RESUMO
BACKGROUND: Postprocedural atrial extrasystole (AES) frequency predicts atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI) in patients with paroxysmal AF. However, the predictive value of preprocedural AES frequency is unknown. We investigate whether preprocedural AES frequency is a feasible marker to predict (timing of) AF recurrence after PVI. METHODS: Patients (N = 684) with paroxysmal or persistent AF undergoing first-time PVI were evaluated for (a) the frequency of AES/day on Holter recordings without AF prior to PVI, (b) AF episodes during the 90 days blanking period, and (c) AF recurrences afterward. The correlation between AES/day and both development and timing of AF recurrences was tested. RESULTS: Preprocedural AES/day was similar in patients with paroxysmal (66 [20-295] AES/day) and persistent AF (115 [12-248] AES/day, P = .915). During the blanking period, 302 (44.2%) patients showed AF episodes. AF recurred in 379 (55.4%) patients at 203 (105-400) days after PVI. AF recurred more frequently in patients with persistent (N = 104 [69.3%]) than in patients with paroxysmal AF (N = 275 [51.5%], P < .001). Frequency of AES prior to PVI was not correlated with development (P = .203) or timing (P = .478) of AF recurrences. AF recurrences occurred both more frequently (P < .001) and earlier (P < .000) in patients with AF during the blanking period. CONCLUSION: AES/day prior to PVI is not correlated with (timing of) AF during the blanking period or AF recurrences, and is therefore not a feasible marker for AF recurrences in patients with PAF. AF during the blanking period is correlated with AF recurrence.
RESUMO
AIMS: Studies in animals and patients indicate that rapamycin affects vasodilatation differently in outer and inner curvatures of blood vessels. We evaluated in this study whether rapamycin affects endothelial nitric oxide synthase (eNOS) responsiveness to shear stress under normo- and hypercholesteraemic conditions to explain these findings. METHODS AND RESULTS: Shear stress levels were varied over a large range of values in carotid arteries of transgenic mice expressing human eNOS fused to enhanced green fluorescence protein. The mice were divided into control, low-dose rapamycin (3 microg/kg/day), and high-dose rapamycin (3 mg/kg/day) groups and into normocholesteraemic and hypercholesteraemic (ApoE-/- on high cholesterol diet for 3-4 weeks) groups. The effect of rapamycin treatment on eNOS was evaluated by quantification of eNOS expression and of intracellular protein levels by en face confocal microscopy. A sigmoid curve fit was used to described these data. The efficacy of treatment was confirmed by measurement of rapamycin serum levels (2.0 +/- 0.5 ng/mL), and of p27kip1 expression in vascular tissue (increased by 2.4 +/- 0.5-fold). In control carotid arteries, eNOS expression increased by 1.8 +/- 0.3-fold in response to rapamycin. In the treated vessels, rapamycin reduced maximal eNOS expression at high shear stress levels (>5 Pa) in a dose-dependent way and shifted the sigmoid curve to the right. Hypercholesteraemia had a tendency to increase the leftward shift and the reduction in maximal eNOS expression (P = 0.07). CONCLUSION: Rapamycin is associated with high eNOS in low shear regions, i.e. in atherogenic regions, protecting these regions against atherosclerosis, and is associated with a reduction of eNOS at high shear stress affecting vasomotion in these regions.
Assuntos
Fármacos Cardiovasculares/farmacologia , Artérias Carótidas/efeitos dos fármacos , Doenças das Artérias Carótidas/prevenção & controle , Endotélio Vascular/efeitos dos fármacos , Hipercolesterolemia/tratamento farmacológico , Óxido Nítrico Sintase Tipo III/metabolismo , Sirolimo/farmacologia , Animais , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Fármacos Cardiovasculares/sangue , Artérias Carótidas/enzimologia , Artérias Carótidas/fisiopatologia , Doenças das Artérias Carótidas/enzimologia , Doenças das Artérias Carótidas/etiologia , Doenças das Artérias Carótidas/fisiopatologia , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Endotélio Vascular/enzimologia , Endotélio Vascular/fisiopatologia , Feminino , Proteínas de Fluorescência Verde/metabolismo , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/enzimologia , Hipercolesterolemia/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microscopia Confocal , Óxido Nítrico Sintase Tipo III/genética , Fluxo Pulsátil , Proteínas Recombinantes de Fusão/metabolismo , Sirolimo/sangue , Estresse MecânicoRESUMO
OBJECTIVE: Severe congestive heart failure is associated with autonomic imbalance consisting of an increased sympathetic and decreased parasympathetic activity. In the present study, we investigated the influence of alterations in autonomic balance on cardiovascular function in 11 swine with left ventricular (LV) dysfunction produced by a 2- to 3-week-old myocardial infarction (MI). METHODS: Swine underwent permanent occlusion of the left circumflex coronary artery resulting in MI of the lateral LV wall. Autonomic activity was studied 2-3 weeks later using blockers of muscarinic (atropine), alpha-adrenergic (phentolamine) and beta-adrenergic (propranolol) receptors. RESULTS: Under resting conditions, parasympathetic and sympathetic control of the heart and coronary circulation were similar in MI and normal swine. In contrast, during exercise of MI compared to normal swine, (i) there was a more pronounced gradual inhibition of parasympathetic control of heart rate with increasing exercise intensity; (ii) circulating catecholamines increased excessively, resulting in an increased beta-adrenergic influence on heart rate, while (iii) the beta-adrenergic influence on global left ventricular contractility was decreased, reflecting a blunted left ventricular beta-adrenergic responsiveness. Furthermore, (iv) an alpha-adrenergic vasoconstrictor influence was absent in the anterior LV wall of both MI and normal swine, while (v) the beta-adrenergic vasodilator influence in the coronary circulation was not different between normal and MI swine, which, in conjunction with the elevated catecholamine levels during exercise, suggests a diminished beta-adrenergic responsiveness of coronary resistance vessels within remote non-infarcted myocardium in MI swine. CONCLUSIONS: Swine with a recent MI display autonomic dysfunction, which is characterized by a more pronounced inhibition of parasympathetic influence and an exaggerated increase in sympathetic drive during exercise, as well as reduced myocardial and coronary vascular beta-adrenergic responsiveness.
Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Animais , Atropina/farmacologia , Circulação Coronária/efeitos dos fármacos , Modelos Animais de Doenças , Teste de Esforço/métodos , Feminino , Hemodinâmica/efeitos dos fármacos , Masculino , Infarto do Miocárdio/complicações , Consumo de Oxigênio/efeitos dos fármacos , Propranolol/farmacologia , Receptores Adrenérgicos beta/fisiologia , Receptores Muscarínicos/fisiologia , Suínos , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
The renin-angiotensin system plays an important role in cardiovascular homeostasis by contributing to the regulation of blood volume, blood pressure, and vascular tone. Because AT(1) receptors have been described in the coronary microcirculation, we investigated whether ANG II contributes to the regulation of coronary vascular tone and whether its contribution is altered during exercise. Since the renin-angiotensin system is activated after myocardial infarction, resulting in an increase in circulating ANG II, we also investigated whether the contribution of ANG II to the regulation of vasomotor tone is altered after infarction. Twenty-six chronically instrumented swine were studied at rest and while running on a treadmill at 1-4 km/h. In 13 swine, myocardial infarction was induced by ligation of the left circumflex coronary artery. Blockade of AT(1) receptors (irbesartan, 1 mg/kg iv) had no effect on myocardial O(2) consumption but resulted in an increase in coronary venous O(2) tension and saturation both at rest and during exercise, reflecting coronary vasodilation. Despite increased plasma levels of ANG II after infarction and maintained coronary arteriolar AT(1) receptor levels, the vasodilation evoked by irbesartan was significantly reduced both at rest and during exercise. In conclusion, despite elevated plasma levels, the vasoconstrictor influence of ANG II on the coronary circulation in vivo is reduced after myocardial infarction. This reduction in ANG II-induced coronary vasoconstriction may serve to maintain perfusion of the remodeled myocardium.
Assuntos
Angiotensina II/farmacologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Vasoconstritores/farmacologia , Angiotensina II/sangue , Bloqueadores do Receptor Tipo 1 de Angiotensina II/metabolismo , Animais , Compostos de Bifenilo/farmacologia , Peso Corporal , Circulação Coronária/fisiologia , Teste de Esforço , Feminino , Irbesartana , Masculino , Infarto do Miocárdio/etiologia , Norepinefrina/sangue , Tamanho do Órgão , Oxigênio/metabolismo , Condicionamento Físico Animal , Sus scrofa , Tetrazóis/farmacologia , Fatores de Tempo , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologia , Sistema Vasomotor/efeitos dos fármacos , Sistema Vasomotor/fisiologiaRESUMO
Left ventricular (LV) dysfunction caused by myocardial infarction (MI) is accompanied by endothelial dysfunction, most notably a loss of nitric oxide (NO) availability. We tested the hypothesis that endothelial dysfunction contributes to impaired tissue perfusion during increased metabolic demands as produced by exercise, and we determined the contribution of NO to regulation of regional systemic, pulmonary, and coronary vasomotor tone in exercising swine with LV dysfunction produced by a 2- to 3-wk-old MI. LV dysfunction resulted in blunted systemic and coronary vasodilator responses to ATP, whereas the responses to nitroprusside were maintained. Exercise resulted in blunted systemic and pulmonary vasodilator responses in MI that resembled the vasodilator responses in normal (N) swine following blockade of NO synthase with N(omega)-nitro-L-arginine (L-NNA, 20 mg/kg iv). However, L-NNA resulted in similar decreases in systemic (43 +/- 3% in N swine and 49 +/- 4% in MI swine), pulmonary (45 +/- 5% in N swine and 49 +/- 4% in MI swine), and coronary (28 +/- 4% in N and 35 +/- 3% in MI) vascular conductances in N and MI swine under resting conditions; similar effects were observed during treadmill exercise. Selective inhibition of inducible NO synthase with aminoguanidine (20 mg/kg iv) had no effect on vascular tone in MI. These findings indicate that while agonist-induced vasodilation is already blunted early after myocardial infarction, the contribution of endothelial NO synthase-derived NO to regulation of vascular tone under basal conditions and during exercise is maintained.
Assuntos
Óxido Nítrico/biossíntese , Esforço Físico/fisiologia , Disfunção Ventricular Esquerda/fisiopatologia , Trifosfato de Adenosina/farmacologia , Animais , Circulação Coronária/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Inibidores Enzimáticos/farmacologia , Guanidinas/farmacologia , Pulmão/irrigação sanguínea , Infarto do Miocárdio/complicações , Infarto do Miocárdio/fisiopatologia , Óxido Nítrico/fisiologia , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II , Nitroarginina/farmacologia , Nitroprussiato/farmacologia , Reprodutibilidade dos Testes , Suínos , Vasodilatação/efeitos dos fármacos , Disfunção Ventricular Esquerda/etiologiaRESUMO
In dogs, only combined blockade of vasodilator pathways [via adenosine receptors, nitric oxide synthase (NOS) and ATP-sensitive K+ (KATP) channels] results in impairment of metabolic vasodilation, which suggests a redundancy design of coronary flow regulation. Conversely, in swine and humans, blocking KATP channels, adenosine receptors, or NOS each impairs coronary blood flow (CBF) at rest and during exercise. Consequently, we hypothesized that these vasodilators act in parallel rather than in redundancy to regulate CBF in swine. Swine exercised on a treadmill (0-5 km/h), during control and after blockade of KATP channels (with glibenclamide), adenosine receptors [with 8-phenyltheophylline (8-PT)], and/or NOS [with Nomega-nitro-l-arginine (l-NNA)]. l-NNA, 8-PT, and glibenclamide each reduced myocardial O2 delivery and coronary venous O2 tension. These effects of l-NNA, 8-PT, and glibenclamide were not modified by simultaneous blockade of the other vasodilators. Combined blockade of KATP channels and adenosine receptors with or without NOS inhibition was associated with increased H+ production and impaired myocardial function. However, despite an increase in O2 extraction to >90% during administration of l-NNA + 8-PT + glibenclamide, vasodilator reserve could still be recruited during exercise. Thus in awake swine, loss of KATP channels, adenosine, or NO is not compensated for by increased participation of the other two vasodilator mechanisms. These findings suggest a parallel rather than a redundancy design of CBF regulation in the porcine circulation.