable Cox regression analysis. RESULTS: Among the 1413 participants (13% <18 years of age, 35% 18-25 years of age, 67% female, 25% with implantable cardioverter defibrillators, 90% genotype positive, 49% with LQT1, 91% were treated with beta-blockers, left cardiac sympathetic denervation, and/or implantable cardioverter defibrillator), 52% participated in vigorous exercise (55% of these competitively). Thirty-seven individuals experienced the composite end point (including one sudden cardiac arrest and one sudden death in the nonvigorous group, one sudden cardiac arrest in the vigorous group) with overall event rates at 3 years of 2.6% in the vigorous and 2.7% in the nonvigorous exercise groups. The unadjusted hazard ratio for experience of events for the vigorous group compared with the nonvigorous group was 0.97 (90% CI, 0.57-1.67), with an adjusted hazard ratio of 1.17 (90% CI, 0.67-2.04). The upper 95% one-sided confidence level extended beyond the 1.5 boundary. Neither vigorous or nonvigorous exercise was found to be superior in any group or subgroup. CONCLUSIONS: Among individuals diagnosed with phenotypic and/or genotypic LQTS who were risk assessed and treated in experienced centers, LQTS-associated cardiac event rates were low and similar between those exercising vigorously and those not exercising vigorously. Consistent with the low event rate, CIs are wide, and noninferiority was not demonstrated. These data further inform shared decision-making discussions between patient and physician about exercise and competitive sports participation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02549664.
Assuntos
Exercício Físico , Síndrome do QT Longo , Humanos , Síndrome do QT Longo/terapia , Síndrome do QT Longo/congênito , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/fisiopatologia , Síndrome do QT Longo/mortalidade , Feminino , Masculino , Adolescente , Criança , Estudos Prospectivos , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Morte Súbita Cardíaca/prevenção & controle , Morte Súbita Cardíaca/epidemiologia , Fatores de RiscoRESUMO
BACKGROUND: CaM (calmodulin)-mediated long-QT syndrome is a genetic arrhythmia disorder (calmodulinopathies) characterized by a high prevalence of life-threatening ventricular arrhythmias occurring early in life. Three distinct genes (CALM1, CALM2, and CALM3) encode for the identical CaM protein. Conventional pharmacotherapies fail to adequately protect against potentially lethal cardiac events in patients with calmodulinopathy. METHODS: Five custom-designed CALM1-, CALM2-, and CALM3-targeting short hairpin RNAs (shRNAs) were tested for knockdown (KD) efficiency using TSA201 cells and reverse transcription-quantitative polymerase chain reaction. A dual-component suppression and replacement (SupRep) CALM gene therapy (CALM-SupRep) was created by cloning into a single construct CALM1-, CALM2-, and CALM3-specific shRNAs that produce KD (suppression) of each respective gene and a shRNA-immune CALM1 cDNA (replacement). CALM1-F142L, CALM2-D130G, and CALM3-D130G induced pluripotent stem cell-derived CMs were generated from patients with CaM-mediated long-QT syndrome. A voltage-sensing dye was used to measure action potential duration at 90% repolarization (APD90). RESULTS: Following shRNA KD efficiency testing, a candidate shRNA was identified for CALM1 (86% KD), CALM2 (71% KD), and CALM3 (94% KD). The APD90 was significantly prolonged in CALM2-D130G (647±9 ms) compared with CALM2-WT (359±12 ms; P<0.0001). Transfection with CALM-SupRep shortened the average APD90 of CALM2-D130G to 457±19 ms (66% attenuation; P<0.0001). Additionally, transfection with CALM-SupRep shortened the APD90 of CALM1-F142L (665±9 to 410±15 ms; P<0.0001) and CALM3-D130G (978±81 to 446±6 ms; P<0.001). CONCLUSIONS: We provide the first proof-of-principle suppression-replacement gene therapy for CaM-mediated long-QT syndrome. The CALM-SupRep gene therapy shortened the pathologically prolonged APD90 in CALM1-, CALM2-, and CALM3-variant CaM-mediated long-QT syndrome induced pluripotent stem cell-derived CM lines. The single CALM-SupRep construct may be able to treat all calmodulinopathies, regardless of which of the 3 CaM-encoding genes are affected.
Assuntos
Calmodulina , Terapia Genética , Síndrome do QT Longo , Humanos , Calmodulina/genética , Calmodulina/metabolismo , Terapia Genética/métodos , Síndrome do QT Longo/genética , Síndrome do QT Longo/terapia , Síndrome do QT Longo/fisiopatologia , Síndrome do QT Longo/metabolismo , Síndrome do QT Longo/diagnóstico , Miócitos Cardíacos/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Potenciais de Ação , Predisposição Genética para Doença , Mutação , Interferência de RNA , Frequência Cardíaca/genéticaRESUMO
Bidirectional ventricular tachycardia (BVT) is a rare form of malignant ventricular arrhythmia characterized by beat-to-beat alternation in the QRS axis. BVT is a hallmark of digitalis toxicity, but digoxin-induced BVT secondary to digoxin-diuretic interaction in cardiac surgery patients is not widely reported. We present the case of a 62-year-old woman undergoing mitral valve replacement with tricuspid annuloplasty who developed postoperative congestive heart failure and vasoplegic syndrome requiring norepinephrine, vasopressin, and loop diuretics. During postoperative care, she presented atrial fibrillation with rapid ventricular response, achieving rate control with digoxin, but later displayed hemodynamically stable BVT associated with digitalis toxicity. The case highlights the importance of physicians monitoring digoxin toxicity when prescribing digoxin to patients with a diuretic regimen, particularly loop diuretics. During digoxin-induced-BVT, supportive treatment, including discontinuing digitalis coupled with potassium and magnesium supplements, can be considered as long as digoxin-specific antibodies are unavailable, and the patient is hemodynamically stable.
La taquicardia ventricular bidireccional (TVB) es una arritmia rara caracterizada por alternancia latido a latido en el eje QRS. La TVB es característica de intoxicación digitálica; sin embargo, la TVB secundaria a interacción digoxina-diurético en pacientes posoperados de cirugía cardíaca no se ha reportado ampliamente. Presentamos el caso de una mujer de 62 años sometida a cirugía cardiaca que desarrolló falla cardiaca congestiva y síndrome vasopléjico en el posoperatorio por lo que requirió noradrenalina, vasopresina y diurético de asa. Durante la hospitalización presentó fibrilación auricular con respuesta ventricular rápida; se logró control con digoxina, pero posteriormente presentó TVB asociada a intoxicación digitálica. Este caso resalta la importancia de detectar intoxicación digitálica durante la prescripción de digoxina a pacientes con un régimen diurético, especialmente diuréticos de asa. Durante la TVB inducida por digoxina, el tratamiento de soporte se puede considerar cuando no haya disponible anticuerpos específicos para digoxina y el paciente este hemodinámicamente estable.
RESUMO
Sinus of Valsalva aneurysm (SoVA) is a rare disease with less than 1% prevalence in the population. Most cases are asymptomatic, however, significant clinical manifestations are possible due to fistula formation and sudden rupture resulting in cardiac shunt. Eventually it may develop into progressive heart failure with high morbidity. We report the case of a 33 year old female patient who presented with shortness of breath, ascites, and recurring hospitalisation. The cardiac examination revealed sinus tachycardia along with loud and continuous murmurs on the left parasternal border. Several standard diagnostic procedures could not be performed due to malignant arrhythmia in supine position. Echocardiography examination revealed SoV rupture with a gerbode defect, which was the underlying cause of severe retractable heart failure.
Assuntos
Ruptura Aórtica , Insuficiência Cardíaca , Seio Aórtico , Humanos , Feminino , Seio Aórtico/diagnóstico por imagem , Seio Aórtico/anormalidades , Adulto , Insuficiência Cardíaca/etiologia , Ruptura Aórtica/complicações , Ruptura Aórtica/diagnóstico por imagem , Ecocardiografia , Aneurisma Aórtico/complicações , Aneurisma Aórtico/diagnóstico por imagemRESUMO
Wellens syndrome, an ST Elevation Myocardial Infarction (STEMI) equivalent, is also known as T-wave left anterior descending (LAD) coronary artery disease. Wellens syndrome is characterized by a unique electrocardiogram (ECG) pattern that suggests a significant stenosis in the left anterior descending coronary artery that warrants immediate intervention. Hereby, we present a case report of Wellens syndrome in a patient with a history of hypertension and chronic obstructive pulmonary disease (COPD) that may be potentially mistaken for pseudo- Wellens syndrome because the ECG pattern mimics left ventricular strain pattern (LVSP) in left ventricular hypertrophy (LVH). Thus, cautious examination of recent chest pain and ECG is important to differentiate Wellens syndrome and LVSP in patients with hypertension and COPD to perform early detection and aggressive intervention since they may help to lessen the adverse results.
Assuntos
Eletrocardiografia , Hipertensão , Doença Pulmonar Obstrutiva Crônica , Humanos , Doença Pulmonar Obstrutiva Crônica/complicações , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Hipertensão/complicações , Masculino , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/fisiopatologia , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Infarto do Miocárdio com Supradesnível do Segmento ST/etiologia , Pessoa de Meia-Idade , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/etiologia , Diagnóstico Diferencial , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/complicações , Estenose Coronária/diagnóstico , Estenose Coronária/fisiopatologia , Dor no Peito/etiologia , Dor no Peito/diagnóstico , Angiografia Coronária , SíndromeRESUMO
OBJECTIVE: To determine the incidence, onset, risk factors and mortality of pulmonary embolism in total knee replacement patients. METHODS: The systematic review was conducted in September 2022, and comprised search on PubMed, ScienceDirect, Scopus and Crossref databases for studies published from 1977 till September 7, 2022, in the English language related to the incidence of pulmonary embolism after primary total knee replacement. Cochrane Handbook for Systematic Reviews of Interventions was used to assess risk of bias, and the Newcastle-Ottawa Scale was used to assess the quality of evidence. RESULTS: Of the 3,910 studies initially identified, 66(1.68%) were analysed in detail, which together had 13,258,455 total knee replacement patients. Pulmonary embolism was reported in 76,515(0.58%) cases. The onset of pulmonary embolism ranged 2-150 days post-surgery. Patients with older age, diabetes mellitus, higher body mass index, atrial fibrillation, previous venous thromboembolism, high Charlson Comorbidity Index score, hypertension, arrhythmia and chronic heart failure were at significantly higher risk (p<0.05). The overall mortality rate of pulmonary embolism in such cases ranged 10.53-100%. CONCLUSIONS: Pulmonary embolism is a rare complication after orthopaedic surgery, but it has a very high mortality rate. By recognising the risk factors, attending physicians can optimise the use of chemoprophylaxis, thus preventing pulmonary embolism.
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Artroplastia do Joelho , Complicações Pós-Operatórias , Embolia Pulmonar , Humanos , Embolia Pulmonar/epidemiologia , Embolia Pulmonar/etiologia , Artroplastia do Joelho/efeitos adversos , Fatores de Risco , Complicações Pós-Operatórias/epidemiologia , Fatores Etários , Incidência , Fibrilação Atrial/epidemiologia , Hipertensão/epidemiologia , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia , Comorbidade , Índice de Massa Corporal , Insuficiência Cardíaca/epidemiologia , Diabetes Mellitus/epidemiologia , Arritmias Cardíacas/epidemiologia , Arritmias Cardíacas/etiologiaAssuntos
Implante de Prótese de Valva Cardíaca , Valva Pulmonar , Tetralogia de Fallot , Humanos , Tetralogia de Fallot/cirurgia , Tetralogia de Fallot/complicações , Tetralogia de Fallot/fisiopatologia , Masculino , Valva Pulmonar/cirurgia , Valva Pulmonar/diagnóstico por imagem , Valva Pulmonar/fisiopatologia , Feminino , Implante de Prótese de Valva Cardíaca/efeitos adversos , Taquicardia Ventricular/fisiopatologia , Taquicardia Ventricular/cirurgia , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/etiologia , Valor Preditivo dos Testes , Adolescente , Adulto Jovem , Adulto , Insuficiência da Valva Pulmonar/cirurgia , Insuficiência da Valva Pulmonar/fisiopatologia , Insuficiência da Valva Pulmonar/diagnóstico por imagem , Insuficiência da Valva Pulmonar/etiologia , Insuficiência da Valva Pulmonar/diagnóstico , Imagem Cinética por Ressonância Magnética , Criança , Resultado do TratamentoRESUMO
BACKGROUND: Thoracic epidural anesthesia (TEA) has been shown to reduce the burden of ventricular tachycardia in small case series of patients with refractory ventricular tachyarrhythmias and cardiomyopathy. However, its electrophysiological and autonomic effects in diseased hearts remain unclear, and its use after myocardial infarction is limited by concerns for potential right ventricular dysfunction. METHODS: Myocardial infarction was created in Yorkshire pigs (N=22) by left anterior descending coronary artery occlusion. Approximately, six weeks after myocardial infarction, an epidural catheter was placed at the C7-T1 vertebral level for injection of 2% lidocaine. Right and left ventricular hemodynamics were recorded using Millar pressure-conductance catheters, and ventricular activation recovery intervals (ARIs), a surrogate of action potential durations, by a 56-electrode sock and 64-electrode basket catheter. Hemodynamics and ARIs, baroreflex sensitivity and intrinsic cardiac neural activity, and ventricular effective refractory periods and slope of restitution (Smax) were assessed before and after TEA. Ventricular tachyarrhythmia inducibility was assessed by programmed electrical stimulation. RESULTS: TEA reduced inducibility of ventricular tachyarrhythmias by 70%. TEA did not affect right ventricular-systolic pressure or contractility, although left ventricular-systolic pressure and contractility decreased modestly. Global and regional ventricular ARIs increased, including in scar and border zone regions post-TEA. TEA reduced ARI dispersion specifically in border zone regions. Ventricular effective refractory periods prolonged significantly at critical sites of arrhythmogenesis, and Smax was reduced. Interestingly, TEA significantly improved cardiac vagal function, as measured by both baroreflex sensitivity and intrinsic cardiac neural activity. CONCLUSIONS: TEA does not compromise right ventricular function in infarcted hearts. Its antiarrhythmic mechanisms are mediated by increases in ventricular effective refractory period and ARIs, decreases in Smax, and reductions in border zone electrophysiological heterogeneities. TEA improves parasympathetic function, which may independently underlie some of its observed antiarrhythmic mechanisms. This study provides novel insights into the antiarrhythmic mechanisms of TEA while highlighting its applicability to the clinical setting.
Assuntos
Infarto do Miocárdio , Taquicardia Ventricular , Animais , Infarto do Miocárdio/fisiopatologia , Taquicardia Ventricular/fisiopatologia , Taquicardia Ventricular/etiologia , Suínos , Lidocaína/farmacologia , Anestesia Epidural/métodos , Barorreflexo/efeitos dos fármacos , Período Refratário Eletrofisiológico/efeitos dos fármacos , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Anestésicos Locais/farmacologia , Função Ventricular Direita/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Feminino , Vértebras Torácicas , Sus scrofa , Contração Miocárdica/efeitos dos fármacos , Masculino , Modelos Animais de Doenças , Função Ventricular Esquerda/efeitos dos fármacosAssuntos
Fibrilação Atrial , Átrios do Coração , Miócitos Cardíacos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fibrilação Atrial/metabolismo , Fibrilação Atrial/etiologia , Fatores de Crescimento de Fibroblastos/metabolismo , Átrios do Coração/metabolismo , Átrios do Coração/fisiopatologia , Miócitos Cardíacos/metabolismo , Complicações Pós-Operatórias/metabolismo , Complicações Pós-Operatórias/etiologiaRESUMO
BACKGROUND: Despite major advances in the clinical management of long QT syndrome, some patients are not fully protected by beta-blocker therapy. Mexiletine is a well-known sodium channel blocker, with proven efficacy in patients with sodium channel-mediated long QT syndrome type 3. Our aim was to evaluate the efficacy of mexiletine in long QT syndrome type 2 (LQT2) using cardiomyocytes derived from patient-specific human induced pluripotent stem cells, a transgenic LQT2 rabbit model, and patients with LQT2. METHODS: Heart rate-corrected field potential duration, a surrogate for QTc, was measured in human induced pluripotent stem cells from 2 patients with LQT2 (KCNH2-p.A561V, KCNH2-p.R366X) before and after mexiletine using a multiwell multi-electrode array system. Action potential duration at 90% repolarization (APD90) was evaluated in cardiomyocytes isolated from transgenic LQT2 rabbits (KCNH2-p.G628S) at baseline and after mexiletine application. Mexiletine was given to 96 patients with LQT2. Patients were defined as responders in the presence of a QTc shortening ≥40 ms. Antiarrhythmic efficacy of mexiletine was evaluated by a Poisson regression model. RESULTS: After acute treatment with mexiletine, human induced pluripotent stem cells from both patients with LQT2 showed a significant shortening of heart rate-corrected field potential duration compared with dimethyl sulfoxide control. In cardiomyocytes isolated from LQT2 rabbits, acute mexiletine significantly shortened APD90 by 113 ms, indicating a strong mexiletine-mediated shortening across different LQT2 model systems. Mexiletine was given to 96 patients with LQT2 either chronically (n=60) or after the acute oral drug test (n=36): 65% of the patients taking mexiletine only chronically and 75% of the patients who performed the acute oral test were responders. There was a significant correlation between basal QTc and ∆QTc during the test (r= -0.8; P<0.001). The oral drug test correctly predicted long-term effect in 93% of the patients. Mexiletine reduced the mean yearly event rate from 0.10 (95% CI, 0.07-0.14) to 0.04 (95% CI, 0.02-0.08), with an incidence rate ratio of 0.40 (95% CI, 0.16-0.84), reflecting a 60% reduction in the event rate (P=0.01). CONCLUSIONS: Mexiletine significantly shortens cardiac repolarization in LQT2 human induced pluripotent stem cells, in the LQT2 rabbit model, and in the majority of patients with LQT2. Furthermore, mexiletine showed antiarrhythmic efficacy. Mexiletine should therefore be considered a valid therapeutic option to be added to conventional therapies in higher-risk patients with LQT2.
Assuntos
Animais Geneticamente Modificados , Células-Tronco Pluripotentes Induzidas , Síndrome do QT Longo , Mexiletina , Miócitos Cardíacos , Mexiletina/farmacologia , Mexiletina/uso terapêutico , Animais , Humanos , Coelhos , Miócitos Cardíacos/efeitos dos fármacos , Síndrome do QT Longo/tratamento farmacológico , Síndrome do QT Longo/fisiopatologia , Síndrome do QT Longo/genética , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Masculino , Feminino , Adulto , Potenciais de Ação/efeitos dos fármacos , Antiarrítmicos/farmacologia , Antiarrítmicos/uso terapêutico , Adolescente , Pessoa de Meia-Idade , Adulto Jovem , Canal de Potássio ERG1/genética , Canal de Potássio ERG1/antagonistas & inibidores , Canal de Potássio ERG1/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Modelos Animais de Doenças , Criança , Resultado do TratamentoRESUMO
BACKGROUND: Conventional focal radiofrequency catheters may be modified to enable multiple energy modalities (radiofrequency or pulsed field [PF]) with the benefit of contact force (CF) feedback, providing greater flexibility in the treatment of arrhythmias. Information on the impact of CF on lesion formation in PF ablations remains limited. METHODS: An in vivo study was performed with 8 swine using an investigational dual-energy CF focal catheter with local impedance. Experiment I: To evaluate atrial lesion formation, contiguity, and width, a point-by-point approach was used to create an intercaval line. The distance between the points was prespecified at 4±1 mm. Half of the line was created with radiofrequency energy, whereas the other half utilized PF (single 2.0 kV application with a proprietary waveform). Experiment II: To evaluate single application lesion dimensions with a proprietary waveform, discrete ventricular lesions were performed with PFA (single 2.0 kV application) with targeted levels of CF: low, 5 to 15 g; medium, 20 to 30 g; and high, 35 to 45 g. Following 1 week of survival, animals underwent endocardial/epicardial remapping, and euthanasia to enable histopathologic examination. RESULTS: Experiment I: Both energy modalities resulted in a complete intercaval line of transmural ablation. PF resulted in significantly wider lines than radiofrequency: minimum width, 14.9±2.3 versus 5.0±1.6 mm; maximum width, 21.8±3.4 versus 7.3±2.1 mm, respectively; P<0.01 for each. Histology confirmed transmural lesions with both modalities. Experiment II: With PF, lesion depth, width, and volume were larger with higher degrees of CF (depth: r=0.82, P<0.001; width: r=0.26, P=0.052; and volume: r=0.55, P<0.001), with depth increasing at a faster rate than width. The mean depths were as follows: low (n=17), 4.3±1.0 mm; medium (n=26), 6.4±1.2 mm; and high (n=14), 9.1±1.4 mm. CONCLUSIONS: Using the same focal point CF-sensing catheter, a novel PF ablation waveform with a single application resulted in transmural atrial lesions that were significantly wider than radiofrequency. Lesion depth showed a significant positive correlation with CF with depths of 6.4 mm at moderate CF.
Assuntos
Cateteres Cardíacos , Ablação por Cateter , Desenho de Equipamento , Animais , Ablação por Cateter/instrumentação , Ablação por Cateter/métodos , Suínos , Átrios do Coração/fisiopatologia , Átrios do Coração/cirurgia , Modelos Animais , Sus scrofa , Ventrículos do Coração/fisiopatologia , Ventrículos do Coração/cirurgiaRESUMO
BACKGROUND: Polyphosphate (polyP), a procoagulant released from platelets, activates coagulation via the contact system and modulates cardiomyocyte viability. High-dose intravenous polyP is lethal in mice, presumably because of thrombosis. Previously, we showed that HRG (histidine-rich glycoprotein) binds polyP and attenuates its procoagulant effects. In this study, we investigated the mechanisms responsible for the lethality of intravenous polyP in mice and the impact of HRG on this process. METHODS: The survival of wild-type or HRG-deficient mice given intravenous synthetic or platelet-derived polyP in doses up to 50 mg/kg or saline was compared. To determine the contribution of thrombosis, the effect of FXII (factor XII) knockdown or enoxaparin on polyP-induced fibrin deposition in the lungs was examined. To assess cardiotoxicity, the ECG was continuously monitored, the levels of troponin I and the myocardial band of creatine kinase were quantified, and the viability of a cultured murine cardiomyocyte cell line exposed to polyP in the absence or presence of HRG was determined. RESULTS: In HRG-deficient mice, polyP was lethal at 30 mg/kg, whereas it was lethal in wild-type mice at 50 mg/kg. Although FXII knockdown or enoxaparin administration attenuated polyP-induced fibrin deposition in the lungs, neither affected mortality. PolyP induced dose-dependent ECG abnormalities, including heart block and ST-segment changes, and increased the levels of troponin and myocardial band of creatine kinase, effects that were more pronounced in HRG-deficient mice than in wild-type mice and were attenuated when HRG-deficient mice were given supplemental HRG. Consistent with its cardiotoxicity, polyP reduced the viability of cultured cardiomyocytes in a dose-dependent manner, an effect attenuated with supplemental HRG. CONCLUSIONS: High-dose intravenous polyP is cardiotoxic in mice, and HRG modulates this effect.
Assuntos
Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos , Polifosfatos , Proteínas , Animais , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Polifosfatos/toxicidade , Proteínas/metabolismo , Proteínas/genética , Sobrevivência Celular/efeitos dos fármacos , Camundongos , Masculino , Fibrina/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Relação Dose-Resposta a Droga , Trombose/prevenção & controle , Trombose/induzido quimicamente , Trombose/metabolismo , Trombose/genética , Trombose/patologia , Troponina I/metabolismo , Modelos Animais de Doenças , Cardiotoxicidade , Linhagem Celular , Eletrocardiografia , Coagulação Sanguínea/efeitos dos fármacosRESUMO
BACKGROUND: Irrigated radiofrequency ablation with half-normal saline can potentially increase lesion size but may increase the risk of steam pops with the risk of emboli or perforation. We hypothesized that pops would be preceded by intracardiac echocardiography (ICE) findings as well as a large impedance fall. METHODS: In 100 consecutive patients undergoing endocardial ventricular arrhythmia radiofrequency ablation with half-normal saline, we attempted to observe the ablation site with ICE. Radiofrequency ablation power was titrated to a 15 to 20 Ohm impedance fall and could be adjusted for tissue whitening and increasing bubble formation on ICE. Steam pops were defined as audible or a sudden explosion of microbubbles on ICE. RESULTS: Of 2190 ablation applications in 100 patients (82% cardiomyopathy, 50% sustained ventricular tachycardia), pops occurred during 43 (2.0%) applications. Sites with pops had greater impedance decreases of 18 [14, 21]% versus 13 [10, 17]% (P<0.001). ICE visualized 1308 (59.7%) radiofrequency sites, and fewer pops occurred when ICE visualized the radiofrequency ablation site (1.4%) compared with without ICE visualization (2.8%; P=0.016). Of the 18 ICE-visible pops, 7 (39%) were silent but recognized as an explosion of bubbles on ICE. With ICE, 89% of pops were preceded by either tissue whitening or a sudden increase in bubbles. In a multivariable model, tissue whitening and a sudden increase in bubbles were associated with steam pops (odds ratio, 7.186; P=0.004, and odds ratio, 29.93; P<0.001, respectively), independent of impedance fall and power. There were no pericardial effusions or embolic events with steam pops. CONCLUSIONS: Steam pops occurred in 2% of half-normal saline radiofrequency applications titrated to an impedance fall and are likely under-recognized without ICE. On ICE, steam pops are usually preceded by tissue whitening or a sudden increase in bubble formation, which can potentially be used to adjust radiofrequency application to help reduce pops.
Assuntos
Ablação por Cateter , Ecocardiografia , Solução Salina , Vapor , Taquicardia Ventricular , Irrigação Terapêutica , Humanos , Masculino , Feminino , Solução Salina/administração & dosagem , Pessoa de Meia-Idade , Ablação por Cateter/efeitos adversos , Taquicardia Ventricular/cirurgia , Taquicardia Ventricular/fisiopatologia , Taquicardia Ventricular/diagnóstico por imagem , Idoso , Embolia Aérea/prevenção & controle , Embolia Aérea/etiologia , Embolia Aérea/diagnóstico por imagem , Resultado do Tratamento , Fatores de Risco , Valor Preditivo dos Testes , Impedância ElétricaRESUMO
Chagas cardiomyopathy caused by infection with the intracellular parasite Trypanosoma cruzi is the most common and severe expression of human Chagas disease. Heart failure, systemic and pulmonary thromboembolism, arrhythmia, and sudden cardiac death are the principal clinical manifestations of Chagas cardiomyopathy. Ventricular arrhythmias contribute significantly to morbidity and mortality and are the major cause of sudden cardiac death. Significant gaps still exist in the understanding of the pathogenesis mechanisms underlying the arrhythmogenic manifestations of Chagas cardiomyopathy. This article will review the data from experimental studies and translate those findings to draw hypotheses about clinical observations. Human- and animal-based studies at molecular, cellular, tissue, and organ levels suggest 5 main pillars of remodeling caused by the interaction of host and parasite: immunologic, electrical, autonomic, microvascular, and contractile. Integrating these 5 remodeling processes will bring insights into the current knowledge in the field, highlighting some key features for future management of this arrhythmogenic disease.