FUNDAMENTO: A função endotelial braquial tem sido associada ao fluxo lento coronário (FLC). O aumento do fluxo sanguíneo para a artéria braquial faz com que o endotélio libere óxido nítrico (ON), com subsequente vasodilatação. Além de sua atividade com betabloqueador, o nebivolol provoca vasodilatação, aumentando a liberação endotelial de ON. OBJETIVO: Avaliar os efeitos do nebivolol na função endotelial vascular em pacientes com FLC. MÉTODOS: 46 pacientes com FLC e 23 indivíduos com artérias coronárias epicárdicas normais foram examinados com ecocardiografia transtorácica e ultrassonografia da artéria braquial. Os pacientes foram reavaliados dois meses após o tratamento com aspirina ou aspirina e nebivolol. RESULTADOS: Os pacientes com FLC apresentaram maior índice de massa corporal (26,5 ± 3,3 vs. 23,8 ± 2,8, p < 0,001), tempo de relaxamento isovolumétrico (TRIV) de influxo mitral (114,9 ± 18,0 vs. 95,0 ± 22,0 mseg, p < 0,001), menor fração de ejeção do ventrículo esquerdo (FEVE) (63,5 ± 3,1% vs. 65,4 ± 2,2, p = 0,009), colesterol HDL (39,4 ± 8,5 vs. 45,8 ± 7,7 mg/dL, p = 0,003) e dilatação fluxo-mediada da artéria braquial (DFM) (6,1 ± 3,9% vs. 17,6 ± 4,5%, p <0,001). Houve correlações significativas entre a DFM e a presença de FLC (r = 0,800, p < 0,001) e o colesterol HDL (r = 0,349, p = 0,003). Dos pacientes com FLC, apesar de os valores médios de DFM em pré-tratamento terem sido semelhantes (6,1 ± 4,3% vs. 6,0 ± ,6%, p = 0,917), em comparação com a DFM do grupo em pós-tratamento apenas com aspirina, a DFM apresentou valores significativamente maiores do que os pacientes tratados com aspirina e nebivolol (6,0 ± 3,5% vs. 8,0 ± 2,9%, p = 0,047). Constatou-se que o tratamento com nebivolol está associado a um significativo aumento na DFM (6,0 ± 3,6 a 8,0 ± 2,9 %, p = 0,030), ao passo que o tratamento apenas com aspirina não apresentou a mesma associação. CONCLUSÃO: A função endotelial pode ser comprometida nas artérias coronárias e braquiais em pacientes com FLC, e o nebivolol pode ser eficaz na melhora da função endotelial em pacientes com FLC.
IHisar Intercontinental Hospital, Cardiology Department, Istanbul, Turkey
IIYuzuncu Yil University, Faculty of Medicine, Cardiology Department, Van, Turkey
IIIMedical Park Hospital, Cardiology Department, Van, Turkey
IVYuksek Ihtısas Research Hospital, Cardiology Department, Van, Turkey
O fluxo lento coronário (FLC) é um fenômeno caracterizado pela opacificação tardia das artérias coronárias, na ausência de doença epicárdica oclusiva, no qual muitos fatores etiológicos, tais como a disfunção microvascular e endotelial e a doença de pequenos vasos, vêm apresentando implicações1-5.
O endotélio é de fundamental importância para a manutenção do tônus vascular. Participa na regulação do fluxo sanguíneo em resposta a mudanças no tecido e necessidades de perfusão dos órgãos. Quando o fluxo sanguíneo aumenta, o vaso sofre dilatação. Esse fenômeno tem sido chamado de dilatação fluxo-mediada (DFM). A vasodilatação fluxo-mediada vem sendo amplamente examinada de forma não invasiva por meio de medições por ultrassom da resposta de vasodilatação da artéria braquial ao aumento do fluxo sanguíneo, refletindo em tensão de cisalhamento na parede vascular. Esse estímulo faz com que o endotélio libere óxido nítrico (ON), com subsequente vasodilatação, que pode ser visualizada e quantificada como um índice da função vasomotora6. Constatou-se que a função endotelial braquial também estava associada ao FLC7,8. O Nebivolol é a terceira geração de antagonistas beta-adrenérgicos altamente cardiosseletivos e também afeta a via L-arginina/ON, causando vasodilatação por aumento da liberação endotelial de ON9.
Neste estudo, buscamos investigar os efeitos do tratamento de nebivolol na DFM de pacientes com FLC.
Neste estudo, 46 pacientes com FLC angiograficamente comprovada, mas com artérias coronárias epicárdicas em geral normais, e 23 indivíduos saudáveis foram selecionados entre pacientes submetidos à coronariografia diagnóstica por suspeita de doença arterial coronariana. Entretanto, descobriu-se que possuíam artérias coronárias epicárdicas normais sem FLC. O fluxo lento coronário foi definido de acordo com o método de contagem de quadros TIMI (TFC), e os indivíduos com um TFC maior do que dois desvios padrões (DP) da variação normal conhecida para o vaso em especial foram considerados com FLC10. Os pacientes com histórico de insuficiência cardíaca congestiva, doença arterial coronariana, incluindo espasmo, placa ou ectasia, valvopatia, hipertireoidismo, doença pulmonar obstrutiva crônica, pré-excitação ventricular, alterações de condução atrioventricular e aqueles que recebiam medicações conhecidas por alterar a condução cardíaca foram excluídos do estudo. Os pacientes foram submetidos à ecocardiografia e à ultrassonografia da artéria braquial antes e dois meses após o tratamento apenas com aspirina ou com aspirina e nebivolol. O estudo foi aprovado pelo comitê de ética da Faculdade de Medicina da Universidade Yuzuncu Yil, de acordo com a Declaração de Helsinki, tendo os pacientes assinado o consentimento livre e esclarecido.
O exame ecocardiográfico foi realizado em repouso, com o paciente em posição decúbito lateral esquerdo, utilizando um dispositivo ecocardiográfico comercialmente disponível (Vivid 3, General Electric), com um transdutor de 3 MHz, por dois ecocardiografistas experientes que não tiveram acesso aos dados clínicos. Utilizando a ecocardiografia modo-M, as medidas do longo eixo foram obtidas em nível dos folhetos da válvula distal a mitral, de acordo com as recomendações atuais11. A fração de ejeção do ventrículo esquerdo foi calculada por meio do método biplano de Simpson dos planos apical duas câmeras e quatro câmaras. O volume de amostra do Doppler pulsado foi disposto entre as pontas dos folhetos da válvula mitral para obter velocidades de enchimento máximas. O fluxo diastólico precoce (E), o sinal de contração atrial (A) e o tempo de desaceleração E (TD) foram medidos. O tempo de relaxamento isovolumétrico (TRIV) foi determinado como o intervalo entre o fim da saída aórtica e o início do sinal de entrada mitral.
As mudanças no diâmetro da artéria braquial direita em resposta à hiperemia reativa foram medidos por meio de sistema de ultrassom de alta resolução (Vivid 3, General Electric), com um transdutor matricial linear de 7 MHz, conforme descrito anteriormente12. Depois que as imagens basais da artéria braquial foram obtidas, um garrote pneumático foi colocado ao redor do antebraço distal da artéria alvo, inflado a uma pressão de 250 mm Hg, e a pressão foi mantida por cinco minutos. Um fluxo aumentado foi induzido pela súbita deflação do manguito. Um segundo exame foi realizado continuamente por 30 segundos antes e por 90 segundos após a deflação do manguito. Quinze minutos depois, mais um exame em repouso foi registrado para confirmar a recuperação vascular. O diâmetro da artéria braquial foi medido a partir da interface anterior e posterior entre a média e a adventícia no final da diástole, incidente com a onda R em um ECG continuamente registrado. Diâmetros de quatro ciclos cardíacos foram determinados a partir de imagens, e a média das medidas foi obtida. Os exames foram avaliados por um único observador sem acesso aos dados clínicos dos pacientes. A DFM foi calculada como aumento de porcentagem no diâmetro arterial durante a hiperemia reativa e foi utilizada como um índice de vasodilatação endotélio-dependente.
Os dados foram apresentados como média ± desvio padrão (DP). Usando um pacote SPSS 10.0 (SPSS Inc., Chicago, Illinois, EUA), as diferenças nos valores médios entre os grupos foram avaliadas utilizando o teste t de Student e com teste U de Mann-Whitney para as variáveis sem distribuição normal. As variáveis categóricas foram comparadas pelo teste qui-quadrado. As alterações nos parâmetros após o tratamento foram comparadas utilizando-se o teste t pareado. A análise de correlação de Pearson foi utilizada para a avaliação da relação entre variáveis. O valor p bicaudal maior que 0,05 foi considerado significativo.
O fluxo lento coronário foi observado em três vasos em 11 pacientes (23,9%), em dois vasos em 21 pacientes (45,7%) e em um vaso em 14 pacientes (30,4%). A artéria descendente anterior esquerda (ADAE) foi afetada em 37 pacientes (80,4%); a artéria circunflexa (Cx), em 25 pacientes (54,3%); e a artéria coronária direita (ACD), em 28 pacientes (60,9%). Trinta e dois pacientes (69,6%) apresentavam sintomas de angina, e 14 (30,4%) tiveram teste ergométrico em esteira positivo. Os pacientes com FLC apresentaram maior índice de massa corporal, TRIV e menor colesterol HDL e DFM. Apesar disso, estavam dentro dos limites normais, e a FEVE apresentou-se ligeiramente menor entre os pacientes com FLC (
Descobrimos que o FLC apresenta associação com o comprometimento da função vascular endotelial da artéria braquial e das funções do VE. Comparado com o tratamento apenas com aspirina, a adição de nebivolol ao tratamento melhorou a função endotelial braquial.
De acordo com estudos anteriores, verificamos que as funções endoteliais vasculares foram comprometidas em pacientes com FLC7,8,13. Constatamos que a disfunção endotelial é um processo generalizado e pode ser detectada em artérias coronárias e periféricas antes do desenvolvimento da aterosclerose14. A formação de imagens da artéria braquial com ultrassom de alta resolução durante a hiperemia reativa é um método aceito de avaliação da resposta vasomotora endotélio-dependente, e as alterações na função vasomotora periférica foram correlacionadas com a presença de disfunção endotelial da artéria coronária15. Além disso, em pacientes com angina microvascular, foi observada uma resposta vasodilatadora do antebraço comprometida à isquemia, sugerindo que o comprometimento vascular não estava restrito à circulação coronariana, mas era parte de um distúrbio vasomotor generalizado16.
Descrevemos a associação do fluxo lento coronário com baixa função sistólica e diastólica do VE17-19, HDL baixo e altos níveis de triglicerídeos13. Também constatamos que, comparado ao grupo controle, o tempo de relaxamento isovolumétrico (TRIV) era maior e que os níveis de HDL eram menores em pacientes com FLC e estavam significativamente correlacionados à DFM. Apesar disso, estava dentro dos limites normais, e a FEVE apresentou-se ligeiramente, mas significativamente, menor entre os pacientes com FLC no presente estudo. No entanto, Barutcu e cols.20 não encontraram diferenças na função sistólica ventricular esquerda entre pacientes com FLC e o grupo controle. Em outro estudo, Sezgin e cols.17 encontraram alterações no preenchimento diastólico, mas uma função sistólica normal do VE em pacientes com FLC. Constatamos também que os pacientes com FLC apresentavam comprometimento regional da função diastólica do VE21.
A disfunção diastólica sem disfunção sistólica pode acontecer em um estágio inicial de isquemia miocárdica em pacientes com doença arterial coronariana, compatível com o fato de que a funções diastólicas do ventrículo esquerdo são mais suscetíveis à isquemia do que as sistólicas22. Diversos estudos demonstraram que o FLC está associado à isquemia miocárdica, mas os dados eram limitados ao modo como as funções ventriculares esquerdas eram afetadas por essa doença2,3,5,23. A associação entre o baixo HDL e a disfunção endotelial foi documentada24, e em pacientes com FLC braquial reduzido, a DFM foi relacionada a baixo nível de HDL13.
Estudos anteriores sugeriram resistência vascular anormalmente elevada e aumento do tônus microvascular como a causa da FLC1,4,25. O estímulo simpático apresentou-se como o principal agente na regulação do tônus arterial coronariano. Os pacientes com FLC demonstraram níveis mais elevados de adrenalina e noradrenalina quando comparados aos pacientes com fluxo coronário normal. Já a contagem de quadros TIMI vem sendo descrita apresentando correlação positiva com os níveis de adrenalina e noradrenalina, sugerindo que a hiperatividade adrenérgica poderia ter um impacto sobre a patogênese do FLC26. Cabe ressaltar que apenas um terço dos pacientes com FLC atenderam aos critérios em um estudo angiográfico repetido27. Apesar disso, o mecanismo exato da resposta dinâmica não foi bem elucidado. Postula-se que esse aumento dinâmico no tônus microvascular pode ocorrer devido ao espasmo microvascular que resulta na recorrência de sintomas. Portanto, as drogas que atuam sobre o sistema simpático e neuroendócrino e que possuem efeitos vasodilatadores coronarianos podem ser úteis no tratamento dessa entidade. Estudos clínicos anteriores que utilizam medições de fluxo coronário sugerem que os antagonistas beta-adrenérgicos não seletivos estão associados a um aumento na resistência vascular coronariana durante a hiperemia e, portanto, reduzem o fluxo coronário de reserva28,29. Esse fenômeno foi atribuído ao tônus vasomotor alfa-adrenérgico sem resistência. No entanto, demonstrou-se que os betabloqueadores seletivos melhoravam a perfusão do miocárdio, aumentando o fluxo coronário de reserva30. O nebivolol, um receptor-bloqueador beta-adrenérgico altamente seletivo com propriedades moduladoras de ON, poderia ser especialmente útil para melhorar a reserva de fluxo coronário devido às propriedades vasodilatadoras em artérias coronarianas pequenas e grandes30. O destacado efeito vasodilatador do nebivolol em microvasos coronarianos humanos é bastante reconhecido em condições
Até onde sabemos, não há estudos sobre os efeitos da aspirina no FLC. No presente estudo, não encontramos melhora na DFM com aspirina. No entanto, os pacientes tratados apenas com aspirina ou com aspirina e nebivolol não apresentaram angina após o tratamento. Essa constatação pode estar relacionada à natureza dinâmica do FLC. Eventos recorrentes podem ser secundários para aumentar a dinâmica do espasmo microvascular secundária ao espasmo microvascular2. Apenas um terço dos pacientes com FLC foram detectados com FLC em um estudo angiográfico repetido36.
O pequeno número de pacientes incluídos neste estudo é a maior limitação. Um seguimento maior e em longo prazo deve fortalecer o valor dos resultados. A angiografia de controle para avaliar os efeitos do nebivolol em TFC não foi realizada devido a questões éticas.
A função endotelial pode ser comprometida nas artérias coronárias e braquiais em pacientes com FLC, e o nebivolol pode ser eficaz na melhora da DFM braquial, um índice de função endotelial, em pacientes com FLC.
Declaro não haver conflito de interesses pertinentes.
O presente estudo não teve fontes de financiamento externas.
Não há vinculação deste estudo a programas de pós-graduação.
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Yilmaz Gunes Hisar Intercontinental Hospital, Cardiology Department 9065-100 - Istanbul, Turkey E-mail:
Artigo recebido em 05/12/10, revisado recebido em 04/03/11, aceito em 04/03/11.
BACKGROUND: Brachial endothelial function has been associated with coronary slow flow (CSF). Increasing blood flow to brachial artery provokes endothelium to release nitric oxide (NO) with subsequent vasodilatation. Besides its β1-blocker activity, nebivolol causes vasodilatation by increasing endothelial NO release. OBJECTIVE: To assess the effects of nebivolol on vascular endothelial function in patients with CSF. METHODS: Forty-six patients with CSF and 23 individuals with normal epicardial coronary arteries were examined with transthoracic echocardiography and brachial artery ultrasonography. The patients were reevaluated two months after treatment with aspirin or aspirin plus nebivolol. RESULTS: Patients with CSF had higher body mass index (26.5 ± 3.3 vs. 23.8 ± 2.8, p < 0.001), mitral inflow isovolumetric relaxation time (IVRT) (114.9 ± 18.0 vs. 95.0 ± 22.0 msec, p < 0.001) and lower left ventricular ejection fraction (LVEF) (63.5 ± 3.1% vs. 65.4 ± 2.2, p = 0.009), HDL-cholesterol (39.4 ± 8.5 vs. 45.8 ± 7.7 mg/dL, p = 0.003) and brachial flow-mediated dilatation (FMD) (6.1 ± 3.9% vs. 17.6 ± 4.5%, p < 0.001). There were significant correlations between FMD and the presence of CSF (r = 0.800, p < 0.001) and HDL-cholesterol (r = 0.349, p = 0.003). Among Patients with CSF, although pretreatment mean FMD values were similar (6.1 ± 4.3% vs. 6.0 ± ,6%, p = 0.917) compared to aspirin alone group, posttreatment FMD was significantly higher in patients treated with aspirin plus nebivolol (6.0 ± 3.5% vs. 8.0 ± 2.9%, p = 0.047). Treatment with nebivolol was associated with a significant increase in FMD (6.0 ± 3.6 to 8.0 ± 2.9 %, p = 0.030) whereas treatment with aspirin alone was not. CONCLUSION: Endothelial function may be impaired in both coronary and brachial arteries in patients with CSF and nebivolol may be effective in the improvement of endothelial function in patients with CSF.
IHisar Intercontinental Hospital, Cardiology Department, Istanbul, Turkey
IIYuzuncu Yil University, Faculty of Medicine, Cardiology Department, Van, Turkey
IIIMedical Park Hospital, Cardiology Department, Van, Turkey
IVYuksek Ihtısas Research Hospital, Cardiology Department, Van, Turkey
Coronary slow flow (CSF) is a phenomenon characterized by delayed opacification of coronary arteries in the a of epicardial occlusive disease, in which many etiological factors such as microvascular and endothelial dysfunction and small vessel disease have been implicated1-5.
The endothelium is of essbsence of epicardial occlusive disease, in which many etiological factors such as microvascular and endothelial dysfunction and small vessel disease have been implicated1-5.ential importance for the maintenance of vascular tone. It participates in the regulation of blood flow in response to changes in tissue and organ perfusion requirements. When blood flow increases through a vessel, the vessel dilates. This phenomenon has been called flow- mediated dilatation (FMD). Flow-mediated vasodilatation has been widely examined non-invasively by ultrasound-based measurements of brachial artery vasodilatory response to increasing blood flow reflecting shear stress on the vascular wall. This stimulus makes the endothelium release nitric oxide (NO) with subsequent vasodilatation that can be imaged and quantitated as an index of vasomotor function6. Brachial endothelial function has also been found to be associated with CSF7,8. Nebivolol is a third-generation highly cardioselective β1-adrenoceptor antagonist and it also affects the L-arginine/ NO pathway, causing vasodilatation by increasing endothelial NO release9.
This study aimed to investigate the effects of nebivolol treatment on FMD in patients with CSF.
Forty-six patients with angiographically proven CSF but normal epicardial coronary arteries and 23 healthy individuals were selected from patients who had undergone diagnostic coronary arteriography because of suspected coronary artery disease and were found to have normal epicardial coronary arteries without CSF. Coronary slow flow was defined according to the TIMI frame count (TFC) method, and the individuals with a TFC greater than 2 standard deviations (SD) from the published normal range for the particular vessel were accepted as having CSF10. Patients with a history of congestive heart failure, coronary artery disease including spasm, plaque, or ectasia, valvular heart disease, hyperthyroidism, chronic obstructive pulmonary disease, ventricular preexcitation, atrioventricular conduction abnormalities and those taking medications known to alter cardiac conduction were excluded from the study. The patients underwent echocardiography and brachial artery ultrasound evaluation before and two months after treatment with aspirin alone or aspirin plus nebivolol. The study was approved by the Yuzuncu Yil University Medical Faculty ethic committee according to the Declaration of Helsinki and the patients gave written informed consent.
The echocardiography examination was performed at rest, with the patient at left lateral decubitis position, using a commercially available echocardiography device (Vivid 3, General Electric) with a 3 MHz transducer, by two experienced echocardiographers who were blinded to the clinical data. Using M-mode echocardiography, long-axis measurements were obtained distally to the mitral valve leaflets according to current recommendations11. Left ventricular ejection fraction was calculated via modified biplane Simpson's method from apical four and two chamber views. The pulsed Doppler sampling volume was placed between the tips of the mitral valve leaflets to obtain maximum filling velocities. Early diastolic flow (E), atrial contraction signal (A) and E deceleration time (DT) were measured. Isovolumetric relaxation time (IVRT) was determined as the interval between the end of the aortic outflow and the start of the mitral inflow signal.
Changes in right brachial artery diameter in response to reactive hyperemia were measured using high-resolution ultrasound system (Vivid 3, General Electric) with a 7-MHz linear-array transducer as previously described12. After baseline images of the brachial artery were obtained, a pneumatic tourniquet placed around the forearm distally to the target artery was inflated to a pressure of 250 mm Hg, and the pressure was held for 5 minutes. Increased flow was induced by sudden cuff deflation. A second scan was performed continuously for 30 seconds before and for 90 seconds after cuff deflation. Fifteen minutes later a further resting scan was recorded to confirm the vessel recovery. Diameter of the brachial artery was measured from the anterior to posterior interface between the media and adventitia at the end of diastole, incident with the R wave on a continuously recorded ECG. Diameters for 4 cardiac cycles were determined from images, and the measurements were averaged. The scans were evaluated by a single observer blinded to the clinical data of the patients. FMD was calculated as percentage increase in arterial diameter during reactive hyperemia and was used as an index of endothelium-dependent vasodilatation.
Data were presented as mean ± standard deviation (SD). Using an SPSS package 10.0 (SPSS Inc., Chicago, Illinois, USA) differences in mean values between groups were assessed using Student
Coronary slow flow was observed in 3 vessels in 11 (23.9%) patients, in 2 vessels in 21 (45.7%) patients and in one vessel in 14 (30.4%) patients. Left anterior descending artery (LAD) was affected in 37 (80.4%) patients, circumflex artery (Cx) in 25 (54.3) patients and right coronary artery (RCA) in 28 (60.9%) patients. Thirty-two (69.6%) patients had angina symptoms and 14 (30.4%) had positive treadmill exercise test. Patients with CSF had higher body mass index, IVRT and lower HDL-cholesterol and FMD. Although it was within normal limits, LVEF was slightly but significantly lower among CSF patients (
We have found that CSF is associated with impaired brachial artery vascular endothelial function and LV functions. Compared with aspirin alone, addition of nebivolol to treatment improved brachial endothelial function.
According to previous studies, we found that vascular endothelial functions were impaired in patients with CSF7,8,13. Endothelial dysfunction appears to be a generalized process and can be detected in coronary and peripheral arteries before the development of atherosclerosis14. Brachial artery imaging with high-resolution ultrasound during reactive hyperemia is an accepted method of assessing endothelium-dependent vasomotion, and abnormalities in peripheral vasomotor function have been correlated with the presence of coronary arterial endothelial dysfunction15. Moreover, in patients with microvascular angina, an impaired forearm vasodilator response to ischemia has been observed, suggesting that the vascular involvement is not restricted to the coronary circulation but is part of a generalized vasomotor disturbance16.
Coronary slow flow has been reported to be associated with low LV systolic and diastolic function17-19 and low HDL and high triglyceride levels13. We have also found that compared to control group, IVRT (a diastolic function parameter) was longer and HDL levels were lower in patients CSF and they were significantly correlated with FMD. Although it was within normal limits, LVEF was slightly but significantly lower among CSF patients in this study. However, Barutcu et al20 found no differences in left ventricular systolic function between patients with CSF and the control group. In another study, Sezgin et al17 found diastolic filling abnormalities but normal LV systolic function in patients with CSF. We have also found that patients with CSF had impaired diastolic and regional LV functions21.
Diastolic dysfunction without systolic dysfunction may appear at an early stage of myocardial ischemia in patients with coronary artery disease, compatible with the fact that left ventricular diastolic functions are more susceptible to ischemia than systolic functions22. Several studies have demonstrated that CSF is associated with myocardial ischemia, but data are limited on how the left ventricular functions are affected by this disease2,3,5,23. The association between low HDL and endothelial dysfunction has been documented24 and in patients with CSF reduced brachial, FMD was found to be associated with low HDL levels13.
Previous studies have suggested abnormally high small vessel resistance and increased microvascular tone as the cause of CSF1,4,25. Sympathetic stimulation has a major role in regulating coronary arterial tonus. Patients with CSF had higher adrenalin and noradrenalin levels compared to patients with normal coronary flow and TIMI frame count was reported to be positively correlated with adrenalin and noradrenalin levels suggesting that adrenergic hyperactivity might have an impact on CSF pathogenesis26. It is noteworthy that only one third of the patients with CSF fulfilled the criteria on a repeat angiographic study27. Although the exact mechanism for this dynamic response is not well elucidated, it is postulated that this dynamic increase in microvascular tone may be due to microvascular spasm resulting in recurrence of symptoms. Therefore, drugs acting on the sympathetic and neuroendocrine system having coronary vasodilatory effects may be useful in the treatment of this entity. Previous clinical studies using coronary flow measurements suggest that non-selective beta-adrenergic antagonists are associated with an increase in coronary vascular resistance during hyperemia and, therefore, reduce coronary flow reserve28,29. This phenomenon has been attributed to the unopposed alpha-adrenergic vasomotor tone. However, selective beta-blockers like metoprolol have been confirmed to improve myocardial perfusion by increasing coronary flow reserve30. Nebivolol, a highly selective beta1-adrenergic receptor-blocker with NO-modulating properties, may be especially useful for improving coronary flow reserve due to its vasodilating properties on the small and large coronary arteries30. The marked vasodilating effect of nebivolol in human coronary microvessels is well established under in vitro conditions31,32. In addition, intracoronary nebivolol has been associated with a significant increase in coronary flow reserve both in patients with coronary artery disease and patients with normal coronary arteries33. Furthermore, it has been shown that nebivolol may be effective for improvement of LV functions and symptoms and brachial FMD in patients with CSF20,34,35. Improvement of FMD with nebivolol in this study may be associated with the fact that endothelial dysfunction may be a generalized process and can be detected both in coronary and peripheral arteries.
As far as we know, there is no study investigating the effects of aspirin in CSF. In this study, we did not find any improvement in FMD with aspirin. However, both patients treated with either aspirin alone or aspirin plus nebivolol were free of angina after treatment. This finding may be related to the dynamic nature of CSF. Recurrent events may be secondary to dynamic increase of microvascular spasm secondary to microvascular spasm2. Only one third of the patients with CSF were detected to have CSF on a repeat angiographic study36.
The small number of patients included in this study is the main limitation. Larger and longer-term follow-up should strengthen the value of the results. Control angiography to assess the effects of nebivolol on TFC was not performed due to ethical concerns.
Endothelial function may be impaired in both coronary and brachial arteries in patients with CSF and nebivolol may be effective in the improvement of brachial FMD, an index of endothelial function, in patients with CSF.
No potential conflict of interest relevant to this article was reported.
There were no external funding sources for this study.
This study is not associated with any post-graduation program.
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Yilmaz Gunes Hisar Intercontinental Hospital, Cardiology Department 9065-100 - Istanbul, Turkey E-mail:
Manuscript received December 05, 2010, revised manuscript received March 04, 2011, accepted March 04, 2011.