Journal of Human Hypertension (2002) 16 (Suppl 1), S34–S37 2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh Endothelial dysfunction, angiotensin- converting enzyme inhibitors and calcium antagonists PLo´pez-Jaramillo1,2 and JP Casas1 1Instituto Colombiano de Investigaciones Biome´dicas (ICIB), Bucaramanga, Colombia; 2Universidad Industrial de Santander, Colombia The endothelium plays a crucial role in the pathogen- lar mortality, an effect that could be the consequence esis of cardiovascular disease. Endothelial function is of an improvement in the endothelial function. Recent attenuated by the presence of different well known car- studies have shown that a calcium antagonist might diovascular risk factors. Evaluation of endothelial vaso- improve the endothelial function, however, there is dilator function serve as an index integrating the overall controversy about this action and also about the poten- stress imposed by cardiovascular risk factors and tial mechanisms for the effect of a calcium antagonist reinforce the suggestion that endothelial dysfunction is in the regulation of endothelial function. an early marker of cardiovascular disease that precedes Journal of Human Hypertension (2002) 16 (Suppl 1), S34– clinical manifestations. Angiotensin-converting enzyme S37. DOI: 10.1038/sj/jhh/1001339 inhibitors have been shown to reduce the cardiovascu- Keywords: endothelial function; angiotensin-converting enzyme inhibitors; calcium antagonists Introduction reactive hyperaemia.5,6 Estimates of endothelial function by this test are remarkably stable over time, The endothelium is a complex endocrine and para- but no clear set of normal values has been crine organ that affects vasodilation, smooth muscle developed.7 Because of the different genetic back- cell proliferation, platelet aggregation, monocyte 1 ground and variability in the distribution of CVD and leukocyte adhesion, and fibrinolysis. The func- risk factors, normal values of FMD may differ among tional integrity of the endothelium is crucial to pro- populations.8 We have found in 253 normotensive portionate to the cardiovascular system vasodilator, healthy volunteers, that the mean %FMD was antiatherosclerotic and antithrombotic effects dependent on the presence of risk factors for CVD. through the secretion of vasoactive substances such Subjects with no risk factors had a mean %FMD of 1–3 as prostacyclin and particularly nitric oxide (NO). 13.74% (95% confidence interval (CI): 13.14, 14.35), while in those with at least one risk factor the mean Endothelial function and cardiovascular was significantly lower: 7.40% (95% CI: 4.33, 9.91).8 disease Obesity, smoking, and hypercholesterolaemia were the modifiable risk factors with the largest Endothelial vasodilator function is attenuated by the independently significant reduction effects on presence of different well known cardiovascular risk %FMD, as evaluated in the multivariate model. factors such as hyperlipidaemia, diabetes mellitus, Obese subjects had a %FMD 4.60% units lower than hypertension and smoking.4 In consequence, attenu- non-obese subjects (95% CI: −6.50, −2.71). Regard- ation of endothelial mediated vasodilatation could less of the effect of other risk factors, smokers and be considered as an early marker of cardiovascular hypercholesterolaemic subjects had a reduction of disease (CVD) and could be an important tool to 4.45 (P Ͻ 0.001) and 3.67 (P Ͻ 0.001) units in investigate cardiovascular pathophysiology. %FMD as compared with non-smokers and non- Recently, a non-invasive method using high-resol- hypercholesterolaemic subjects, respectively.8 ution ultrasound has been developed to assess flow We did a receiver operating characteristic (ROC) mediated dilation (FMD) of the brachial artery, analysis to identify the best %FMD cut-off point which is modulated by the release of NO during useful to identify subjects with and without cardio- vascular risk factors. The area under the ROC curve Correspondence: P Lo´pez-Jaramillo, Scientific Director, ICIB, PO was 83.28% (95% CI: 77.80, 88.77). The ROC plot Box: 384, Bucaramanga. Colombia suggested a cut-off point of 12 for %FMD. Sensi- E-mail: [email protected] tivity and specificity for this cut-off point were Endothelium and pharmacological interventions PLo´pez-Jaramillo and JP Casas S35 76.7% and 66.1%, respectively. The positive predic- term effects of therapeutic interventions on systemic tive value for this cut-off point was 47.9%, while endothelial function. the negative predictive values reached 87.5%. We also explored the performance of other cut-off Angiotensin-converting enzyme (ACE) points, based on their validity and predictive capacity and selected the point at which the number inhibitors and calcium antagonists as of false-positive began to exceed the number of false- alternatives to improve endothelial negative test results. Based on this criterium, the dysfunction best %FMD cut-off point was 10.4, which resulted A functional ACE system present in the vascular in a sensitivity of 71.2% and a specificity of 77.2%. endothelium contributes to the regulation of Positive and negative predictive values for this cut- 17 off point were 55.9% and 86.9%, respectively. Using adequate vascular biology. ACE inhibitors have been shown to reduce cardio- this cut-off point, endothelial dysfunction was 3.13 times more frequent in subjects with, than in sub- vascular mortality in patients with left ventricular dysfunction, acute myocardial infarction and also in jects without cardiovascular risk factors (95% CI: 18–20 8 patients at high risk of cardiovascular events. 2.30, 4.25). Similar analyses have been realised to 21 evaluate if the %FMD is useful in identifying sub- Vanhoutte et al, showed that ACE inhibition had jects with and without coronary artery disease. beneficial effects on endothelial function in animal models. The TREND and BANFF Studies, carry out These analysis reported that %FMD was a sensitive and specific (71.3% and 81% respectively) screen- in humans, evaluated the effect of quinapril, a highly specific tissular ACE inhibitor on endothelial ing test to predict the presence of coronary artery function, in resistance and conduit arteries respect- disease.9 Moreover, our results showed that FMD measure- ively, and confirmed the beneficial effects of ACE inhibitors in reversing the endothelial dysfunc- ments can be made with high accuracy and pre- tion.22,23 cision (Lin’s correlation coefficient of 0.88), and very low bias (mean inter-observer difference of Several studies have suggested that the mech- anism by which the tissular ACE inhibition might −0.30%).8 These results clearly show that no invas- improve the endothelial function involve the NO ive evaluation of endothelial vasodilator function may serve as an index integrating the overall stress pathway. Accumulating bradykinin may lead to increased NO synthesis and activity.24 Another imposed by CVD risk factors and reinforce the potential mechanism involves the inhibition of the suggestion that endothelial dysfunction is an early marker of CVD that precedes clinical manifes- production of angiotensin II and as a consequence decrease formation of superoxide anion (O− ). It is tations.8,10 2 well known that angiotensin II stimulates the An important body of evidence suggests that endothelial dysfunction is a generalised process that NADH/NAD(P)H oxidase of endothelial and smooth muscle cells.25 Figure 1 shows the effects of highly is not necessarily confined to vessels with overt 4–10 specific tissular ACE inhibitors in restoring the bal- atherosclerotic alterations. This proposal is − strengthened by the high correlation (Ͼ0.75) ance on the endothelial production of NO and O 2. Recent evidence has shown that acute adminis- reported between the coronary vasomotor response and the peripheral endothelial function of the brach- tration of calcium antagonists improves the abnor- ial artery evaluated by FMD.11,12 mal coronary vasomotion response in hypertension, atherosclerosis and hypercholesterolaemia.26,27 In Recently, three different groups10,13,14 have dem- onstrated that the diagnostic of endothelial dysfunc- addition, amlodipine and nifedipine have been tion realised in coronary and peripheral arteries in recently shown to increase the coronary vaso- patients with different stages of coronary artery dis- ease is related with an increased incidence of an adverse long-term outcome of coronary heart dis- ease. Several studies have demonstrated that treatment of cardiovascular risk factors known to lead to endo- thelial dysfunction is associated with a decrease in cardiac events in both primary and secondary pre- vention studies,15,16 underscoring the concept that the reduction in cardiac events in this patient’s population may be secondary to improvement in coronary endothelial function. In conclusion, FMD is attractive as a non-invasive method to assess the integrity of vascular endo- thelial function and can be recommended as a Figure 1 Action mechanism of ACE inhibitors (ACE-I) to reverse screening test for the detection of patients at risk of endothelial dysfunction, through improving the imbalance − CVD. It also can be used to assess short and long- between nitric oxide (NO) and superoxide (O2). Journal of Human Hypertension Endothelium and pharmacological interventions PLo´pez-Jaramillo and JP Casas S36 dilation and also the NO production from canine 9 Schroeder S et al. Noninvasive determination of endo- microvessels.28,29 thelium-mediated