- Email: [email protected]
Family history of coronary heart disease is more strongly associated to coronary atherosclerosis than to carotid atherosclerosis
Abstracts
0.41 (p = 0.01). Only the correlation between Mean SC and distal aorta PWV remained significant after correction for age (Table 1). Conclusions: In patients with PAOD, mean and maximum peripheral stenosis severity is strongly correlated with PWV in the distal aorta as compared to carotid VWA, while correlation with PWV in the proximal aorta is absent. Our findings indicate site-specific coupling between aortic wall stiffness and atherosclerotic burden.
Age Mean SC
R β p β p
PWVproximal
PWVdistal
VWA/BSA
0.45 0.50 0.10 −0.11 0.56
0.63 0.39 0.02 0.33 0.04
0.57 0.40 0.02 0.24 0.15
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Medicine A, Wolfson Hospital, Holon, Israel
Purpose: To assess risk factors of ischemic heart disease in women with surgical menopause. Methods: 141 women with surgical menopause were included in the investigation. All of them underwent general clinical examination, body mass index (BMI) calculation, measurement of waist circumference, menopausal index evaluation, ambulatory blood pressure and electrocardiogram monitoring (Cardiotens-01, Meditech, Hungary), determination of general cholesterol, lipid fractions and glucose tolerance. We also measured the level of non-etherized fatty acids and glycerol in blood serum. Postmenopausal women were 45.3 ± 2.8 years old and the duration of menopause was from 6 months to 7 years. The expression of menopausal syndrome was assessed according to the menopausal index dimension, which was 41.3 ± 11.06 score. Control group consisted of 17 healthy women (mean age 37.2 ± 4.2). Patients with coronary heart disease, essential hypertension, endocrine and grievous somatic diseases were excluded. Results: 74% (105 pts) of involved women had 2 or more attributes of menopausal metabolic syndrome: obesity (BMI 32.6 ± 1.4 kg/m2) with the prevalence of visceral adipose tissue (waist circumference ≥ 80 cm), hypercholesterolemia, hypertriglyceridemia, pathological glucose tolerance, arterial hypertension, and stages 1–2 (only 32% of patients had normal daily profile of blood pressure). Moreover, it was found, that the level of nonetherized fatty acids in patients with surgical menopause consisted 134% from the level of this index in healthy women (p b 0.05); and the level of glycerol was decreased in 29% (p b 0.05). The ratio of non-etherized fatty acids to glycerol permits to estimate the velocity of substrate utilization by peripheral tissues and myocardium as well. This index in postmenopausal women was 42% more than in control group (p b 0.01). We can conclude that the level of non-etherized fatty acids increased not only owing to lipolytic processes activation, but also resulted from the disturbances of this substrate utilization. The increase of non-etherized fatty acid level contributes to the development of insulin resistance, which is the key link of menopausal metabolic syndrome. Conclusions: Thus, postmenopausal women have expressive disorders in lipid and glucose metabolism, which may cause rapid atherosclerosis development in these patients.
DP
a
b
Therapy Department, Chita State Medical Academy, Chita, Russian Federation
RO
doi:10.1016/j.ejim.2013.08.093
ID: 331 Is HDL-Cholesterol still a target for pharmacologic therapy? D. Gavisha,b
ID: 375 Ischemic heart disease risk factors in postmenopausal women N. Lareva, A. Govorin
OF
Table 1 Linear regression modeling between proximal and distal aortic PWV and carotid VWA/BSA as dependent variables and age and mean peripheral stenosis class (Mean SC) as predictors.
e39
UN
CO
RR
EC
TE
Low HDL-C is associated with increased risk for cardiovascular disease (CVD) according to epidemiologic observational studies. The assumption that raising HDL-C by pharmacologic intervention will reduce CVD and reduce atherosclerosis is based on those observations as well as on small studies in animal models and in humans showing a reduction in plaques induced by raising HDL-C. Two prospective studies using Niacin and Niacin/laropiprant have failed to demonstrate reduction in CVD. (AIM HIGH and HPS2-Thrive).The negative results were partially explained by the excellent background treatment with statins in the control group and by safety issues related to niacin. A different method for raising HDL-C is by inhibiting Cholesterol Esther Transport (CETP).The first drug used was torcetrapib, this effort failed due to the increase in hypertension and aldosteron induced by the drug causing increased CVD and total mortality despite having good effects on lipids. A second CETP inhibitor without the blood pressure raising effect was dalcetrapib. This drug seemed to be very effective in raising HDL-C and improving endothelial function as well as reducing atheroma volume in the first studies. However the large prospective program was stopped due to no effects on CVD. There are two other more potent and safe CETP inhibitors still being studied in Large prospective studies: Anacetrapib and Evacetrapib. Those two drugs can cause a reduction in LDL-C as well as an increase in HDL-C. Alternative methods for reducing CVD include infusion of reconstituted HDL particles or Apo A-I during the acute coronary event, using methods for improving HDL function (Targeting inflammation and oxidation) and targeting other peptides or receptors related to HDL function such as SR-BP, ABCG1, LXR, and more. In summary: Although currently the status of HDL directed therapy is cloudy I believe that the future may still be bright and promising.
doi:10.1016/j.ejim.2013.08.094
doi:10.1016/j.ejim.2013.08.095
ID: 526 Family history of coronary heart disease is more strongly associated to coronary atherosclerosis than to carotid atherosclerosis B. Suha, D.W. Shina, S.P. Leeb, H. Leea, B. Choa a
Department of Family Medicine, Seoul National University Hospital, Seoul, South Korea b Department of Cardiology, Seoul National University Hospital, Seoul, South Korea
Background: Many new noninvasive tests for cardiovascular disease (CVD) risk assessment have added valuable clinical insights beyond traditional risk factors. Family history (FH) of coronary heart disease (CHD) is a major CVD risk that has been shown to be independent from other major risk factors. Methods: 662 asymptomatic Korean adults older than 30 years were investigated. Multivariable logistic regression analysis was employed to investigate comparative
Abstracts
association of FH of CHD to coronary computed tomography angiography (CTA) and carotid ultrasonography (USG). Results: Adjusted for major CVD risk factors, FH of CHD was shown to be significantly associated to significant coronary stenosis (aOR 4.92, 95% CI 1.58–15.4). Association of FH of CHD to increased carotid IMT (aOR 1.44, 95% CI 0.40–5.22) was much lower in strength and statistical power compared to its coronary counterpart. Moreover, the predictive model for significant coronary stenosis had a significantly higher predictive value when FH of CHD was included (AUC 0.808) compared to when it was not (AUC 0.772; likelihood ratio test (LRT) P = 0.0129), whereas no significant difference was observed upon inclusion of FH of CHD in the predictive model for increased carotid IMT (AUC 0.778 vs. 0.783, LRT P = 0.591). Conclusion: To our knowledge our study is the first to show specific comparative evidence that FH of CHD is more strongly associated to coronary atherosclerosis than to carotid atherosclerosis. Our results suggest that for asymptomatic adults with low-tointermediate CVD risk, compared to carotid USG, coronary CTA may be better suited to screen for subclinical atherosclerosis.
doi:10.1016/j.ejim.2013.08.097
ID: 687 Metabolic syndrome and acid uric P. Giorgini, S. Ciarla, M. Struglia, R. Striuli, P. Di Giosia, G. Properzi, C. Ferri Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
Objective: elevated serum uric acid (SUA) levels are frequently observed in patients with the (MS), although the clinical implication is still controversial. Usually, high SUA concentrations observed in MS have been partly attributed to insulin resistance. Concordantly, recent studies indicated that hyperuricemia may represent also a predictor of MS development. Methods: 139 subjects (72 females) aged 18 to 70 years (47 ± 12 years) were enrolled. Anthropometric parameters, blood pressure, fasting serum lipid, glucose, insulin, high-sensitive C-reactive protein (hs-CRP) and SUA levels were evaluated in all subjects. MS diagnosis was then made according to the National Cholesterol Education Program/Adult Treatment Panel III criteria. Results: subjects were divided into 6 groups according to the presence of 0 (healthy controls, n = 25), 1 (n = 29), 2 (n = 23), 3 (n = 27), 4 (n = 24) or 5 (n = 11) MS components. SUA levels were significantly higher in subjects with (6.19 ± 1.84 mg/dl) than without MS (4.88 ± 1.55 mg/dl) (p b 0.0001). Moreover, mean SUA levels raised gradually with the increasing number of MS components (p for trend b0.0001). In the whole population of subjects, SUA directly correlated with serum creatinine levels (p b 0.0001, r = 0.44), body weight (p b 0.0001, r = 0.46), BMI (p = 0.0002, r = 0.31), waist circumference (p b 0.0001, r = 0.40), fasting serum glucose (p = 0.003, r = 0.25) and insulin concentrations (p b 0.0001, r = 0.42), HOMA-IR (p b 0.0001, r = 0.42), serum triglyceride (p b 0.0001, r = 0.45) and hs-CRP levels (p b 0.0001, r = 0.37); and inversely correlated with serum HDL-cholesterol levels (p b 0.0001, r = − 0.51). Conclusions: SUA levels were higher in subjects with than without MS, and raised gradually as the number of MS components increased. The link between SUA levels and various metabolic parameters suggests that SUA might be considered as a component of MS.
RO
doi:10.1016/j.ejim.2013.08.096
time intervals between appointments. With such data we assume that there must be follow-up time related factors that contribute more to RF control than the number of appointments scheduled with the doctor.
OF
e40
DP
ID: 682 Time related outcomes and cardiovascular risk factors control R. Salvado, M. Araújo, M. Faria, G. Peres, J. Araújo, M.C. Matos Medicina Interna, Hospital de Cascais, Cascais, Portugal
UN
CO
RR
EC
TE
Aims/objectives: To evaluate whether outpatient appointment intervals influence cardiovascular risk factors (CVD RF) control. Material and methods: We retrospectively studied patients attending an outpatient clinic which was specialized in CVD RF control. In this analysis, we included patients whose first visit took place between 2005 and 2009 and that were followed for at least two years. We excluded patients that had CVD focused appointments with other doctors during this period. During the first year all patients had one appointment every three months. During the second year there were patients evaluated every three months, the others were evaluated every six months; we analyzed if there were any association between CVD RF control and those two different intervals. We also tried to understand whether CVD RF were better controlled by the end of the first or second year of follow-up. We focused our attention on the following CVD RF: weight, LDL cholesterol, HDL cholesterol, serum triglycerides, type 2 diabetes mellitus (DM) and blood pressure (BP). To determine whether the patient had achieved RF control we used the goals established by the European Society of Cardiology. Results: We analyzed 42 patients, 23 of which were male (55%), mean age 63 ± 9.09 years (std dev). 29 (69%) were in secondary prevention, 15 suffered from DM. The number of patients that achieved the desired cholesterol levels, DM and BP control increased with follow-up time. Controlled LDL cholesterol: 7 patients in the first appointment (1a), 26 by the end of the first year (1 y), 32 by the end of the second year (2 y); HDL cholesterol: 23 (1a), 23 (1 y), 25 (2 y); serum triglycerides: 17 (1a), 22 (1 y), 28 (2 y); DM: 4 (1a), 7 (1 y), 9 (2 y); BP: 23 (1a), 24 (1 y), 33 (2 y). There wasn't an improvement in weight control: 17 (1a), 13 (1 y), 16 (2 y). During the second year of follow-up, 16 patients had a six-monthly appointment; the remainder 26 were checked every three months. This difference was not related with CVD RF control (chi-square, p b 0.05): LDL (p = 0.37), HDL (p = 0.71), serum triglycerides (p = 0.36), DM (p = 0.3), and BP (p = 0.73). We didn't find any correlation between CVD RF control with either age or gender. Discussion and conclusion: In our population CVD RF control improved with follow-up time but it was not related with the
doi:10.1016/j.ejim.2013.08.098
ID: 688 Serum uric acid levels and endothelial function P. Di Giosia, A.V. Di Giacomantonio, P. Giorgini, R. Striuli, P. Cheli, S. Necozione, G. Desideri, G. Properzi, D. Grassi, C. Ferri Department of Life, Health and Environmental Sciences, San Salvatore Hospital, University of L'Aquila, L'Aquila, Italy
Objective: Several studies supported the hypothesis that asymptomatic hyperuricemia could be associated not only to hypertension, type 2 diabetes and renal failure, but also could represent an independent risk factor for cardiovascular disease. Endothelium plays a crucial role in atherogenesis and related adverse outcomes. It has been described that hyperuricemia can stimulate endothelial
0.41 (p = 0.01). Only the correlation between Mean SC and distal aorta PWV remained significant after correction for age (Table 1). Conclusions: In patients with PAOD, mean and maximum peripheral stenosis severity is strongly correlated with PWV in the distal aorta as compared to carotid VWA, while correlation with PWV in the proximal aorta is absent. Our findings indicate site-specific coupling between aortic wall stiffness and atherosclerotic burden.
Age Mean SC
R β p β p
PWVproximal
PWVdistal
VWA/BSA
0.45 0.50 0.10 −0.11 0.56
0.63 0.39 0.02 0.33 0.04
0.57 0.40 0.02 0.24 0.15
Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel Medicine A, Wolfson Hospital, Holon, Israel
Purpose: To assess risk factors of ischemic heart disease in women with surgical menopause. Methods: 141 women with surgical menopause were included in the investigation. All of them underwent general clinical examination, body mass index (BMI) calculation, measurement of waist circumference, menopausal index evaluation, ambulatory blood pressure and electrocardiogram monitoring (Cardiotens-01, Meditech, Hungary), determination of general cholesterol, lipid fractions and glucose tolerance. We also measured the level of non-etherized fatty acids and glycerol in blood serum. Postmenopausal women were 45.3 ± 2.8 years old and the duration of menopause was from 6 months to 7 years. The expression of menopausal syndrome was assessed according to the menopausal index dimension, which was 41.3 ± 11.06 score. Control group consisted of 17 healthy women (mean age 37.2 ± 4.2). Patients with coronary heart disease, essential hypertension, endocrine and grievous somatic diseases were excluded. Results: 74% (105 pts) of involved women had 2 or more attributes of menopausal metabolic syndrome: obesity (BMI 32.6 ± 1.4 kg/m2) with the prevalence of visceral adipose tissue (waist circumference ≥ 80 cm), hypercholesterolemia, hypertriglyceridemia, pathological glucose tolerance, arterial hypertension, and stages 1–2 (only 32% of patients had normal daily profile of blood pressure). Moreover, it was found, that the level of nonetherized fatty acids in patients with surgical menopause consisted 134% from the level of this index in healthy women (p b 0.05); and the level of glycerol was decreased in 29% (p b 0.05). The ratio of non-etherized fatty acids to glycerol permits to estimate the velocity of substrate utilization by peripheral tissues and myocardium as well. This index in postmenopausal women was 42% more than in control group (p b 0.01). We can conclude that the level of non-etherized fatty acids increased not only owing to lipolytic processes activation, but also resulted from the disturbances of this substrate utilization. The increase of non-etherized fatty acid level contributes to the development of insulin resistance, which is the key link of menopausal metabolic syndrome. Conclusions: Thus, postmenopausal women have expressive disorders in lipid and glucose metabolism, which may cause rapid atherosclerosis development in these patients.
DP
a
b
Therapy Department, Chita State Medical Academy, Chita, Russian Federation
RO
doi:10.1016/j.ejim.2013.08.093
ID: 331 Is HDL-Cholesterol still a target for pharmacologic therapy? D. Gavisha,b
ID: 375 Ischemic heart disease risk factors in postmenopausal women N. Lareva, A. Govorin
OF
Table 1 Linear regression modeling between proximal and distal aortic PWV and carotid VWA/BSA as dependent variables and age and mean peripheral stenosis class (Mean SC) as predictors.
e39
UN
CO
RR
EC
TE
Low HDL-C is associated with increased risk for cardiovascular disease (CVD) according to epidemiologic observational studies. The assumption that raising HDL-C by pharmacologic intervention will reduce CVD and reduce atherosclerosis is based on those observations as well as on small studies in animal models and in humans showing a reduction in plaques induced by raising HDL-C. Two prospective studies using Niacin and Niacin/laropiprant have failed to demonstrate reduction in CVD. (AIM HIGH and HPS2-Thrive).The negative results were partially explained by the excellent background treatment with statins in the control group and by safety issues related to niacin. A different method for raising HDL-C is by inhibiting Cholesterol Esther Transport (CETP).The first drug used was torcetrapib, this effort failed due to the increase in hypertension and aldosteron induced by the drug causing increased CVD and total mortality despite having good effects on lipids. A second CETP inhibitor without the blood pressure raising effect was dalcetrapib. This drug seemed to be very effective in raising HDL-C and improving endothelial function as well as reducing atheroma volume in the first studies. However the large prospective program was stopped due to no effects on CVD. There are two other more potent and safe CETP inhibitors still being studied in Large prospective studies: Anacetrapib and Evacetrapib. Those two drugs can cause a reduction in LDL-C as well as an increase in HDL-C. Alternative methods for reducing CVD include infusion of reconstituted HDL particles or Apo A-I during the acute coronary event, using methods for improving HDL function (Targeting inflammation and oxidation) and targeting other peptides or receptors related to HDL function such as SR-BP, ABCG1, LXR, and more. In summary: Although currently the status of HDL directed therapy is cloudy I believe that the future may still be bright and promising.
doi:10.1016/j.ejim.2013.08.094
doi:10.1016/j.ejim.2013.08.095
ID: 526 Family history of coronary heart disease is more strongly associated to coronary atherosclerosis than to carotid atherosclerosis B. Suha, D.W. Shina, S.P. Leeb, H. Leea, B. Choa a
Department of Family Medicine, Seoul National University Hospital, Seoul, South Korea b Department of Cardiology, Seoul National University Hospital, Seoul, South Korea
Background: Many new noninvasive tests for cardiovascular disease (CVD) risk assessment have added valuable clinical insights beyond traditional risk factors. Family history (FH) of coronary heart disease (CHD) is a major CVD risk that has been shown to be independent from other major risk factors. Methods: 662 asymptomatic Korean adults older than 30 years were investigated. Multivariable logistic regression analysis was employed to investigate comparative
Abstracts
association of FH of CHD to coronary computed tomography angiography (CTA) and carotid ultrasonography (USG). Results: Adjusted for major CVD risk factors, FH of CHD was shown to be significantly associated to significant coronary stenosis (aOR 4.92, 95% CI 1.58–15.4). Association of FH of CHD to increased carotid IMT (aOR 1.44, 95% CI 0.40–5.22) was much lower in strength and statistical power compared to its coronary counterpart. Moreover, the predictive model for significant coronary stenosis had a significantly higher predictive value when FH of CHD was included (AUC 0.808) compared to when it was not (AUC 0.772; likelihood ratio test (LRT) P = 0.0129), whereas no significant difference was observed upon inclusion of FH of CHD in the predictive model for increased carotid IMT (AUC 0.778 vs. 0.783, LRT P = 0.591). Conclusion: To our knowledge our study is the first to show specific comparative evidence that FH of CHD is more strongly associated to coronary atherosclerosis than to carotid atherosclerosis. Our results suggest that for asymptomatic adults with low-tointermediate CVD risk, compared to carotid USG, coronary CTA may be better suited to screen for subclinical atherosclerosis.
doi:10.1016/j.ejim.2013.08.097
ID: 687 Metabolic syndrome and acid uric P. Giorgini, S. Ciarla, M. Struglia, R. Striuli, P. Di Giosia, G. Properzi, C. Ferri Department of Life, Health and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
Objective: elevated serum uric acid (SUA) levels are frequently observed in patients with the (MS), although the clinical implication is still controversial. Usually, high SUA concentrations observed in MS have been partly attributed to insulin resistance. Concordantly, recent studies indicated that hyperuricemia may represent also a predictor of MS development. Methods: 139 subjects (72 females) aged 18 to 70 years (47 ± 12 years) were enrolled. Anthropometric parameters, blood pressure, fasting serum lipid, glucose, insulin, high-sensitive C-reactive protein (hs-CRP) and SUA levels were evaluated in all subjects. MS diagnosis was then made according to the National Cholesterol Education Program/Adult Treatment Panel III criteria. Results: subjects were divided into 6 groups according to the presence of 0 (healthy controls, n = 25), 1 (n = 29), 2 (n = 23), 3 (n = 27), 4 (n = 24) or 5 (n = 11) MS components. SUA levels were significantly higher in subjects with (6.19 ± 1.84 mg/dl) than without MS (4.88 ± 1.55 mg/dl) (p b 0.0001). Moreover, mean SUA levels raised gradually with the increasing number of MS components (p for trend b0.0001). In the whole population of subjects, SUA directly correlated with serum creatinine levels (p b 0.0001, r = 0.44), body weight (p b 0.0001, r = 0.46), BMI (p = 0.0002, r = 0.31), waist circumference (p b 0.0001, r = 0.40), fasting serum glucose (p = 0.003, r = 0.25) and insulin concentrations (p b 0.0001, r = 0.42), HOMA-IR (p b 0.0001, r = 0.42), serum triglyceride (p b 0.0001, r = 0.45) and hs-CRP levels (p b 0.0001, r = 0.37); and inversely correlated with serum HDL-cholesterol levels (p b 0.0001, r = − 0.51). Conclusions: SUA levels were higher in subjects with than without MS, and raised gradually as the number of MS components increased. The link between SUA levels and various metabolic parameters suggests that SUA might be considered as a component of MS.
RO
doi:10.1016/j.ejim.2013.08.096
time intervals between appointments. With such data we assume that there must be follow-up time related factors that contribute more to RF control than the number of appointments scheduled with the doctor.
OF
e40
DP
ID: 682 Time related outcomes and cardiovascular risk factors control R. Salvado, M. Araújo, M. Faria, G. Peres, J. Araújo, M.C. Matos Medicina Interna, Hospital de Cascais, Cascais, Portugal
UN
CO
RR
EC
TE
Aims/objectives: To evaluate whether outpatient appointment intervals influence cardiovascular risk factors (CVD RF) control. Material and methods: We retrospectively studied patients attending an outpatient clinic which was specialized in CVD RF control. In this analysis, we included patients whose first visit took place between 2005 and 2009 and that were followed for at least two years. We excluded patients that had CVD focused appointments with other doctors during this period. During the first year all patients had one appointment every three months. During the second year there were patients evaluated every three months, the others were evaluated every six months; we analyzed if there were any association between CVD RF control and those two different intervals. We also tried to understand whether CVD RF were better controlled by the end of the first or second year of follow-up. We focused our attention on the following CVD RF: weight, LDL cholesterol, HDL cholesterol, serum triglycerides, type 2 diabetes mellitus (DM) and blood pressure (BP). To determine whether the patient had achieved RF control we used the goals established by the European Society of Cardiology. Results: We analyzed 42 patients, 23 of which were male (55%), mean age 63 ± 9.09 years (std dev). 29 (69%) were in secondary prevention, 15 suffered from DM. The number of patients that achieved the desired cholesterol levels, DM and BP control increased with follow-up time. Controlled LDL cholesterol: 7 patients in the first appointment (1a), 26 by the end of the first year (1 y), 32 by the end of the second year (2 y); HDL cholesterol: 23 (1a), 23 (1 y), 25 (2 y); serum triglycerides: 17 (1a), 22 (1 y), 28 (2 y); DM: 4 (1a), 7 (1 y), 9 (2 y); BP: 23 (1a), 24 (1 y), 33 (2 y). There wasn't an improvement in weight control: 17 (1a), 13 (1 y), 16 (2 y). During the second year of follow-up, 16 patients had a six-monthly appointment; the remainder 26 were checked every three months. This difference was not related with CVD RF control (chi-square, p b 0.05): LDL (p = 0.37), HDL (p = 0.71), serum triglycerides (p = 0.36), DM (p = 0.3), and BP (p = 0.73). We didn't find any correlation between CVD RF control with either age or gender. Discussion and conclusion: In our population CVD RF control improved with follow-up time but it was not related with the
doi:10.1016/j.ejim.2013.08.098
ID: 688 Serum uric acid levels and endothelial function P. Di Giosia, A.V. Di Giacomantonio, P. Giorgini, R. Striuli, P. Cheli, S. Necozione, G. Desideri, G. Properzi, D. Grassi, C. Ferri Department of Life, Health and Environmental Sciences, San Salvatore Hospital, University of L'Aquila, L'Aquila, Italy
Objective: Several studies supported the hypothesis that asymptomatic hyperuricemia could be associated not only to hypertension, type 2 diabetes and renal failure, but also could represent an independent risk factor for cardiovascular disease. Endothelium plays a crucial role in atherogenesis and related adverse outcomes. It has been described that hyperuricemia can stimulate endothelial