RESUMO
Recurrent episodes of decompensated heart failure (HF) represent an emerging cause of hospitalizations in developed countries with an urgent need for effective therapies. Recently, the pregnancy-related hormone relaxin (RLN) was found to mediate cardio-protective effects and act as a positive inotrope in the cardiovascular system. RLN binds to the RLN family peptide receptor 1 (RXFP1), which is predominantly expressed in atrial cardiomyocytes. We therefore hypothesized that ventricular RXFP1 expression might exert potential therapeutic effects in an in vivo model of cardiac dysfunction. Thus, mice were exposed to pressure overload by transverse aortic constriction and treated with AAV9 to ectopically express RXFP1. To activate RXFP1 signaling, RLN was supplemented subcutaneously. Ventricular RXFP1 expression was well tolerated. Additional RLN administration not only abrogated HF progression but restored left ventricular systolic function. In accordance, upregulation of fetal genes and pathological remodeling markers were significantly reduced. In vitro, RLN stimulation of RXFP1-expressing cardiomyocytes induced downstream signaling, resulting in protein kinase A (PKA)-specific phosphorylation of phospholamban (PLB), which was distinguishable from ß-adrenergic activation. PLB phosphorylation corresponded to increased calcium amplitude and contractility. In conclusion, our results demonstrate that ligand-activated cardiac RXFP1 gene therapy represents a therapeutic approach to attenuate HF with the potential to adjust therapy by exogenous RLN supplementation.
Assuntos
Terapia Genética/métodos , Insuficiência Cardíaca/terapia , Receptores Acoplados a Proteínas G/genética , Receptores de Peptídeos/genética , Relaxina/administração & dosagem , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Dependovirus/genética , Modelos Animais de Doenças , Vetores Genéticos/administração & dosagem , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Injeções Subcutâneas , Ligantes , Masculino , Camundongos , Fosforilação , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Peptídeos/metabolismo , Resultado do Tratamento , Função VentricularRESUMO
BACKGROUND: Patients with reduced left ventricular (LV) function undergoing coronary artery bypass graft surgery or/and aortic valve replacement occasionally show severe mitral valve (MV) regurgitation and thus also undergo surgical mitral annuloplasty. Over time, further deterioration of LV function and additional ischemic events cause recurrence of severe MV regurgitation due to the Carpentier IIIb morphology of the MV that is not adequately addressed by the previously implanted annuloplasty ring. METHODS: Seven patients (Society of Thoracic Surgeons score: 7.5⯱ 1.5%) with Carpentier type-IIIb recurrent severe MV regurgitation, having undergone prior cardiothoracic surgery (median: 40 months) including mitral annuloplasty, were treated with the MitraClip device. RESULTS: MitraClip implantation resulted in significantly reduced MV regurgitation and improved New York Heart Association functional state, translating into an increased exercise capability and improved cardiac biomarkers. The morphology of the MV was adequately addressed without causing relevant MV stenosis, while the MV annulus area remained unaltered. The procedure was safe with a 30-day mortality rate of 0%. CONCLUSION: MitraClip-in-the-ring is feasible and in principle safe for treating Carpentier type IIIb severe MV regurgitation after surgical MV repair using mitral annuloplasty. MitraClip-in-the-ring resulted in immediate amelioration of clinical symptoms and increased physical exercise capacity.
Assuntos
Implante de Prótese de Valva Cardíaca , Próteses Valvulares Cardíacas , Anuloplastia da Valva Mitral , Insuficiência da Valva Mitral , Humanos , Valva Mitral/diagnóstico por imagem , Valva Mitral/cirurgia , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/cirurgia , Resultado do TratamentoRESUMO
Background The tandem of P domains in a weak inward rectifying K+ channel (TWIK)-related acid-sensitive K+ channel (TASK-1; hK2P3.1) two-pore-domain potassium channel was recently shown to regulate the atrial action potential duration. In the human heart, TASK-1 channels are specifically expressed in the atria. Furthermore, upregulation of atrial TASK-1 currents was described in patients suffering from atrial fibrillation (AF). We therefore hypothesized that TASK-1 channels represent an ideal target for antiarrhythmic therapy of AF. In the present study, we tested the antiarrhythmic effects of the high-affinity TASK-1 inhibitor A293 on cardioversion in a porcine model of paroxysmal AF. Methods and Results Heterologously expressed human and porcine TASK-1 channels are blocked by A293 to a similar extent. Patch clamp measurements from isolated human and porcine atrial cardiomyocytes showed comparable TASK-1 currents. Computational modeling was used to investigate the conditions under which A293 would be antiarrhythmic. German landrace pigs underwent electrophysiological studies under general anesthesia. Paroxysmal AF was induced by right atrial burst stimulation. After induction of AF episodes, intravenous administration of A293 restored sinus rhythm within cardioversion times of 177±63 seconds. Intravenous administration of A293 resulted in significant prolongation of the atrial effective refractory period, measured at cycle lengths of 300, 400 and 500 ms, whereas the surface ECG parameters and the ventricular effective refractory period lengths remained unchanged. Conclusions Pharmacological inhibition of atrial TASK-1 currents exerts antiarrhythmic effects in vivo as well as in silico, resulting in acute cardioversion of paroxysmal AF. Taken together, these experiments indicate the therapeutic potential of A293 for AF treatment.
Assuntos
Antiarrítmicos/farmacologia , Fibrilação Atrial/tratamento farmacológico , Frequência Cardíaca/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Proteínas do Tecido Nervoso/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio de Domínios Poros em Tandem/antagonistas & inibidores , Sulfonamidas/farmacologia , ortoaminobenzoatos/farmacologia , Animais , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/metabolismo , Fibrilação Atrial/fisiopatologia , Modelos Animais de Doenças , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Feminino , Humanos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Simulação de Acoplamento Molecular , Miócitos Cardíacos/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Canais de Potássio de Domínios Poros em Tandem/genética , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Estudo de Prova de Conceito , Período Refratário Eletrofisiológico/efeitos dos fármacos , Sus scrofa , Fatores de Tempo , Xenopus laevisRESUMO
BACKGROUND: Peritoneal ultrafiltration (pUF) in refractory heart failure (HF) reduces the incidence of decompensation episodes, which is of particular significance as each episode incrementally adds to mortality. Nevertheless, there are insufficient data about which patient cohort benefits the most. The objective of this study was to compare pUF in HFrEF and HFpEF, focusing on functional status, hospitalizations, surrogate endpoints and mortality. METHODS: This study involves 143 patients, who could be classified as either HFpEF (n = 37, 25.9%) or HFrEF (n = 106, 74.1%) and who received pUF due to refractory HF. RESULTS: Baseline eGFR was similar in HFrEF (23.1 ± 10.6 mg/dl) and HFpEF (27.8 ± 13.2 mg/dl). Significant improvements in NYHA class were found in HFpEF (3.19 ± 0.61 to 2.72 ± 0.58, P < 0.001) and HFrEF (3.45 ± 0.52 to 2.71 ± 0.72, P < 0.001). CRP decreased in HFrEF (19.4 ± 17.6 mg/l to 13.7 ± 21.4 mg/l, P = 0.018) and HFpEF (33.7 ± 52.6 mg/l to 17.1 ± 26.3 mg/l, P = 0.004). Body weight was significantly reduced in HFrEF (81.1 ± 14.6 kg to 77.2 ± 15.6 kg, P = 0.003) and HFpEF (86.9 ± 15.8 kg to 83.1 ± 15.9 kg, P = 0.005). LVEF improved only in HFrEF (25.9 ± 6.82% to 30.4 ± 12.2%, P = 0.046). BCR decreased significantly in HFrEF and HFpEF (55.7 ± 21.9 to 34.3 ± 17.9 P > 0.001 and 50.5 ± 68.9 to 37.6 ± 21.9, P = 0.006). Number of hospitalization episodes as well as number of hospitalization days decreased significantly only in HFpEF (total number 2.88 ± 1.62 to 1.25 ± 1.45, P < 0.001, days 40.4 ± 31.7 to 18.3 ± 22.5 days, P = 0.005). CONCLUSIONS: pUF offers various benefits in HFpEF and HFrEF, but there are also substantial differences. In particular, hospitalization rates were found to be significantly reduced in HFpEF patients, indicating a greater medical and economical advantage. However, LVEF was only found to be improved in HFrEF patients. While pUF can now be regarded as an option to supplement classical HF therapy, further studies are desirable to obtain specifications about pUF in HFpEF, HFmEF and HFrEF patients.
Assuntos
Insuficiência Cardíaca/terapia , Hemofiltração/métodos , Hospitalização/estatística & dados numéricos , Diálise Peritoneal/métodos , Volume Sistólico , Desequilíbrio Hidroeletrolítico/terapia , Diuréticos/uso terapêutico , Feminino , Insuficiência Cardíaca/fisiopatologia , Hemodiafiltração/métodos , Humanos , Masculino , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Diálise Peritoneal Ambulatorial Contínua/métodos , Resultado do Tratamento , Desequilíbrio Hidroeletrolítico/fisiopatologiaRESUMO
PURPOSE: Left bundle branch block (LBBB) has a predictive value for response to cardiac resynchronization therapy as reported by Zareba et al. (Circulation 123(10):1061-1072, 2011). However, based on ECG criteria, the discrimination between complete LBBB and nonspecific intraventricular conduction delay is challenging. We tested the hypothesis that discrimination can be performed using standard electrophysiological catheters and a simple stimulation protocol. METHODS: Fifty-nine patients were analyzed retrospectively. Patients were divided into groups of narrow QRS (n = 20), wide QRS of right bundle branch block (RBBB) morphology (n = 14), and wide QRS of LBBB morphology (n = 25). Using a diagnostic catheter placed in the coronary sinus, left ventricular activation was assessed during intrinsic conduction as well as during right ventricular (RV) stimulation. RESULTS: In patients with narrow QRS and RBBB, the Q-LV/QRS ratio was 0.43 ± 0.013 (n = 20) and 0.41 ± 0.026 (n = 14), respectively. In patients with LBBB morphology, the Q-LV/QRS split up into a group of patients with normal (0.43 ± 0.022, n = 7) and a group with delayed left ventricular activation (0.75 ± 0.016, n = 18). By direct comparison of the Q-LV/QRS ratio during intrinsic conduction with the Q-LV/QRS ratio during RV pacing leading to a functional LBBB, a clear distinction between a group of "true LBBB" and another group of "apparent LBBB"/nonspecific intraventricular conduction delay (NICD) could be generated. CONCLUSIONS: We present a novel and practical method that might facilitate discrimination between patients with apparent LBBB and true LBBB by comparing Q-LV/QRS ratios during intrinsic activation and during RV stimulation. Although this method can already be directly applied, validation by 3D electrical mapping and prospective correlation to cardiac resynchronization therapy (CRT) response will be required for further translation into clinical practice.
Assuntos
Bloqueio de Ramo , Estimulação Cardíaca Artificial/métodos , Técnicas Eletrofisiológicas Cardíacas/métodos , Bloqueio de Ramo/diagnóstico , Bloqueio de Ramo/fisiopatologia , Diagnóstico Diferencial , Eletrocardiografia/métodos , Fenômenos Eletrofisiológicos , Feminino , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Causative treatment of patients with wild-type transthyretin amyloid cardiomyopathy (wtATTR-CM) is lacking. Recent reports indicate the potential use of epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea, to inhibit amyloid fibril formation. We sought to investigate changes of cardiac function and morphology in patients with wtATTR-CM after consumption of green tea extract (GTE). METHODS: Twenty-five male patients (71 [64; 80] years) with wtATTR-CM were submitted to clinical examination, echocardiography, cardiac magnetic resonance imaging (cMRI) (n=14), and laboratory testing before and after daily consumption of GTE capsules containing 600 mg epigallocatechin-3-gallate for at least 12 months. RESULTS: A significant decrease of left ventricular (LV) myocardial mass by 6% (196 [100; 247] vs 180 [85; 237] g; P=0.03) by cMRI and total cholesterol by 8.4% (191 [118; 267] vs 173 [106; 287] mg/dL; P=0.006) was observed after a 1-year period of GTE consumption. LV ejection fraction by cMRI (53% [33%; 69%] vs 54% [28%; 71%]; P=0.75), LV wall thickness (17 [13; 21] vs 18 [14; 25] mm; P=0.1), and mitral annular plane systolic excursion (10 [5; 23] vs 8 [4; 13] mm; P=0.3) by echocardiography remained unchanged. CONCLUSION: This study supports LV mass stabilization in patients with wtATTR-CM consuming GTE potentially indicating amyloid fibril reduction.
Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Catequina/análogos & derivados , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Chá/química , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Amiloide/antagonistas & inibidores , Amiloide/metabolismo , Neuropatias Amiloides Familiares/diagnóstico , Catequina/administração & dosagem , Catequina/isolamento & purificação , Catequina/farmacologia , Catequina/uso terapêutico , Estudos de Coortes , Humanos , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Esquerda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/administração & dosagem , Extratos Vegetais/isolamento & purificaçãoRESUMO
Restoring expression levels of the EF-hand calcium (Ca(2+)) sensor protein S100A1 has emerged as a key factor in reconstituting normal Ca(2+) handling in failing myocardium. Improved sarcoplasmic reticulum (SR) function with enhanced Ca(2+) resequestration appears critical for S100A1's cyclic adenosine monophosphate-independent inotropic effects but raises concerns about potential diastolic SR Ca(2+) leakage that might trigger fatal arrhythmias. This study shows for the first time a diminished interaction between S100A1 and ryanodine receptors (RyR2s) in experimental HF. Restoring this link in failing cardiomyocytes, engineered heart tissue and mouse hearts, respectively, by means of adenoviral and adeno-associated viral S100A1 cDNA delivery normalizes diastolic RyR2 function and protects against Ca(2+)- and ß-adrenergic receptor-triggered proarrhythmogenic SR Ca(2+) leakage in vitro and in vivo. S100A1 inhibits diastolic SR Ca(2+) leakage despite aberrant RyR2 phosphorylation via protein kinase A and calmodulin-dependent kinase II and stoichiometry with accessory modulators such as calmodulin, FKBP12.6 or sorcin. Our findings demonstrate that S100A1 is a regulator of diastolic RyR2 activity and beneficially modulates diastolic RyR2 dysfunction. S100A1 interaction with the RyR2 is sufficient to protect against basal and catecholamine-triggered arrhythmic SR Ca(2+) leak in HF, combining antiarrhythmic potency with chronic inotropic actions.
Assuntos
Insuficiência Cardíaca/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Proteínas S100/metabolismo , Animais , Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Calmodulina/metabolismo , DNA Complementar/metabolismo , Eletrocardiografia , Técnicas de Transferência de Genes , Insuficiência Cardíaca/prevenção & controle , Masculino , Camundongos , Microscopia de Fluorescência , Miocárdio/metabolismo , Miócitos Cardíacos/citologia , Fosforilação , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismo , Engenharia Tecidual/métodosRESUMO
OBJECTIVES: T1 mapping by cardiac magnetic resonance imaging (CMR) is able to determine the extracellular volume fraction. Wild-type transthyretin amyloidosis (WT-ATTR) is characterized by extracellular amyloid deposition in the heart. Recent reports indicated a reduction of left ventricular (LV) myocardial mass in WT-ATTR after consumption of epigallocatechin-3-gallate, the main catechin in green tea. It remained unclear, whether reduction of LV myocardial mass reflects decrease of amyloid load or progressive atrophy of cardiomyocytes. METHODS: This study included 7 male patients with CMR repetitively performed before and 12 months after daily consumption of green tea extract (600 mg epigallocatechin-3-gallate). Short axis slices as well as 2-, 3-, and 4-chamber views were acquired using SSFP sequences. T1 mapping was created out of 11 mid-ventricular short axis views with increasing inversion times using a single breath-hold modified look-locker inversion recovery sequence before and 15 min after Gadolinium contrast administration. RESULTS: After 12 months, a significant decrease of LV myocardial mass [198 (160; 212) vs. 180 (142; 204) g; p < 0.05] was observed. Moreover, a significant decrease of native [T1 1110 (1072; 1150) ms vs. 1080 (970; 1101), p < 0.05 or p = 0.03] was noticed. The calculated extracellular volume decreased in 5 patients (62.5%) by 7% and increased in 2 patients (37.5%) by 9.5%, in trend resulting in a (not significant) decrease of median ECV by 2.4%. Left ventricular ejection fraction (LVEF) [57 (48; 65) vs. 55 (47; 64) %; p = 0.3] remained unchanged. CONCLUSIONS: This study provided further evidence of LV myocardial mass reduction in patients with WT-ATTR daily consuming green tea extract. Additionally, this study gave first insights into the histomorphological correlate of LV mass reduction using T1 mapping. LV mass reduction appeared to be rather due to a decrease of amyloid load than atrophy of cardiomyocytes.
Assuntos
Amiloidose/tratamento farmacológico , Camellia sinensis , Cardiomiopatias/tratamento farmacológico , Catequina/análogos & derivados , Matriz Extracelular/metabolismo , Imagem Cinética por Ressonância Magnética , Miocárdio/patologia , Extratos Vegetais/química , Remodelação Ventricular/efeitos dos fármacos , Administração Oral , Idoso , Amiloide/metabolismo , Amiloidose/metabolismo , Amiloidose/patologia , Camellia sinensis/química , Cápsulas , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Catequina/administração & dosagem , Catequina/isolamento & purificação , Meios de Contraste , Fibrose , Gadolínio DTPA , Alemanha , Humanos , Interpretação de Imagem Assistida por Computador , Masculino , Miocárdio/metabolismo , Extratos Vegetais/isolamento & purificação , Valor Preditivo dos Testes , Fatores de Tempo , Resultado do TratamentoRESUMO
Direct oral anticoagulants (DOACs) are effective for stroke prevention in nonvalvular atrial fibrillation (AF). Cardioversion (CV) is frequently performed in patients with AF or flutter. To further explore the safety profile of DOACs in the context of CV, we sought to assess the prevalence of intracardiac thrombi under DOAC therapy in comparison with treatment with vitamin K antagonists. A total of 672 transesophageal echocardiograms performed in 643 patients with a history of nonvalvular AF were analyzed. The median CHA2DS2-VASc score was 4. Cases were stratified according to anticoagulation with dabigatran (n = 79), rivaroxaban (n = 122), phenprocoumon (n = 180), or bridging therapy (n = 287). In a subgroup analysis, only patients receiving phenprocoumon with an international normalized ratio ≥2 on the day of the investigation or on DOAC therapy for ≥3 weeks were considered. The prevalence of intracardiac thrombi under phenprocoumon was significantly higher than under DOACs (phenprocoumon, 17.8%; all DOACs, 3.9%; dabigatran, 3.8%; rivaroxaban, 4.1%) and showed no significant difference to bridging therapy (12.5%). In patients with sufficient short-term anticoagulation, similar differences between DOAC and phenprocoumon groups were observed (phenprocoumon, 18.4%; all DOACs, 3.8%; dabigatran, 0%; rivaroxaban, 6.6%). The influence of anticoagulation medication on thrombus rates was confirmed after adjusting for baseline intergroup differences regarding left atrial size and CHA2DS2-VASc score. In conclusion, the prevalence of intracardiac thrombi was lower under DOAC therapy than under phenprocoumon in this high-risk patient cohort. Safety of CV during DOAC treatment requires further prospective evaluation.
Assuntos
Anticoagulantes/uso terapêutico , Arritmias Cardíacas/tratamento farmacológico , Benzimidazóis/uso terapêutico , Morfolinas/uso terapêutico , Femprocumona/uso terapêutico , Tiofenos/uso terapêutico , Trombose/epidemiologia , beta-Alanina/análogos & derivados , Idoso , Arritmias Cardíacas/complicações , Estudos de Coortes , Dabigatrana , Cardioversão Elétrica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Rivaroxabana , Vitamina K/antagonistas & inibidores , Vitamina K/uso terapêutico , beta-Alanina/uso terapêuticoAssuntos
Ablação por Cateter , Rim/inervação , Simpatectomia/métodos , Taquicardia Ventricular/cirurgia , Potenciais de Ação , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Humanos , Pessoa de Meia-Idade , Recidiva , Taquicardia Ventricular/diagnóstico , Taquicardia Ventricular/fisiopatologia , Fatores de Tempo , Falha de TratamentoRESUMO
BACKGROUND: Inherited arrhythmias were originally considered isolated electrical defects. There is growing evidence that ion channel dysfunction also contributes to myocardial disorders, but genetic overlap has not been reported for sinus node dysfunction (SND) and noncompaction cardiomyopathy (NCCM). OBJECTIVES: The study sought to investigate a familial electromechanical disorder characterized by SND and NCCM, and to identify the underlying genetic basis. METHODS: The index family and a cohort of unrelated probands with sinus bradycardia were examined by electrocardiography, Holter recording, exercise stress test, echocardiography, and/or cardiac magnetic resonance imaging. Targeted next-generation and direct sequencing were used for candidate gene analysis and mutation scanning. Ion channels were expressed in HEK293 cells and studied using patch-clamp recordings. RESULTS: SND and biventricular NCCM were diagnosed in multiple members of a German family. Segregation analysis suggested autosomal-dominant inheritance of the combined phenotype. When looking for potentially disease-causing gene variants with cosegregation, a novel hyperpolarization-activated cyclic nucleotide channel 4 (HCN4)-G482R mutation and a common cysteine and glycine-rich protein 3 (CSRP3)-W4R variant were identified. HCN4-G482R is located in the highly conserved channel pore domain. Mutant subunits were nonfunctional and exerted dominant-negative effects on wild-type current. CSRP3-W4R has previously been linked to dilated and hypertrophic cardiomyopathy, but was also found in healthy subjects. Moreover, different truncation (695X) and missense (P883R) HCN4 mutations segregated with a similar combined phenotype in an additional, unrelated family and a single unrelated proband respectively, which both lacked CSRP3-W4R. CONCLUSIONS: The symptom complex of SND and NCCM is associated with heritable HCN4 defects. The NCCM phenotype may be aggravated by a common CSRP3 variant in one of the families.
Assuntos
Cardiopatias Congênitas/genética , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Proteínas Musculares/genética , Canais de Potássio/genética , Síndrome do Nó Sinusal/genética , Adolescente , Animais , Ecocardiografia , Técnicas Eletrofisiológicas Cardíacas , Feminino , Alemanha/epidemiologia , Células HEK293 , Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/epidemiologia , Humanos , Masculino , Potenciais da Membrana , Pessoa de Meia-Idade , Linhagem , Fenótipo , Prevalência , Síndrome do Nó Sinusal/diagnóstico por imagem , Síndrome do Nó Sinusal/epidemiologia , Síndrome , Adulto JovemRESUMO
Genetically encoded Ca(2+) indicators constitute a powerful set of tools to investigate functional aspects of Ca(2+) signaling in isolated cardiomyocytes, cardiac tissue, and whole hearts. Here, we provide an overview of the concepts, experiences, state of the art, and ongoing developments in the use of genetically encoded Ca(2+) indicators for cardiac cells and heart tissue. This review is supplemented with in vivo viral gene transfer experiments and comparisons of available genetically encoded Ca(2+) indicators with each other and with the small molecule dye Fura-2. In the context of cardiac myocytes, we provide guidelines for selecting a genetically encoded Ca(2+) indicator. For future developments, we discuss improvements of a broad range of properties, including photophysical properties such as spectral spread and biocompatibility, as well as cellular and in vivo applications.
Assuntos
Sinalização do Cálcio/genética , Corantes Fluorescentes , Miócitos Cardíacos/química , Miócitos Cardíacos/fisiologia , Transgenes , Animais , Diagnóstico por Imagem/métodos , Técnicas de Transferência de Genes , Humanos , Miócitos Cardíacos/metabolismoRESUMO
The human KCNK18 gene is predominantly expressed in brain, spinal cord, and dorsal root ganglion neurons. Encoded K2P18.1K(+) channels are functionally implicated in migraine, pain and anesthesia. Data delineating the in vivo significance of K2P18.1 are still limited owing to a lack of model systems allowing for rapid, whole organism phenotypic analyses. We hypothesized that zebrafish (Danio rerio) might close this scientific gap. This work was designed to characterize the zebrafish ortholog of K2P18.1 in comparison to human K2P18.1 channels. The complete coding sequence of zKCNK18 was amplified from zebrafish cDNA. Zebrafish KCNK18 expression was assessed by in situ hybridization. Human and zebrafish K2P18.1 currents were functionally analyzed using two-electrode voltage clamp electrophysiology and the Xenopus oocyte expression system. KCNK18 mRNA is expressed in zebrafish brain and eyes. Human and zebrafish K2P18.1 proteins share 32 % identity. Zebrafish K2P18.1 channels mediate K(+)-selective background currents that stabilize the negative resting membrane potential. Functional similarities between human and zK2P18.1 currents include open rectification properties, inhibition by barium, and regulation by signaling molecules protein kinase (PK)C, PKA, and phospholipase C. In contrast to the human ortholog, zK2P18.1 exhibited reduced sensitivity to elevation of intracellular calcium levels by ionomycin and was virtually insensitive to inhibition by quinidine. Zebrafish and human K2P18.1 channels share functional and regulatory properties, indicating that the zebrafish may serve as model to assess K2P18.1 function in vivo. However, distinct differences in K2P18.1 current regulation require careful consideration when zebrafish data are extrapolated to human physiology.
Assuntos
Canais de Potássio de Domínios Poros em Tandem/metabolismo , Canais de Potássio/metabolismo , Animais , Cálcio/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , DNA Complementar/genética , Feminino , Humanos , Hibridização In Situ , Potenciais da Membrana/fisiologia , Oócitos , Técnicas de Patch-Clamp , Canais de Potássio/genética , Proteína Quinase C/metabolismo , Quinidina/farmacologia , Especificidade da Espécie , Fosfolipases Tipo C/metabolismo , Xenopus laevis , Peixe-ZebraRESUMO
In the setting of acute myocardial infarction and sinus rhythm, the heart rate (HR) has been demonstrated to correlate closely with mortality. In patients presenting with acute myocardial infarction and atrial fibrillation (AF) on admission, however, the prognostic relevance of the HR has not yet been systematically addressed. A post hoc subgroup analysis of the data from the OMEGA trial was conducted to analyze whether the admission HR determines the 1-year mortality in patients presenting with AF in the setting of acute myocardial infarction. Of 3,851 patients enrolled in the OMEGA study, 211 (6%) presented with AF on admission. This subgroup was dichotomized according to the admission HR (cutoff 95 beats/min). Multiple regression analysis revealed that an admission HR of ≥95 beats/min independently determined the 1-year mortality in patients with AF (odds ratio 4.69, 95% confidence interval 1.47 to 15.01; p = 0.01). In conclusion, this is the first study demonstrating that a high HR (≥95 beats/min) on admission in patients with AF and acute myocardial infarction is associated with an almost fivefold mortality risk.
Assuntos
Fibrilação Atrial/mortalidade , Frequência Cardíaca/fisiologia , Infarto do Miocárdio/mortalidade , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/fisiopatologia , Método Duplo-Cego , Ácidos Graxos Ômega-3/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/fisiopatologia , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Análise de Regressão , Fatores de RiscoRESUMO
RATIONALE: Mice lacking the EF-hand Ca2+ sensor S100A1 display endothelial dysfunction because of distorted Ca2+ -activated nitric oxide (NO) generation. OBJECTIVE: To determine the pathophysiological role of S100A1 in endothelial cell (EC) function in experimental ischemic revascularization. METHODS AND RESULTS: Patients with chronic critical limb ischemia showed almost complete loss of S100A1 expression in hypoxic tissue. Ensuing studies in S100A1 knockout (SKO) mice subjected to femoral artery resection unveiled insufficient perfusion recovery and high rates of autoamputation. Defective in vivo angiogenesis prompted cellular studies in SKO ECs and human ECs, with small interfering RNA-mediated S100A1 knockdown demonstrating impaired in vitro and in vivo proangiogenic properties (proliferation, migration, tube formation) and attenuated vascular endothelial growth factor (VEGF)-stimulated and hypoxia-stimulated endothelial NO synthase (eNOS) activity. Mechanistically, S100A1 deficiency compromised eNOS activity in ECs by interrupted stimulatory S100A1/eNOS interaction and protein kinase C hyperactivation that resulted in inhibitory eNOS phosphorylation and enhanced VEGF receptor-2 degradation with attenuated VEGF signaling. Ischemic SKO tissue recapitulated the same molecular abnormalities with insufficient in vivo NO generation. Unresolved ischemia entailed excessive VEGF accumulation in SKO mice with aggravated VEGF receptor-2 degradation and blunted in vivo signaling through the proangiogenic phosphoinositide-3-kinase/Akt/eNOS cascade. The NO supplementation strategies rescued defective angiogenesis and salvaged limbs in SKO mice after femoral artery resection. CONCLUSIONS: Our study shows for the first time downregulation of S100A1 expression in patients with critical limb ischemia and identifies S100A1 as critical for EC function in postnatal ischemic angiogenesis. These findings link its pathological plasticity in critical limb ischemia to impaired neovascularization, prompting further studies to probe the microvascular therapeutic potential of S100A1.
Assuntos
Células Endoteliais/enzimologia , Isquemia/enzimologia , Músculo Esquelético/irrigação sanguínea , Neovascularização Fisiológica , Óxido Nítrico Sintase Tipo III/metabolismo , Proteínas S100/deficiência , Idoso , Idoso de 80 Anos ou mais , Animais , Cálcio/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Feminino , Membro Posterior , Células Endoteliais da Veia Umbilical Humana/enzimologia , Humanos , Isquemia/tratamento farmacológico , Isquemia/genética , Isquemia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Músculo Esquelético/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Proteína Quinase C/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Fluxo Sanguíneo Regional , Proteínas S100/genética , Transdução de Sinais , Fatores de Tempo , Transfecção , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
AIMS: HCN4 channels are involved in generation, regulation, and stabilization of heart rhythm and channel dysfunction is associated with inherited sinus bradycardia. We asked whether dysfunctional HCN4 channels also contribute to the generation of cardiac tachyarrhythmias. METHODS AND RESULTS: In a candidate gene approach, we screened 422 patients with atrial and/or ventricular tachyarrhythmias and detected a novel HCN4 gene mutation that replaced the positively charged lysine 530 with an asparagine (HCN4-K530N) in a highly conserved region of the C-linker. The index patient developed tachycardia-bradycardia syndrome and persistent atrial fibrillation (AF) in an age-dependent fashion. Pedigree analysis identified eight affected family members with a similar course of disease. Whole-cell patch clamp electrophysiology of HEK293 cells showed that homomeric mutant channels almost are indistinguishable from wild-type channels. In contrast, heteromeric channels composed of mutant and wild-type subunits displayed a significant hyperpolarizing shift in the half-maximal activation voltage. This may be caused by a shift in the equilibrium between the tonically inhibited nucleotide-free state of the C-terminal domain of HCN4 believed to consist of a 'dimer of dimers' and the activated ligand-bound tetrameric form, leading to an increased inhibition of activity in heteromeric channels. CONCLUSION: Altered C-linker oligomerization in heteromeric channels is considered to promote familial tachycardia-bradycardia syndrome and persistent AF, indicating that f-channel dysfunction contributes to the development of atrial tachyarrhythmias.
Assuntos
Fibrilação Atrial/genética , Bradicardia/genética , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Mutação/genética , Taquicardia/genética , Adulto , Análise de Variância , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Feminino , Células HEK293 , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/química , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
We report a case of Anderson-Fabry disease in a young man presenting with cardiac hypertrophy and asymptomatic non-sustained ventricular tachycardia. The patient was referred for evaluation of implantable cardioverter/defibrillator therapy. Assessment of left ventricular ejection fraction is considered the gold standard for identifying patients at risk of sudden cardiac death. However, this patient's left ventricular function was preserved. Electrophysiological study did not reveal inducible arrhythmia or cardiac conduction abnormalities. Review of the literature indicates limited knowledge on the electrophysiology of Fabry cardiomyopathy and highlights the need for optimized risk stratification strategies.
Assuntos
Cardiomiopatias/fisiopatologia , Doença de Fabry/fisiopatologia , Adulto , Códon sem Sentido , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Doença de Fabry/genética , Humanos , Masculino , Linhagem , Medição de RiscoRESUMO
BACKGROUND: Treatment options in patients with amyloidotic transthyretin (ATTR) cardiomyopathy are limited. Epigallocatechin-3-gallate (EGCG), the most abundant catechin in green tea (GT), inhibits fibril formation from several amyloidogenic proteins in vitro. Thus, it might also halt progression of TTR amyloidosis. This is a single-center observational report on the effects of GT consumption in patients with ATTR cardiomopathy. METHODS: 19 patients with ATTR cardiomyopathy were evaluated by standard blood tests, echocardiography, and cardiac MRI (n = 9) before and after consumption of GT and/or green tea extracts (GTE) for 12 months. RESULTS: Five patients were not followed up for reasons of death (n = 2), discontinuation of GT/GTE consumption (n = 2), and heart transplantation (n = 1). After 12 months no increase of left ventricular (LV) wall thickness and LV myocardial mass was observed by echocardiography. In the subgroup of patients evaluated by cardiac MRI a mean decrease of LV myocardial mass (-12.5 %) was detected in all patients. This was accompanied by an increase of mean mitral annular systolic velocity of 9 % in all 14 patients. Total cholesterol (191.9 ± 8.9 vs. 172.7 ± 9.4 mg/dL; p < 0.01) and LDL cholesterol (105.8 ± 7.6 vs. 89.5 ± 8.0 mg/dL; p < 0.01) decreased significantly during the observational period. No serious adverse effects were reported by any of the participants. CONCLUSIONS: Our observation suggests an inhibitory effect of GT and/or GTE on the progression of cardiac amyloidosis. We propose a randomized placebo-controlled investigation to confirm our observation.
Assuntos
Neuropatias Amiloides Familiares/tratamento farmacológico , Cardiomiopatias/tratamento farmacológico , Catequina/análogos & derivados , Chá/química , Idoso , Neuropatias Amiloides Familiares/fisiopatologia , Cardiomiopatias/fisiopatologia , Catequina/isolamento & purificação , Catequina/farmacologia , Colesterol/sangue , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Valva Mitral/metabolismo , Extratos Vegetais/farmacologiaRESUMO
BACKGROUND AND PURPOSE: Remote robotic navigation (RRN) technology has been developed to facilitate catheter ablation of symptomatic atrial fibrillation (AF). Here, we assess procedural parameters of AF ablation obtained during initial use of RRN compared with a control group treated with a manual ablation approach. METHODS: Consecutive patients with symptomatic paroxysmal or persistent AF were subjected to radiofrequency catheter ablation with RRN (Sensei X [Hansen Medical, Mountain View, CA]; n = 25; mean age, 60 ± 2.3 years) or using the standard manual technique (n = 61; mean age, 62 ± 1.4 years). A circumferential pulmonary vein isolation approach guided by 3-dimensional electroanatomical mapping was followed. RESULTS: Remote robotic navigation was associated with reduction of overall fluoroscopy time by 26%. In a case-control subgroup analysis comparing 25 patients with similar clinical characteristics from each group, mean fluoroscopy time was reduced by 22%. Acute isolation of pulmonary veins was achieved in 97% (RRN) and 96% (conventional ablation), respectively. Ablation times and frequency of adverse events were not significantly different among study groups. CONCLUSIONS: The early use of RRN resulted in a significant reduction of overall fluoroscopy time and was equally effective and safe compared with manual catheter ablation.
Assuntos
Fibrilação Atrial/cirurgia , Ablação por Cateter/métodos , Robótica/métodos , Fibrilação Atrial/fisiopatologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas/métodos , Feminino , Fluoroscopia , Humanos , Masculino , Pessoa de Meia-Idade , Veias Pulmonares/fisiopatologia , Veias Pulmonares/cirurgia , Fatores de Tempo , Resultado do TratamentoRESUMO
Two-pore-domain potassium (K(2P)) channels mediate K(+) background currents that stabilize the resting membrane potential and contribute to repolarization of action potentials in excitable cells. The functional significance of K(2P) currents in cardiac electrophysiology remains poorly understood. Danio rerio (zebrafish) may be utilized to elucidate the role of cardiac K(2P) channels in vivo. The aim of this work was to identify and functionally characterize a zebrafish otholog of the human K(2P)10.1 channel. K(2P)10.1 orthologs in the D. rerio genome were identified by database analysis, and the full zK(2P)10.1 coding sequence was amplified from zebrafish cDNA. Human and zebrafish K(2P)10.1 proteins share 61% identity. High degrees of conservation were observed in protein domains relevant for structural integrity and regulation. K(2P)10.1 channels were heterologously expressed in Xenopus oocytes, and currents were recorded using two-electrode voltage clamp electrophysiology. Human and zebrafish channels mediated K(+) selective background currents leading to membrane hyperpolarization. Arachidonic acid, an activator of hK(2P)10.1, induced robust activation of zK(2P)10.1. Activity of both channels was reduced by protein kinase C. Similar to its human counterpart, zK(2P)10.1 was inhibited by the antiarrhythmic drug amiodarone. In summary, zebrafish harbor K(2P)10.1 two-pore-domain K(+) channels that exhibit structural and functional properties largely similar to human K(2P)10.1. We conclude that the zebrafish represents a valid model to study K(2P)10.1 function in vivo.