Molecular architecture of the human sinus node: insights into the function of the cardiac pacemaker.

BACKGROUND: Although we know much about the molecular makeup of the sinus node (SN) in small mammals, little is known about it in humans. The aims of the present study were to investigate the expression of ion channels in the human SN and to use the data to predict electrical activity. METHODS AND RESULTS: Quantitative polymerase chain reaction, in situ hybridization, and immunofluorescence were used to analyze 6 human tissue samples. Messenger RNA (mRNA) for 120 ion channels (and some related proteins) was measured in the SN, a novel paranodal area, and the right atrium (RA). The results showed, for example, that in the SN compared with the RA, there was a lower expression of Na(v)1.5, K(v)4.3, K(v)1.5, ERG, K(ir)2.1, K(ir)6.2, RyR2, SERCA2a, Cx40, and Cx43 mRNAs but a higher expression of Ca(v)1.3, Ca(v)3.1, HCN1, and HCN4 mRNAs. The expression pattern of many ion channels in the paranodal area was intermediate between that of the SN and RA; however, compared with the SN and RA, the paranodal area showed greater expression of K(v)4.2, K(ir)6.1, TASK1, SK2, and MiRP2. Expression of ion channel proteins was in agreement with expression of the corresponding mRNAs. The levels of mRNA in the SN, as a percentage of those in the RA, were used to estimate conductances of key ionic currents as a percentage of those in a mathematical model of human atrial action potential. The resulting SN model successfully produced pacemaking. CONCLUSIONS: Ion channels show a complex and heterogeneous pattern of expression in the SN, paranodal area, and RA in humans, and the expression pattern is appropriate to explain pacemaking.

Falls and fractures in the elderly with sinus node disease: the impact of pacemaker implantation

Background. Falls and fractures in the elderly are among the leading causes of disability. We investigated whether pacemaker implantation prevents falls in patients with SND in a large cohort of patients. Methods. Patient demographics and medical history were collected prospectively. Fall history was retrospectively reconstituted from available medical records. The 10-year probability for major osteoporotic fractures was calculated retrospectively from available medical records using the Swiss fracture risk assessment tool FRAX-Switzerland. Results. During a mean observation period of 2.3 years after implantation, the rates of fallers and injured fallers with fracture were reduced to 15% and 6%, respectively. This corresponds to a relative reduction in the number of fallers of 75% (P < 0.001) and of injured fallers of 63% (P = 0.014) after pacemaker implantation. Similarly, the number of falls was reduced from 60 (48%) before pacemaker implantation to 22 (18%) thereafter (relative reduction 63%, P = 0.035) and the number of falls with injury from 22 (18%) to 7 (6%), which corresponds to a relative reduction of 67%, P = 0.013. Conclusion. In patients with SND, pacemaker implantation significantly reduces the number of patients experiencing falls, the total number of falls, and the risk for osteoporotic fractures.

Comparative analysis between ventricular and sinoatrial node vascularization in cats

Biasi C., Borelli V., Benedicto H.G., Pereira M.R., Favaron P.O. & Bombonato P.P. 2012. [Comparative analysis between ventricular and sinoatrial node vascularization in cats.] Analise comparativa entre a vascularizacao ventricular e do no sinoatrial em gatos. Pesquisa Veterinaria Brasileira 31(1): 78-82. Setor de Anatomia dos Animais Domesticos e Silvestres, Faculdade de Medicina Veterinaria e Zootecnia, Universidade de Sao Paulo, Av. Prof. Dr. Orlando Marques de Paiva 87, Cidade Universitaria, Sao Paulo, SP 05508-000, Brazil. E-mail: caiobiasi@usp.br The possible existence of interdependence in the blood nutrition of both atrial and ventricular territories has been a subject of concern to cardiologists, mainly related to vascularization of the sinoatrial node and its dependence on just one coronary artery or both, and its relation with the predominance of these vessels in the ventricular vascularization. Therefore, this research aimed evaluated the relation of blood irrigation of the sinoatrial node in relation to the coronary artery predominance in the ventricle vascularization. In doing so, we analyzed 30 hearts of cats without pedigree, males and females, adults of several ages. They were not carrying any heart problems. The hearts were injected by the thoracic aorta with Neoprene Latex 450, stained with red pigment, and then they were dissected. It was found that when there was a prevalence of ventricular vascularization of the left type (63.34%) the sinoatrial node irrigation was predominantly in the dependency of the Ramus proximalis atrii dextri (78.9%) or with less frequency by Ramus proximalis atrii sinister (21.1%). In the ventricular vascularization of the balanced type (33.34%), the pacemaker irrigation was in dependence more often of Ramus proximalis atrii dextri (80%) or with less frequency the nutrition of the sinoatrial node occurred by Ramus proximalis atril sinister (20%). In a single-case, we observed the ventricular vascularization of the right type (3.34%), the pacemaker nutrition was in an exclusive dependence of the Ramus intermedius atril dextri. These results suggest in this species there is no relationship between both the sinoatrial node irrigation and the type of ventricular vascularization, regardless of gender.

The left atrial ganglionated plexus : its function and pathways relative to atrial fibrillation surgery

Le système nerveux autonome cardiaque est devenu une cible dans les thérapies ablatives de la fibrillation auriculaire. Nous avons étudié les voies de communication et la fonction des plexus ganglionnaires (PG) de l'oreillette gauche (PGOG) afin de clarifier la validité physiopathologique des méthodes de détection et des thérapies impliquant ces groupes de neuronnes. Méthodes: Vingt-deux chiens ont subi une double thoracotomie et ont été instrumentés avec des plaques auriculaires épidcardiques de multiélectrodes. Une stimulation électrique (2 mA, 15 Hz) des PGOG a été réalisée à l'état basal et successivement après: 1) une décentralisation vagale, 2) l'ablation par radiofréquence des plexus péri-aortiques et de la veine cave supérieure (Ao/VCS) et 3) l'ablation du PG de l'oreillette droite (PGOD). Ces procédures de dénervation ont été réalisées suivant une séquence antérograde (n = 17) ou rétrograde (n = 5). Résultats: Chez 17 des 22 animaux, la stimulation des PGOG a induit une bradycardie sinusale (149 ± 34 bpm vs 136 ± 28 bpm, p < 0.002) et des changements de repolarization (ΔREPOL) auriculaires isointégrales. Dans le groupe des ablations antérogrades, les réponses aux stimulations vagales ont été supprimées suite à la décentralisation vagale chez un seul animal, par l'ablation des plexus Ao/VCS dans 4 cas et par l'ablation du PGOG dans 5 autres animaux. Des changements ont persisté tout au long chez 2 chiens. La valeur de surface des ΔREPOL a diminué avec les dénervations séquentielles, passant de 365 ± 252 mm2 en basale à 53 ± 106 mm2 après l'ablation du PGOD (p < 0.03). Dans le groupe de dénervation rétrograde, les changements de repolarisation et chronotropiques ont été supprimés suite à l'ablation du PGOD chez deux chiens et suite à l'ablation Ao/VCS chez trois. La valeur de surface du ΔREPOL a aussi diminué après l'ablation du PGOD (269±144mm2 vs 124±158mm2, p<0.05). Conclusion: Les PGOD sont identifiables en préablation par la réponse bradycardique à la stimulation directe dans la plupart des cas. Le PGOD semble former la principale, mais non la seule, voie de communication avec le nœud sinusal. Ces résultats pourraient avoir des implications dans le traitement de la FA par méthodes ablatives.

Biopacemaker acceleration without increased synchronization by chronic exposure to phorbol myristate acetate

L'activité électrique du coeur est initiée par la génération spontanée de potentiels d'action venant des cellules pacemaker du noeud sinusal (SN). Toute dysfonction au niveau de cette région entraîne une instabilité électrique du coeur. La majorité des patients souffrant d'un noeud sinusal déficient nécessitent l'implantation chirurgicale d'un pacemaker électronique; cependant, les limitations de cette approche incitent à la recherche d'une alternative thérapeutique. La base moléculaire des courants ioniques jouant un rôle crucial dans l'activité du noeud sinusal sont de plus en plus connues. Une composante importante de l'activité des cellules pacemakers semble être le canal HCN, responsable du courant pacemaker If. Le facteur T-box 3 (Tbx3), un facteur de transcription conservé durant le processus de l'évolution, est nécessaire au développement du système de conduction cardiaque. De précédentes études ont démontré que dans différentes lignées cellulaires le Phorbol 12-myristate 13-acetate (PMA) active l'expression du gène codant Tbx3 via des réactions en cascade partant de la protéine kinase C (PKC). L'objectif principal de cette étude est de tester si le PMA peut augmenter la fréquence et la synchronisation de l'activité spontanée du pacemaker biologique en culture. Plus précisément, nous avons étudié les effets de l'exposition chronique au PMA sur l'expression du facteur de transcription Tbx3, sur HCN4 et l'activité spontanée chez des monocouches de culture de myocytes ventriculaires de rats néonataux (MVRN). Nos résultats démontrent que le PMA augmente significativement le facteur transcription de Tbx3 et l'expression ARNm de HCN4, favorisant ainsi l'augmentation du rythme et de la stabilité de l'activité autonome. De plus, une diminution significative de la vitesse de conduction a été relevée et est attribuée à la diminution du couplage intercellulaire. La diminution de la vitesse de conduction pourrait expliquer l'effet négatif du PMA sur la synchronisation de l'activité autonome du pacemaker biologique. Ces résultats ont été confirmés par un modèle mathématique multicellulaire suggérant que des fréquences et résistances intercellulaires plus élevée pourraient induire une activité plus stable et moins synchrone. Cette étude amène de nouvelles connaissances très importantes destinées à la production d'un pacemaker biologique efficient et robuste.

Noções básicas de variabilidade da frequência cardíaca e sua aplicabilidade clínica

O sistema nervoso autônomo (SNA) desempenha um papel importante na regulação dos processos fisiológicos do organismo humano tanto em condições normais quanto patológicas. Dentre as técnicas utilizadas para sua avaliação, a variabilidade da frequência cardíaca (VFC) tem emergido como uma medida simples e não-invasiva dos impulsos autonômicos, representando um dos mais promissores marcadores quantitativos do balanço autonômico. A VFC descreve as oscilações no intervalo entre batimentos cardíacos consecutivos (intervalos R-R), assim como oscilações entre frequências cardíacas instantâneas consecutivas. Trata-se de uma medida que pode ser utilizada para avaliar a modulação do SNA sob condições fisiológicas, tais como em situações de vigília e sono, diferentes posições do corpo, treinamento físico, e também em condições patológicas. Mudanças nos padrões da VFC fornecem um indicador sensível e antecipado de comprometimentos na saúde. Uma alta variabilidade na frequência cardíaca é sinal de boa adaptação, caracterizando um indivíduo saudável, com mecanismos autonômicos eficientes, enquanto que, baixa variabilidade é frequentemente um indicador de adaptação anormal e insuficiente do SNA, implicando a presença de mau funcionamento fisiológico no indivíduo. Diante da sua importância como um marcador que reflete a atividade do SNA sobre o nódulo sinusal e como uma ferramenta clínica para avaliar e identificar comprometimentos na saúde, este artigo revisa aspectos conceituais da VFC, dispositivos de mensuração, métodos de filtragem, índices utilizados para análise da VFC, limitações de utilização e aplicações clínicas da VFC.

Variabilidade da freqüência cardíaca como ferramenta de análise da função autonômica: revisão de literatura e comparação do comportamento autonômico e metabólico em recuperação pós-exercício

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Variabilidade da frequência cardíaca como ferramenta de análise da função autonômica de tabagistas: revisão de literatura e estudo do plot de Poincaré

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Influence of the resistance training on heart rate variability, functional capacity and muscle strength in the chronic obstructive pulmonary disease

Background. The chronic obstructive pulmonary disease (COPD) is associated with the strength and resistance decreasing in addition to the dysfunction on autonomic nervous system (ANS). The aerobic training isolated or in association with the resistance training showed evidence of beneficial effects on an autonomic modulation of COPD; however, there are no studies addressing the effect of isolated resistance training.Aims. This study aims at investigating the influence of resistance training on an autonomic modulation through heart rate variability (HRV), functional capacity and muscle strength in individuals with COPD.Design. Clinical series study.Setting. Outpatients.Population. The study involved 13 individuals with COPD.Methods. The experimental protocol was composed by an initial and final evaluation that consisted in autonomic evaluations (HRV), cardiopulmonary functional capacity evaluation (6-minute walk test) and strength evaluation (dynamometry) in addition by the resistance training performed by 24 sessions lasted 60 minutes each one and on a frequency of three times a week. The intensity was determined initially with 60% of one maximum repetition and was progressively increased in each five sessions until 80%.Results. The HRV temporal and spectral indexes analysis demonstrates improvement of autonomic modulation, with significant statistical increases to sympathetic and parasympathetic components of ANS representing by SDNN, LF and HF. In addition, it was observed significant statistical increases to shoulder abduction and. knee flexion strength and functional capacity.Conclusion. The exclusive resistance training performed was able to positively influence the autonomic modulation; in addition it promoted benefits on cardiorespiratory functional capacity and strength benefits in individuals with COPD.Clinical Rehabilitation Impact. This study could contribute to clinical and professionals researchers that act with COPD, even though the resistance component of pulmonary rehabilitation presents consensual benefits on several healthy indicators parameters. There is no evidence about the effects on HRV before. Moreover, this study showed, on clinical practice, the HRV uses as an ANS activity on sinus node evaluation and highlights further importance on scientific context.

Ivabradine: Just another New Pharmacological Option for Heart Rate Control?

Ivabradine (IVB) is a heart rate lowering agent that acts via selective inhibition of the pacemaker funny current in sinoatrial nodal P cells, thus, reducing heart rate at rest and during exercise with minimal effect on myocardial contractility, blood pressure, and intracardiac conduction. IVB exerts no effect on external respiratory function parameters and it may also play a role in patients with concurrent chronic obstructive pulmonary disease. This property constitutes an important advantage over β-blockers. IVB acts by reducing the heart rate in a mechanism different from β-blockers, calcium channel blockers or late sodium channel blockers, three commonly prescribed antianginal drugs. As clinical trials have shown, it is remarkably well-tolerated and offers an alternative for patients who cannot take β-blockers. The combination of IVB and atenolol at commonly used doses in patients with chronic stable angina produced additional efficacy with no untoward effect on safety or tolerability. Additionally, side effects are rare and largely limited to a luminous phenomenon or phosphenes. This sensation is thought to be due to a block of Ih in the retina, a current very similar to cardiac If channels. IVB is contraindicated in patients with sick sinus syndrome or sinus node dysfunction and in patients taking hepatic inhibitors of Cytochrome P450 family 3, subfamily A, polypeptide 4 (abbreviated CYP3A4), with exception of omeprazole or lansoprazole. This review briefly summarizes the main studies regarding this drug.

Respostas da frequência cardíaca ao teste de 1RM e da modulação autonômica da frequência cardíaca no período de recuperação em indivíduos com fatores de risco para doenças cardiovasculares

Pós-graduação em Desenvolvimento Humano e Tecnologias - IBRC

Behandlung bradykarder Rhythmusstörungen – wer benötigt einen Herzschrittmacher?

Bradyarrhythmias are caused by a disturbed impulse formation in the sinus node and/or a disturbed impulse conduction and can be subclassified clinically as sinus node dysfunction, atrioventricular (AV) block, or functional bradycardia. Persistent bradycardia can be diagnosed by standard ECG. For diagnosis of intermittent bradycardia, often long-term ECG monitoring and/or additional testing is necessary. Symptomatic bradycardias are the standard indication for cardiac pacing after exclusion of reversible causes. Since sinus node dysfunction is associated with a good prognosis, pacing in this condition is only indicated in the presence of bradycardia-related symptoms. For prognostic reasons, pacemaker implantation is indicated in third degree AV block and second degree AV block Mobitz Type II, even if asymptomatic. Cardiac pacing for recurrent unpredictable neurocardiogenic syncope due to a cardioinhibitory reflex should be considered in certain circumstances. The implantation of cardiac pacemakers has been performed for more than half of a century. Due to the enormous technological progress, pacemaker implantations can nowadays be performed under local anesthesia in an outpatient setting. However, complications of pacemaker therapy are still not uncommon.

Biopacemaker acceleration without increased synchronization by chronic exposure to phorbol myristate acetate

L'activité électrique du coeur est initiée par la génération spontanée de potentiels d'action venant des cellules pacemaker du noeud sinusal (SN). Toute dysfonction au niveau de cette région entraîne une instabilité électrique du coeur. La majorité des patients souffrant d'un noeud sinusal déficient nécessitent l'implantation chirurgicale d'un pacemaker électronique; cependant, les limitations de cette approche incitent à la recherche d'une alternative thérapeutique. La base moléculaire des courants ioniques jouant un rôle crucial dans l'activité du noeud sinusal sont de plus en plus connues. Une composante importante de l'activité des cellules pacemakers semble être le canal HCN, responsable du courant pacemaker If. Le facteur T-box 3 (Tbx3), un facteur de transcription conservé durant le processus de l'évolution, est nécessaire au développement du système de conduction cardiaque. De précédentes études ont démontré que dans différentes lignées cellulaires le Phorbol 12-myristate 13-acetate (PMA) active l'expression du gène codant Tbx3 via des réactions en cascade partant de la protéine kinase C (PKC). L'objectif principal de cette étude est de tester si le PMA peut augmenter la fréquence et la synchronisation de l'activité spontanée du pacemaker biologique en culture. Plus précisément, nous avons étudié les effets de l'exposition chronique au PMA sur l'expression du facteur de transcription Tbx3, sur HCN4 et l'activité spontanée chez des monocouches de culture de myocytes ventriculaires de rats néonataux (MVRN). Nos résultats démontrent que le PMA augmente significativement le facteur transcription de Tbx3 et l'expression ARNm de HCN4, favorisant ainsi l'augmentation du rythme et de la stabilité de l'activité autonome. De plus, une diminution significative de la vitesse de conduction a été relevée et est attribuée à la diminution du couplage intercellulaire. La diminution de la vitesse de conduction pourrait expliquer l'effet négatif du PMA sur la synchronisation de l'activité autonome du pacemaker biologique. Ces résultats ont été confirmés par un modèle mathématique multicellulaire suggérant que des fréquences et résistances intercellulaires plus élevée pourraient induire une activité plus stable et moins synchrone. Cette étude amène de nouvelles connaissances très importantes destinées à la production d'un pacemaker biologique efficient et robuste.

Developmental changes in expression of GABA(A) receptor-channels in rat intrinsic cardiac ganglion neurones

The effects of gamma-aminobutyric acid (GABA) on the electrophysiological properties of intracardiac neurones were investigated in the intracardiac ganglion plexus in situ and in dissociated neurones from neonatal, juvenile and adult rat hearts. Focal application of GABA evoked a depolarizing, excitatory response in both intact and dissociated intracardiac ganglion neurones. Under voltage clamp, both GABA and muscimol elicited inward currents at -60 mV in a concentration-dependent manner. The fast, desensitizing currents were mimicked by the GABA(A) receptor agonists muscimol and taurine, and inhibited by the GABA(A) receptor antagonists, bicuculline and picrotoxin. The GABA(A0) antagonist (1,2,5,6-tetrahydropyridin-4-yl)methyl phosphonic acid (TPMPA), had no effect on GABA-induced currents, suggesting that GABA(A) receptor-channels mediate the response. The GABA-evoked current amplitude recorded from dissociated neurones was age dependent whereby the peak current density measured at -100 mV was similar to 20 times higher for intracardiac neurones obtained from neonatal rats (P2-5) compared with adult rats (P45-49). The decrease in GABA sensitivity occurred during the first two postnatal weeks and coincides with maturation of the sympathetic innervation of the rat heart. Immunohistochemical staining using antibodies against GABA demonstrate the presence of GABA in the intracardiac ganglion plexus of the neonatal rat heart. Taken together, these results suggest that GABA and taurine may act as modulators of neurotransmission and cardiac function in the developing mammalian intrinsic cardiac nervous system.