RESUMO
AIMS: Aircraft noise disturbs sleep, and long-term exposure has been shown to be associated with increases in the prevalence of hypertension and an overall increased risk for myocardial infarction. The exact mechanisms responsible for these cardiovascular effects remain unclear. METHODS AND RESULTS: We performed a blinded field study in 75 healthy volunteers (mean age 26 years), who were exposed at home, in random order, to one control pattern (no noise) and two different noise scenarios [30 or 60 aircraft noise events per night with an average maximum sound pressure level (SPL) of 60 dB(A)] for one night each. We performed polygraphy during each study night. Noise caused a worsening in sleep quality (P < 0.0001). Noise60, corresponding to equivalent continuous SPLs of 46.3 dB (Leq) and representing environmental noise levels associated with increased cardiovascular events, caused a blunting in FMD (P = 0.016). As well, although a direct comparison among the FMD values in the noise groups (control: 10.4 ± 3.8%; Noise30: 9.7 ± 4.1%; Noise60: 9.5 ± 4.3%, P = 0.052) did not reach significance, a monotone dose-dependent effect of noise level on FMD was shown (P = 0.020). Finally, there was a priming effect of noise, i.e. the blunting in FMD was particularly evident when subjects were exposed first to 30 and then to 60 noise events (P = 0.006). Noise-induced endothelial dysfunction (ED) was reversed by the administration of Vitamin C (P = 0.0171). Morning adrenaline concentration increased from 28.3 ± 10.9 to 33.2 ± 16.6 and 34.1 ± 19.3 ng/L (P = 0.0099). Pulse transit time, reflecting arterial stiffness, was also shorter after exposure to noise (P = 0.003). CONCLUSION: In healthy adults, acute nighttime aircraft noise exposure dose-dependently impairs endothelial function and stimulates adrenaline release. Noise-induced ED may be in part due to increased production in reactive oxygen species and may thus be one mechanism contributing to the observed association of chronic noise exposure with cardiovascular disease.
Assuntos
Aeronaves , Endotélio Vascular/fisiologia , Exposição Ambiental , Epinefrina/metabolismo , Ruído dos Transportes , Adulto , Feminino , Voluntários Saudáveis , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Sono/fisiologia , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: Cardiac troponin testing is central to the diagnosis of acute myocardial infarction. We evaluated a sensitive troponin I assay for the early diagnosis and risk stratification of myocardial infarction. METHODS: In a multicenter study, we determined levels of troponin I as assessed by a sensitive assay, troponin T, and traditional myocardial necrosis markers in 1818 consecutive patients with suspected acute myocardial infarction, on admission and 3 hours and 6 hours after admission. RESULTS: For samples obtained on admission, the diagnostic accuracy was highest with the sensitive troponin I assay (area under the receiver-operating-characteristic curve [AUC], 0.96), as compared with the troponin T assay (AUC, 0.85) and traditional myocardial necrosis markers. With the use of the sensitive troponin I assay (cutoff value, 0.04 ng per milliliter) on admission, the clinical sensitivity was 90.7%, and the specificity was 90.2%. The diagnostic accuracy was virtually identical in baseline and serial samples, regardless of the time of chest-pain onset. In patients presenting within 3 hours after chest-pain onset, a single sensitive troponin I assay had a negative predictive value of 84.1% and a positive predictive value of 86.7%; these findings predicted a 30% rise in the troponin I level within 6 hours. A troponin I level of more than 0.04 ng per milliliter was independently associated with an increased risk of an adverse outcome at 30 days (hazard ratio, 1.96; 95% confidence interval, 1.27 to 3.05; P=0.003). CONCLUSIONS: The use of a sensitive assay for troponin I improves early diagnosis of acute myocardial infarction and risk stratification, regardless of the time of chest-pain onset.
Assuntos
Infarto do Miocárdio/diagnóstico , Troponina I/sangue , Idoso , Angina Instável/sangue , Angina Instável/diagnóstico , Área Sob a Curva , Biomarcadores/sangue , Dor no Peito/etiologia , Comorbidade , Diagnóstico Precoce , Eletrocardiografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Valor Preditivo dos Testes , Curva ROC , Sensibilidade e Especificidade , Troponina T/sangueRESUMO
A 37-year old male patient presented with frequent angina attacks (up to 40/day) largely resistant to classical vasodilator therapy. The patient showed severe coronary and peripheral endothelial dysfunction, increased platelet aggregation and increased platelet-derived superoxide production. The endothelial nitric oxide synthase (eNOS)-inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) reduced superoxide formation in platelets identifying "uncoupled" eNOS as a superoxide source. Oral L-arginine normalized coronary and peripheral endothelial dysfunction and reduced platelet aggregation and eNOS-derived superoxide production. Plasma concentrations of the endogenous NOS inhibitor asymmetric dimethyl-L-arginine (ADMA), representing an independent risk factor for cardiovascular disease, were normal in the patient. However, immediately after oral administration of cationic amino acid (CAA), plasma ADMA levels rose markedly, demonstrating increased ADMA efflux from intracellular stores. ADMA efflux from mononuclear cells of the patient was accelerated by CAA, but not neutral amino acids (NAA) demonstrating impairment of y(+)LAT (whose expression was found reduced in these cells). These data suggest that impairment of y(+)LAT may cause intracellular (endothelial) ADMA accumulation leading to systemic endothelial dysfunction. This may represent a novel mechanism underlying vasospastic angina and vascular dysfunction in general. Moreover, these new findings contribute to the understanding of the l-arginine paradox, the improvement of eNOS activity by oral L-arginine despite sufficient cellular l-arginine levels to ensure proper function of this enzyme.
Assuntos
Angina Pectoris/metabolismo , Arginina/análogos & derivados , Vasoespasmo Coronário/metabolismo , Endotélio Vascular/enzimologia , Óxido Nítrico Sintase Tipo III/metabolismo , Adulto , Angina Pectoris/sangue , Angina Pectoris/tratamento farmacológico , Arginina/administração & dosagem , Arginina/sangue , Arginina/metabolismo , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Vasoespasmo Coronário/sangue , Vasoespasmo Coronário/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Humanos , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo III/antagonistas & inibidores , Superóxidos/metabolismoRESUMO
CONTEXT: Introduction of highly sensitive troponin assays into clinical practice has substantially improved the evaluation of patients with chest pain. OBJECTIVE: To evaluate the diagnostic performance of a highly sensitive troponin I (hsTnI) assay compared with a contemporary troponin I (cTnI) assay and their serial changes in the diagnosis of acute myocardial infarction (AMI). DESIGN, SETTING, AND PATIENTS: A total of 1818 patients with suspected acute coronary syndrome were consecutively enrolled at the chest pain units of the University Heart Center Hamburg, the University Medical Center Mainz, and the Federal Armed Forces Hospital Koblenz, all in Germany, from 2007 to 2008. Twelve biomarkers including hsTnI (level of detection, 3.4 pg/mL) and cTnI (level of detection, 10 pg/mL) were measured on admission and after 3 and 6 hours. MAIN OUTCOME MEASURES: Diagnostic performance for AMI of baseline and serial changes in hsTnI and cTnI results at 3 hours after admission to the emergency department. RESULTS: Of the 1818 patients, 413 (22.7%) were diagnosed as having AMI. For discrimination of AMI, the area under the receiver operating characteristic (ROC) curve was 0.96 (95% CI, 0.95-0.97) for hsTnI on admission and 0.92 (95% CI, 0.90-0.94) for cTnI on admission. Both were superior to the other evaluated diagnostic biomarkers. The use of hsTnI at admission (with the diagnostic cutoff value at the 99th percentile of 30 pg/mL) had a sensitivity of 82.3% and a negative predictive value (for ruling out AMI) of 94.7%. The use of cTnI (with the diagnostic cutoff value at the 99th percentile of 32 pg/mL) at admission had a sensitivity of 79.4% and a negative predictive value of 94.0%. Using levels obtained at 3 hours after admission, the sensitivity was 98.2% and the negative predictive value was 99.4% for both hsTnI and cTnI assays. Combining the 99th percentile cutoff at admission with the serial change in troponin concentration within 3 hours, the positive predictive value (for ruling in AMI) for hsTnI increased from 75.1% at admission to 95.8% after 3 hours, and for cTnI increased from 80.9% at admission to 96.1% after 3 hours. CONCLUSIONS: Among patients with suspected acute coronary syndrome, hsTnI or cTnI determination 3 hours after admission may facilitate early rule-out of AMI. A serial change in hsTnI or cTnI levels from admission (using the 99th percentile diagnostic cutoff value) to 3 hours after admission may facilitate an early diagnosis of AMI.
Assuntos
Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico , Biomarcadores/sangue , Infarto do Miocárdio/sangue , Infarto do Miocárdio/diagnóstico , Troponina I/sangue , Idoso , Bioensaio , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Valores de Referência , Sensibilidade e Especificidade , Fatores de TempoRESUMO
Recent animal data suggest that reduced lipoic acid (LA) prevents oxidative inhibition of the nitrate bioactivating enzyme, the mitochondrial aldehyde dehydrogenase (ALDH-2), and that pentaerythritol tetranitrate (PETN) does not induce nitrate tolerance because of its intrinsic antioxidative properties, thereby preserving ALDH-2 activity. We sought to determine whether ALDH-2 activity in circulating white blood cells (WBCs) can be used to monitor nitrate tolerance and whether LA can prevent nitroglycerin tachyphylaxis in humans. Eight healthy male volunteers received, in randomized order, a single dose of glyceryl trinitrate (GTN; 0.8 mg), PETN (80 mg), or GTN plus LA (600 mg) orally. GTN (30 min) and PETN (120 min) administration lead to a comparable dilation of the brachial artery (15 +/- 1%). In contrast to PETN, acute GTN treatment resulted in a 60% decrease in WBC ALDH-2 activity (high-performance liquid chromatography), 30% reduction of nitrate bioactivation, and 25% decrease in serum antioxidant capacity (fluorescence assay), which all were prevented by pretreatment with LA. Mechanistic studies in rats identified oxidative stress, ALDH-2 inactivation, and vascular dysfunction as common features in acute and chronic nitrate tolerance. Treatment with GTN, but not PETN, acutely inhibits ALDH-2 activity and nitrate bioactivation in healthy volunteers. These effects were prevented by LA pretreatment, emphasizing the role of oxidative stress-triggered ALDH-2 dysfunction. Assessment of WBC ALDH-2 activity could be used as an easily accessible marker for the detection of nitroglycerin-induced tachyphylaxis in humans and may be of high clinical interest because recent data suggest that ALDH-2 activity correlates with protection from ischemic heart damage in infarct models.
Assuntos
Aldeído Desidrogenase/metabolismo , Leucócitos/enzimologia , Mitocôndrias Cardíacas/enzimologia , Nitratos/uso terapêutico , Aldeído Desidrogenase/antagonistas & inibidores , Animais , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Humanos , Leucócitos/efeitos dos fármacos , Masculino , Mitocôndrias Cardíacas/efeitos dos fármacos , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/enzimologia , Nitratos/farmacologia , Ratos , Ratos Wistar , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
Antiplatelet therapy with clopidogrel has been shown to reduce major adverse cardiac events in acute coronary syndromes and after percutaneous interventions. This effect is not only due to its anti-platelet effect but also possibly due to an anti-inflammatory effect. The effect of clopidogrel cessation after one year of therapy on markers of inflammation has been investigated in diabetics and showed an increase in platelet aggregation as well as hsCRP and surface P-selectin levels. This was an exploratory multicenter prospective open-label single arm study of 98 non-diabetic patients who had received one or more drug eluting stents and were coming to the end of their 12 months course of clopidogrel therapy. The effect of clopidogrel cessation on expression of biomarkers: sCD40L, soluble P-selectin and hsCRP was measured right before clopidogrel cessation (day 0), and subsequently at 1, 2, 3 and 4 weeks after drug withdrawal. A median increase in sCD40L expression from 224 to 324.5 pg/ml was observed between baseline and 4 weeks after clopidogrel cessation, which corresponded to a 39% mean percent change based on an ANCOVA model (P < 0.001). Over the 4 weeks observation period the change in sCD40L expression correlated weakly with soluble P-selectin levels (at 4 weeks Spearman's correlation coefficient = 0.32; P = 0.0024). Increase in P-selectin expression from baseline was statistically significant at week 1 and 2. Conversely, hsCRP level decreased by 21% at 1 week (P = 0.008) and was still reduced by 18% by 4 weeks (P = 0.062). The change in sCD40L expression appeared to vary with the type of drug eluting stent. Patients treated with drug eluting stents at 1 year after implantation display significant increase in sCD40L and decrease in hsCRP after clopidogrel cessation. Further studies should elucidate if this increase in sCD40L levels reflects solely the removal of the inhibitory effects of clopidogrel on platelet activity or rather an increase in pro-inflammatory state. The latter hypothesis may be less likely given decrease in hsCRP levels. Randomized studies are urgently needed to establish potential link of clopidogrel discontinuation and vascular outcomes.
Assuntos
Proteína C-Reativa/biossíntese , Ligante de CD40/sangue , Stents Farmacológicos , Selectina-P/sangue , Ticlopidina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Ligante de CD40/biossíntese , Clopidogrel , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Selectina-P/biossíntese , Ticlopidina/administração & dosagem , Fatores de TempoRESUMO
Cyclooxygenase 2-selective inhibitors (coxibs) and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increase in cardiovascular events. The current study was designed to test the effect of coxibs and nonselective NSAIDs on vascular superoxide and nitric oxide (NO) production. mRNA expression of endothelial NO synthase (eNOS) and of the vascular NADPH oxidases was studied in spontaneously hypertensive rats (SHR) and in human endothelial cells. The expression of Nox1, Nox2, Nox4, and p22phox was increased markedly by the nonselective NSAIDs diclofenac or naproxen and moderately by rofecoxib or celecoxib in the aorta and heart of SHR. The up-regulation of NADPH oxidases by NSAIDs was associated with increased superoxide content in aorta and heart, which could be prevented by the NADPH oxidase inhibitor apocynin. NSAIDs reduced plasma nitrite and diminished the phosphorylation of vasodilator-stimulated phosphoprotein. This demonstrates a reduction in vascular NO production. Aortas from diclofenac-treated SHR showed an enhanced protein nitrotyrosine accumulation, indicative of vascular peroxynitrite formation. Peroxynitrite can uncouple oxygen reduction from NO synthesis in eNOS. Accordingly, the eNOS inhibitor N(G)-nitro-L-arginine methyl ester reduced superoxide content in aortas of NSAID-treated animals, demonstrating eNOS uncoupling under those conditions. Also in human endothelial cells, NSAIDs increased Nox2 expression and diminished production of bioactive NO. In healthy volunteers, NSAID treatment reduced nitroglycerin-induced, NO-mediated vasodilatation of the brachial artery. These results indicate that NSAIDs may increase cardiovascular risk by inducing oxidative stress in the vasculature, with nonselective NSAIDs being even more critical than coxibs in this respect.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Inibidores de Ciclo-Oxigenase 2/farmacologia , Endotélio Vascular/enzimologia , NADPH Oxidases/biossíntese , Estresse Oxidativo/fisiologia , Regulação para Cima/fisiologia , Adulto , Animais , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Endotélio Vascular/efeitos dos fármacos , Feminino , Humanos , Masculino , NADPH Oxidases/genética , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Regulação para Cima/efeitos dos fármacosRESUMO
OBJECTIVE: Nitric oxide (NO)-induced vasorelaxation involves activation of large conductance Ca2+-activated K+ channels (BK). A regulatory BKbeta1 subunit confers Ca2+, voltage, and NO/cGMP sensitivity to the BK channel. We investigated whether endothelial function and NO/cGMP signaling is affected by a deletion of the beta1-subunit. METHODS AND RESULTS: Vascular superoxide in BKbeta1-/- was measured using the fluorescent dye hydroethidine and lucigenin-enhanced chemiluminescence. Vascular NO formation was analyzed using electron paramagnetic resonance (EPR), expression of NADPH oxidase subunits, the endothelial NO synthase (eNOS), the soluble guanylyl cyclase (sGC), as well as the activity and expression of the cyclic GMP-dependent kinase I (cGK-I) were assessed by Western blotting technique. eNOS, sGC, cGK-I expression and acetylcholine-induced NO production were unaltered in Bkbeta1-/- animals, whereas endothelial function was impaired and the activity of the cGK-I was reduced. Vascular O2- and expression of the NADPH oxidase subunits p67phox and Nox1 were increased. Endothelial dysfunction was normalized by the NADPH oxidase inhibitor apocynin. Potassium chloride- and iberiotoxin-induced depolarization mimicked the effect of BKbeta1-deletion by increasing vascular O2- in an NADPH-dependent fashion. CONCLUSIONS: The deletion of BKbeta1 causes endothelial dysfunction by increasing O2- formation via increasing activity and expression of the vascular NADPH oxidase.
Assuntos
Endotélio Vascular/fisiopatologia , Canais de Potássio Ativados por Cálcio de Condutância Alta/deficiência , Músculo Liso Vascular/fisiopatologia , NADPH Oxidases/metabolismo , Superóxidos/metabolismo , Vasodilatação , Animais , Aorta Torácica/fisiopatologia , Moléculas de Adesão Celular/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Guanilato Ciclase/metabolismo , Humanos , Camundongos , Camundongos Knockout , Proteínas dos Microfilamentos/metabolismo , NADH NADPH Oxirredutases/metabolismo , NADPH Oxidase 1 , Óxido Nítrico/biossíntese , Óxido Nítrico/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Fosfoproteínas/metabolismo , Isoformas de Proteínas/deficiência , Transdução de SinaisRESUMO
BACKGROUND: The determination of cardiac troponin is essential for diagnosing myocardial infarction. A troponin I assay has recently been developed that provides the highest analytical sensitivity to date. METHODS: The analysis included 1560 patients with chest pain, of whom 1098 were diagnosed with non-coronary chest pain, 189 with unstable angina pectoris and 273 with non-ST-segment elevation myocardial infarction. The troponin I concentration was determined on admission (0 hours) and 3 hours later. The diagnostic algorithm incorporated troponin I elevation above the gender-specific 99th percentile as well as predefined relative or absolute 3-hour changes in the troponin I concentration (delta). RESULTS: The diagnostic criterion of troponin I above the 99th percentile resulted in a negative predictive value of 98.0% and 98.2% in men and women, respectively. For rule-in of non-ST-segment elevation myocardial infarction, the use of absolute deltas yielded higher positive predictive values and sensitivities compared to relative deltas. With detection rates of about 85% and 82% in men and women, respectively, non-ST-segment elevation myocardial infarction was diagnosed with a positive predictive value close to 84% in men and 80% in women. CONCLUSIONS: The investigational troponin I assay provides an excellent non-ST-segment elevation myocardial infarction rule out. With gender-specific differences, the application of absolute changes in troponin concentration was superior to relative changes to rule in patients with non-ST-segment elevation myocardial infarction.
Assuntos
Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio sem Supradesnível do Segmento ST/diagnóstico , Troponina I/metabolismo , Idoso , Algoritmos , Biomarcadores/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/metabolismo , Valor Preditivo dos Testes , Caracteres SexuaisRESUMO
Coronary endothelial dysfunction is a powerful prognostic marker in patients with coronary artery disease (CAD) that is centrally related to oxidative inhibition of nitric oxide (NO)-dependent vascular cell signaling. Xanthine oxidase (XO), which both binds to and is expressed by endothelial cells, generates superoxide and hydrogen peroxide upon oxidation of purines. Whether inhibition of xanthine oxidase activity results in improved coronary vasomotor function in patients with CAD, however, remains unknown. We assessed coronary and peripheral (brachial artery) endothelial function in 18 patients (pts; 65+/-8 years, 86% male) with angiographically documented CAD, preserved left ventricular function, and non-elevated uric acid levels (233+/-10 microM). Patients received incremental doses of intracoronary acetylcholine (ACh; 10(-7) to 10(-5) microM), and minimal lumen diameter (MLD) and coronary blood flow (CBF) were assessed before and after intravenous administration of oxypurinol (200 mg). Oxypurinol inhibited plasma XO activity 63% (0.051+/- 0.001 vs 0.019+/- 0.005 microU/mg protein; p<0.01). In pts who displayed endothelial dysfunction as evidenced by coronary vasoconstriction in response to ACh (n=13), oxypurinol markedly attenuated ACh-induced vasoconstriction (-23+/- 4 vs -15+/- 4% at ACh 10(-5) microM, p<0.05) and significantly increased CBF (16+/-17 vs 62+/-18% at ACh 10(-5) microM, p<0.05), whereas in patients with preserved coronary endothelial function, oxypurinol had no effect on ACh-dependent changes in MLD (+2.8+/- 4.2 vs 5.2+/- 0.7%, p>0.05) or CBF (135+/-75 vs 154+/-61%, p>0.05). Flow-mediated dilation of the brachial artery, assessed in eight consecutive patients, increased from 5.1+/-1.5 before to 7.6+/-1.5% after oxypurinol administration (p < 0.05). Oxypurinol inhibition of XO improves coronary vascular endothelial dysfunction, a hallmark of patients with CAD. These observations reveal that XO-derived reactive oxygen species significantly contribute to impaired coronary NO bioavailability in CAD and that XO inhibition represents an additional treatment concept for inflammatory vascular diseases that deserves further investigation.
Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Circulação Coronária/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Oxipurinol/uso terapêutico , Xantina Oxidase/antagonistas & inibidores , Idoso , Doença da Artéria Coronariana/fisiopatologia , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/fisiopatologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Endotélio Vascular/citologia , Inibidores Enzimáticos/sangue , Inibidores Enzimáticos/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxipurinol/sangue , Oxipurinol/farmacologia , Purinas/sangue , Purinas/metabolismo , Vasoconstrição/efeitos dos fármacos , Xantina Oxidase/sangueRESUMO
OBJECTIVE: With the present studies we sought to determine how treatment with nitroglycerin (NTG) affects endothelial function, oxidative stress and nitric oxide (NO)-downstream signaling in Watanabe heritable hyperlipidemic rabbits (WHHL). BACKGROUND: In vitro experiments have demonstrated potent antiatherosclerotic effects of NO suggesting that treatment with NO-donors such as NTG could compensate for the diminished availability of endothelial NO. Nitric oxide may, however, not only be scavenged by reaction with endothelium-derived superoxide but also form the potent oxidant and inhibitor of vascular function, peroxynitrite (ONOO(-)). METHODS: Watanabe heritable hyperlipidemic rabbits were treated for three days with NTG patches. Normolipidemic New Zealand White rabbits (NZWR) served as controls. Endothelial function was assessed ex vivo with organ chamber experiments and vascular superoxide was quantified using lucigenin (5 and 250 microM) and CLA-enhanced chemiluminescence. Vascular ONOO(-) formation was determined using nitrotyrosine antibodies. The activity of the cGMP-dependent kinase (cGK-I) was assessed by determining the phosphorylation of vasodilator-stimulated phosphoprotein VASP (P-VASP). RESULTS: Nitroglycerin treatment caused endothelial dysfunction in NZWR and WHHL, associated with an increase in superoxide and ONOO(-) production and a substantial drop in cGK-I activity. In vivo NTG-treatment decreased lipophilic antioxidants (alpha- and beta-carotene) in NZWR and WHHL. Treatment of NZWR with NTG also decreased plasma extracellular superoxide dismutase (EC-SOD)-activity. CONCLUSIONS: Nitroglycerin treatment of WHHL with exogenous NO worsens rather than improves endothelial dysfunction secondary to increased formation of superoxide and/or peroxynitrite leading to decreased cGK-I activity. The decrease in plasma levels of alpha- and beta-carotene may be at least in part due to a decrease in EC-SOD activity.
Assuntos
Proteínas Quinases Dependentes de GMP Cíclico/efeitos dos fármacos , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Hiperlipidemias/tratamento farmacológico , Nitroglicerina/efeitos adversos , Tirosina/análogos & derivados , Tirosina/efeitos dos fármacos , Vasodilatadores/efeitos adversos , Animais , Antioxidantes/metabolismo , Avaliação Pré-Clínica de Medicamentos , Radicais Livres/sangue , Hiperlipidemias/genética , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Imuno-Histoquímica , Masculino , Óxido Nítrico/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Coelhos , Espécies Reativas de Oxigênio/sangue , Superóxido Dismutase/sangue , Superóxido Dismutase/efeitos dos fármacos , Tirosina/imunologia , beta Caroteno/sangueRESUMO
Recent studies demonstrated that glycoprotein (GP) IIb/IIIa receptor antagonists improve endothelial dysfunction of forearm resistance vessels in patients with stable coronary artery disease. However, it remains unclear whether these findings can be extended to the conductance vessel level. In this study, we aimed to evaluate the acute effect of tirofiban on endothelial function of arterial conductance vessels in patients undergoing percutaneous coronary intervention (PCI). Endothelial function was examined by ultrasonographic measurement of flow-mediated vasodilation (FMD) of the brachial artery. Endothelium-independent vasodilation was determined in response to nitroglycerin. Sixty-six patients who underwent PCI were included in the study. Thirty-three patients received a bolus of 10 microg/kg body weight of tirofiban, whereas 33 patients who did not receive tirofiban served as the control group. FMD was measured in all patients before and 30 minutes after PCI. Tirofiban significantly improved FMD (6.0 +/- 0.4% before vs 7.8 +/- 0.5% after PCI, p <0.0001), whereas FMD deteriorated in patients in the control group (6.1 +/- 0.6% before vs 4.7 +/- 0.7% after PCI, p = 0.006). Nitroglycerin-induced dilation remained unaltered in response to PCI. In another group of 11 patients with coronary artery disease, FMD did not change after coronary angiography without coronary intervention. In conclusion, PCI induces endothelial dysfunction in forearm conductance vessels that can be reversed with tirofiban.
Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/fisiopatologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/uso terapêutico , Tirosina/análogos & derivados , Tirosina/farmacologia , Tirosina/uso terapêutico , Idoso , Artéria Braquial , Doença da Artéria Coronariana/terapia , Feminino , Humanos , Masculino , TirofibanaRESUMO
The hemodynamic and anti-ischemic effects of nitroglycerin (NTG) are rapidly blunted as a result of the development of nitrate tolerance. With initiation of NTG therapy, it is possible to detect neurohormonal activation and intravascular volume expansion. These so-called pseudotolerance mechanisms may compromise the vasodilatory effects of NTG. Long-term nitrate treatment also is associated with decreased vascular responsiveness caused by changes in intrinsic mechanisms of the tolerant vasculature itself. According to the oxidative stress concept, increased vascular superoxide (O2-) production and an increased sensitivity to vasoconstrictors secondary to activation of protein kinase C contribute to the development of tolerance. Nicotinamide adenine dinucleotide phosphate oxidase and the uncoupled endothelial nitric oxide synthase may be O2- -producing enzymes. Nitric oxide (NO) and O2-, both derived from NTG and the vessel wall, form peroxynitrite in a diffusion-limited rapid reaction. Peroxynitrite, O2-, or both may be responsible for the development of nitrate tolerance and cross-tolerance to direct NO donors (eg, sodium nitroprusside, sydnonimines) and endothelium-dependent NO synthase-activating vasodilators. Hydralazine is an efficient reactive oxygen species (ROS) scavenger and an inhibitor of O2- generation. When given concomitantly with NTG, hydralazine prevents the development of nitrate tolerance and normalizes endogenous rates of vascular O2- production. Recent experimental work has defined new tolerance mechanisms, including inhibition of the enzyme that bioactivates NTG (ie, mitochondrial aldehyde dehydrogenase isoform 2 [ALDH2]) and mitochondria as potential sources of ROS. NTG-induced ROS inhibit the bioactivation of NTG by ALDH2. Both mechanisms increase oxidative stress and impair NTG bioactivation, and now converge at the level of ALDH2 to support a new theory for NTG tolerance and NTG-induced endothelial dysfunction. The consequences of these processes for NTG downstream targets (eg, soluble guanylyl cyclase, cyclic guanosine monophosphate-dependent protein kinase), toxic effects contributing to endothelial dysfunction (eg, prostacyclin synthase inhibition) and novel applications of the antioxidant properties of hydralazine are discussed.
Assuntos
Resistência a Medicamentos , Hidralazina/administração & dosagem , Isquemia Miocárdica/tratamento farmacológico , Nitroglicerina/administração & dosagem , Nitroglicerina/efeitos adversos , Estresse Oxidativo/efeitos dos fármacos , Animais , Ensaios Clínicos como Assunto , Angiografia Coronária , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Interações Medicamentosas , Endotélio Vascular/efeitos dos fármacos , Teste de Esforço , Feminino , Testes de Função Cardíaca , Humanos , Hidralazina/efeitos adversos , Assistência de Longa Duração , Masculino , Dose Máxima Tolerável , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/mortalidade , Índice de Gravidade de Doença , Resistência Vascular/efeitos dos fármacosRESUMO
Endothelial dysfunction in the setting of cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes mellitus and chronic smoking, as well as in the setting of heart failure, has been shown to be at least partly dependent on the production of reactive oxygen species in endothelial and/or smooth muscle cells and the adventitia, and the subsequent decrease in vascular bioavailability of NO. Superoxide-producing enzymes involved in increased oxidative stress within vascular tissue include NAD(P)H-oxidase, xanthine oxidase and endothelial nitric oxide synthase in an uncoupled state. Recent studies indicate that endothelial dysfunction of peripheral and coronary resistance and conductance vessels represents a strong and independent risk factor for future cardiovascular events. Ways to reduce endothelial dysfunction include risk-factor modification and treatment with substances that have been shown to reduce oxidative stress and, simultaneously, to stimulate endothelial NO production, such as inhibitors of angiotensin-converting enzyme or the statins. In contrast, in conditions where increased production of reactive oxygen species, such as superoxide, in vascular tissue is established, treatment with NO, e.g. via administration of nitroglycerin, results in a rapid development of endothelial dysfunction, which may worsen the prognosis in patients with established coronary artery disease.
Assuntos
Doenças Cardiovasculares/etiologia , Endotélio Vascular/patologia , Estresse Oxidativo/fisiologia , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Humanos , Fatores de RiscoRESUMO
The results of recent randomized trials to test the influence of antioxidants on coronary-event rates and prognosis in patients with coronary-artery disease were disappointing. In none of these studies did the use of vitamin E improve prognosis. In contrast, treatment of coronary-artery disease with angiotensin-converting-enzyme (ACE) inhibitors reduced coronary-event rates and improved prognosis. ACE inhibition prevents the formation of angiotensin II, which has been shown to be a potent stimulus of superoxide-producing enzymes in atherosclerosis. The findings suggest that inhibition of superoxide production at enzymatic levels, rather than symptomatic superoxide scavenging, may be the better choice of treatment.
RESUMO
BACKGROUND: The purpose of this study was to determine the predictive value of a single measurement of reactive hyperemia (RH) and brachial flow-mediated dilation (FMD) in patients with established stable coronary artery disease (CAD). METHODS: RH and brachial artery FMD were ultrasonographically measured in 325 patients with stable CAD. Patients were followed for cerebro-cardiovascular events. The median follow-up was 3.7 years (range 0.01-5.7 years). RESULTS: Sixty-seven patients (20.6%) had an cerebro-cardiovascular event. Patients with subsequent events had lower FMD (4.9 ± 3.3% versus 6.3 ± 3.5%, p = 0.003), higher brachial artery resting diameter (5.1 ± 0.7 mm versus 4.8 ± 0.7 mm, p = 0.002) and lower NMD (11.2 ± 5.1% versus 12.8 ± 5.4%, p = 0.02), while the mean hyperemic flow velocity and shear stress did not differ from patients without cerebro-cardiovascular events. Cox proportional hazard model adjusted for sex, age, BMI, and traditional cardiovascular risk factors revealed a hazard ratio of 0.84 for lower FMD (p = 0.01). CONCLUSIONS: We conclude that single spot measurements of peak RH do not provide long-term prognostic information, but evaluation of conduit artery FMD predicts long-term cerebro-cardiovascular events in patients with stable CAD. The prognostic value of FMD is incremental to traditional cardiovascular risk factors and may therefore be of clinical importance.
Assuntos
Artéria Braquial/patologia , Hiperemia/metabolismo , Velocidade do Fluxo Sanguíneo , Doença da Artéria Coronariana , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de RiscoRESUMO
AIMS: Percutaneous treatment of mitral regurgitation (MR) has been shown to reduce MR severity and improve functional outcomes. Surgical treatment of MR usually includes mitral annulus reduction. The influence of the MitraClip on annulus geometry is not clear. We wanted to investigate whether the procedure itself reduces annulus diameter and if there may be differences between secondary or functional (SMR) and primary (PMR) MR. METHODS AND RESULTS: We retrospectively assessed 3D echocardiography (3D-TEE) data of 55 patients acquired during the procedure shortly before and after clip placement for changes in annulus diameter and area. Measurements were done with QLAB software. Patients were categorized as having either SMR (n = 41) or PMR (n = 14). In SMR, we were able to demonstrate a significant reduction in annulus area (meanΔ 1.30 ± 1.44 cm2; P < 0.001), anterior-posterior (AP)-diameter (meanΔ 0.28 ± 0.32 cm; P < 0.001), tenting area (meanΔ 0.39 ± 0.49 cm2; P < 0.001). No significant change could be found for latero-medial (LM)-diameter. In contrast, we could not demonstrate significant changes in any of the parameters described above in patients with PMR. CONCLUSION: Percutaneous treatment with the MitraClip device can produce immediate reductions in mitral annulus size in SMR, probably supporting procedural success. It also reduces tenting, which may have prognostic implications. In contrast, these effects on mitral geometry cannot be demonstrated in PMR. Knowledge of this difference between SMR and PMR may be important to improve procedural strategies.
Assuntos
Procedimentos Cirúrgicos Cardíacos/instrumentação , Insuficiência da Valva Mitral/cirurgia , Idoso , Idoso de 80 Anos ou mais , Ecocardiografia Tridimensional , Ecocardiografia Transesofagiana , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/diagnóstico por imagem , Estudos Retrospectivos , Software , Resultado do TratamentoRESUMO
AIMS: Fractional flow reserve (FFR) allows accurate investigation of the functional significance of intermediate coronary stenoses. The present study set out to study the impact of gender on FFR measurements. METHODS AND RESULTS: Three hundred and seventeen intermediate (40-70% at angiography) stenoses were assessed with FFR in 270 patients (mean age 65.8 ± 10.3 years, 84 females). Resting Pd/Pa (the ratio of mean blood pressure measured distal to the stenosis to mean aortic blood pressure in resting conditions), FFR (Pd/Pa during adenosine-induced hyperaemia) and the ΔPd/Pa (calculated as the change in Pd/Pa during hyperaemia) were measured. There was no difference in the location and degree of stenoses between genders (p>0.5). Similarly, there was no difference in age and in the prevalence of cardiovascular risk factors (all p>0.2). Resting Pd/Pa also did not differ between genders (0.92 ± 0.08 vs. 0.93 ± 0.05, p=0.23). In response to adenosine, however, a significantly larger ΔPd/Pa (0.14 ± 0.07 vs. 0.11 ± 0.07, p=0.001) and a significantly lower FFR (0.79 ± 0.12 vs. 0.82 ± 0.10, p=0.008) were observed in males. This difference was maintained in a multivariate regression analysis. CONCLUSIONS: We observed gender-based differences in FFR data in daily routine. Further studies are necessary to test the mechanism of this observation and how these differences impact on the assessment of haemodynamically relevant stenoses.
Assuntos
Cateterismo Cardíaco , Estenose Coronária/diagnóstico , Reserva Fracionada de Fluxo Miocárdico , Adenosina , Idoso , Aorta/fisiopatologia , Pressão Arterial , Angiografia Coronária , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/fisiopatologia , Estudos Transversais , Feminino , Humanos , Hiperemia/fisiopatologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Fatores SexuaisRESUMO
BACKGROUND: Atherosclerosis is a chronic inflammatory process involving polymorphonuclear neutrophils (PMN) and formation of reactive oxygen species (ROS). The aim of the present study was to investigate the phenotype of inflammatory cells in regard to the expression of triggering receptor expressed on myeloid cells (TREM)-1 and its soluble form (sTREM-1) as well as its relationship with oxidative stress in peripheral artery disease (PAD) patients. METHODS: In total 90 patients with PAD (N = 30 intermittent claudication (IC) > 300 m absolute walking distance, N = 30 IC < 300 m absolute walking distance, N = 30 critical limb ischaemia (CLI)) and 30 control persons were included. ROS formation was measured at basal or stimulated conditions using the luminol analogue L-012 chemiluminescence. Peripheral blood leucocytes were analysed from whole blood by flow cytometry using different gating strategies to identify PMN and monocytes and analyse TREM-1 expression. RESULTS: CLI patients showed a significant higher ROS production at basal levels (p < 0.05) and upon stimulation with PDBu (p < 0.0001), LPS (p < 0.05) and zymosan A (p < 0.0001). TREM-1 was expressed significantly more on PMN of CLI patients (p < 0.01) in comparison to all other groups, whereas monocytic expression of TREM-1 was similar between all 4 groups. The serum concentration of its soluble form sTREM-1 however was increased in CLI and IC < 300 m patients (p < 0.0001). sTREM-1 concentrations correlated with basal ROS levels as wells with ROS production upon stimulation. Furthermore, we found the walking distance of IC patients to inversely correlate with sTREM-1 (rs = - 0.29; p = 0.03). CONCLUSIONS: We found an increased oxidative stress as well as an increased expression of TREM-1 and serum levels of sTREM-1 in patients with CLI. IC < 300 m patients showed a similar patter in regard to oxidative stress, TREM-1 expression and sTREM-1 concentration. Thus, sTREM-1 might represent a potential inflammatory biomarker to evaluate the severity of PAD. Whether this implies the potential for therapeutic recommendations, i.e. conservative vs. interventional/operative treatment, or a possibility to monitor the efficacy of interventions, requires further studies.
Assuntos
Isquemia/imunologia , Isquemia/metabolismo , Glicoproteínas de Membrana/metabolismo , Neutrófilos/imunologia , Neutrófilos/metabolismo , Espécies Reativas de Oxigênio/sangue , Receptores Imunológicos/metabolismo , Idoso , Aterosclerose/epidemiologia , Aterosclerose/imunologia , Aterosclerose/metabolismo , Biomarcadores/sangue , Progressão da Doença , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Feminino , Citometria de Fluxo , Humanos , Isquemia/epidemiologia , Masculino , Glicoproteínas de Membrana/sangue , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Estresse Oxidativo/fisiologia , Doença Arterial Periférica/epidemiologia , Doença Arterial Periférica/imunologia , Doença Arterial Periférica/metabolismo , Prevalência , Receptores Imunológicos/sangue , Fatores de Risco , Receptor Gatilho 1 Expresso em Células Mieloides , CaminhadaRESUMO
OBJECTIVE: The relation of noninvasive vascular function to sex, sex hormones, and reproductive history in the general population is little understood. METHODS: We simultaneously assessed flow-mediated dilation (FMD) and peripheral arterial tonometry in 454 women (mean age 40.4±16.1 years, age range 19-78 years) and 100 men (mean age 44.7±15.3 years) in a community-based cohort. Plasma estradiol, progesterone, luteinizing hormone, and follicle stimulating hormones were measured, and menstrual cycle and reproductive history were recorded. RESULTS: Vascular function was blunted in men as compared to women irrespective of menopausal status and adjustment for classical cardiovascular risk factors and hormones. Vascular reactivity changed during the menstrual cycle and correlated with estradiol concentrations for FMD, r=0.13 and inversely with progesterone for pulse amplitude, r=-0.14, and brachial artery diameter, r=-0.10. Multivariable-adjusted regressions showed a relation of estradiol with FMD, ß 0.658, 95% confidence interval (CI) 0.084/1.232, P=0.025 in women. Age at menarche (ß 0.070, 95% CI 0.039/0.101, P<0.0001) and breastfeeding duration (ß -0.006, 95% CI -0.011/-0.001, P=0.036) were related to brachial artery diameter, age at menarche also to FMD (ß -0.455, 95% CI -0.886/-0.023, P=0.039). CONCLUSION: Sex differences in noninvasive conduit and peripheral arterial function with better vascular reactivity in women were not fully explained by female sex hormones and menopausal status. Age at menarche and duration of breastfeeding were also related to vascular function and need further investigation.