|Year : 2020 | Volume
| Issue : 1 | Page : 4-9
Endothelial dysfunction in children with frequently relapsing and steroid-resistant nephrotic syndrome
Anuja Bhatia1, Abhijeet Saha2, Bobbity Deepthi2, Parul Goyal3, Ashish Datt Upadhyay4, Nand Kishore Dubey1
1 Department of Pediatrics, Division of Pediatric Nephrology, Postgraduate Institute of Medical Education and Research and Associated Dr. Ram Manohar Lohia Hospital, New Delhi, India
2 Division of Pediatric Nephrology, Department of Pediatrics, Lady Hardinge Medical College and Kalawati Saran Children Hospital, New Delhi, India
3 Department of Biochemistry, Postgraduate Institute of Medical Education and Research and Associated Dr Ram Manohar Lohia Hospital, New Delhi, India
4 Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India
|Date of Submission||27-Nov-2019|
|Date of Decision||14-Feb-2020|
|Date of Acceptance||31-Mar-2020|
|Date of Web Publication||27-Jun-2020|
Department of Pediatrics, Division of Pediatric Nephrology, Lady Hardinge Medical College and Kalawati Saran Children Hospital, New Delhi - 110001
Source of Support: None, Conflict of Interest: None
Background: Impaired endothelial function is a precursor of the atherosclerotic process leading to cardiovascular adverse events. This study evaluated endothelial dysfunction using endothelial markers in children with steroid-resistant NS (SRNS) and frequently relapsing or steroid-dependent NS (FRNS/SDNS). Methods: This was a cross-sectional study with short-term follow up. Thirty-five patients with nephrotic syndrome (NS), aged 1–18 years, including 19 with frequent relapses or steroid-dependent NS (FRNS/SDNS) and 16 with steroid resistant NS (SRNS), and 19 age- and gender-matched controls, were enrolled for the study. Soluble thrombomodulin (sTM), plasminogen activator inhibitor 1 (PAI-1), and von Willebrand factor (vWF) levels were measured in patients with FRNS/SDNS in relapse and after 6 months of steroid-induced remission, at diagnosis in SRNS, and in controls. Results: Levels of vWF, PAI-1, and sTM were significantly higher than controls in patients with active NS (FRNS/SDNS in relapse or SRNS; P < 0.0001). Patients with FRNS/SDNS had significantly elevated vWF levels, compared to controls, even after 6 months of corticosteroid therapy. Levels of vWF were significantly higher for patients with recently diagnosed SRNS than relapse of FRNS/SDNS (P < 0.0001). Conclusion: Children with FRNS/SDNS and SRNS have significant endothelial dysfunction in all stages of disease in varying severity. It is unclear whether persistently elevated biomarkers of endothelial dysfunction contribute to future atherosclerotic events in patients with NS.
Keywords: Atherosclerosis, cardiovascular morbidity, minimal change disease
|How to cite this article:|
Bhatia A, Saha A, Deepthi B, Goyal P, Upadhyay AD, Dubey NK. Endothelial dysfunction in children with frequently relapsing and steroid-resistant nephrotic syndrome. Asian J Pediatr Nephrol 2020;3:4-9
|How to cite this URL:|
Bhatia A, Saha A, Deepthi B, Goyal P, Upadhyay AD, Dubey NK. Endothelial dysfunction in children with frequently relapsing and steroid-resistant nephrotic syndrome. Asian J Pediatr Nephrol [serial online] 2020 [cited 2023 Jun 7];3:4-9. Available from: https://www.ajpn-online.org/text.asp?2020/3/1/4/288151
| Introduction|| |
Recent literature suggests that children with idiopathic nephrotic syndrome (NS) are predisposed to endothelial dysfunction, leading to atherosclerotic changes, and even acute myocardial infarction.,,,,, While altered lipid metabolism is an established modifiable risk factor for atherosclerosis and cardiovascular health in adults, analogous cardiovascular risk factors in children with NS are still being studied.,, The characterization of endothelial dysfunction using biomarkers might help in early identification of early premature onset atherosclerosis and subclinical cardiovascular morbidity.
Impaired endothelial function might evolve into symptomatic atherosclerosis, and hence indirectly indicates risk of future cardiovascular events., Exposure to proatherogenic risk factors leads to endothelial activation and injury, leading to release of circulatory markers from activated or apoptotic endothelial cells.,, Von Willebrand factor (vWF), released in response to endothelial damage, is a multimeric glycoprotein that serves as a carrier to factor VIII and helps mediate intimal platelet adhesion through the glycoprotein Ib-IX complex.,, The soluble form of thrombomodulin (sTM) or CD141, cleaved from the transmembrane form following endothelial injury during inflammation, promotes thrombin-mediated protein C activation., Plasminogen activator inhibitr-1 (PAI-1), a single-chain glycoprotein, is the principal inhibitor of the activators of plasminogen, and hence fibrinolysis, and is released soon after endothelial damage. Hence, all three substances appear to be valid markers of endothelial injury. We have previously reported their levels at onset of NS. Since there is a paucity of literature on endothelial injury in patients with steroid-resistant NS (SRNS) and frequently relapsing or steroid-dependent NS (FRNS/SDNS), the present study was planned to compare the plasma levels of vWF, PAI-1, and sTM in these patients with those in healthy children.
| Methods|| |
Study design and participants
This cross-sectional study, with short-term follow-up, was performed over 16 months, from November 2013 to March 2015 at a tertiary care hospital in New Delhi, India. Following approval by the Institutional Ethics Committee (1-40/65/2013/IEC/Thesis/PGIMER-RMLH/0318) and informed parental consent, patients between 1 and 18 years of age and diagnosed with FRNS (≥2 relapses within 6 months of initial response or >4 relapses in any year), SDNS (two consecutive relapses when on alternate day prednisolone, or within 14 days of its discontinuation), and SRNS (persistent proteinuria despite daily prednisolone therapy at a dose of 2 mg/kg/day for 4 weeks, after ensuring lack of infection or nonadherence to medication) were enrolled. Exclusion criteria included secondary NS, venous thromboembolism, preexisting hypertension, diabetes mellitus, recent transfusion of blood product, therapy with drugs affecting endothelial function, and refusal of consent. We also included healthy, age- and sex-matched controls. Patients with FRNS/SDNS were sampled twice, at diagnosis and 6 months later. At enrollment and during follow-up, these patients were only on corticosteroids and did not receive a second-line therapeutic agent. Patients with SRNS were sampled once at diagnosis and underwent ultrasound-guided percutaneous renal biopsy to confirm histology.
The primary outcome measure was levels of sTM, PAI-1, and vWF at diagnosis of FRNS/SDNS, as compared to after 6 months of steroid-induced remission, at diagnosis of SRNS and in controls. Blood samples were centrifuged at 2800 G for 10 min to derive plasma, which was immediately stored in four aliquots at −70°C until assays. Endothelial markers were quantitatively estimated using commercially available solid-phase sandwich enzyme-linked immunosorbent assay (ELISA) kits. The Gen-Probe (Diaclone SAS, Besancon Cedex, France) kit was used for estimating sTM, while the AssayMax Human ELISA kits (St. Charles, MO, USA) were used to detect PAI-1 and vWF. All measurements were done using Evolis Twin Plus instrument (Bio-Rad™). The intra-assay and inter-assay coefficients of variations were 4.9% and 7.1%, respectively, for vWF, 3.9% and 9.8%, respectively, for sTM, and 4.7% and 7.2%, respectively, for PAI-1.
Sample size calculation
Using reference values for mean ± standard deviation (SD) for sTM, tPA, and vWF levels from previous studies, for power of 80%, and alpha error of 5%, sample size was estimated at 20, 8, and 4 patients, respectively. In children with SRNS, using reference mean ± SD, power of 90%, and alpha error of 5%, the sample size was estimated at 10, 10, and 4 patients for sTM, tPA, and vWF, respectively.
Analysis was performed using SPSS (SPSS Inc., version 16.0, 2007; Chicago, USA). Continuous variables are presented as mean ± SD or median (interquartile range) depending on the normality of distribution, tested using the Kolmogorov–Smirnov test. Categorical variables were presented as frequency (percentage). Continuous data were compared among groups using one-way analysis of variance or Kruskall–Wallis test, as appropriate, and between paired and matched samples using the Wilcoxon signed-rank sum test. P < 0.05 was considered statistically significant.
| Results|| |
We enrolled 35 patients with NS, including 19 patients with FRNS/SDNS at diagnosis, and 16 patients at diagnosis of SRNS, along with 19 controls. [Table 1] shows the baseline characteristics of the cases and controls. All children with FRNS/SDNS were in relapse with a spot urine protein-to-creatinine ratio (Up: Uc) of 5.9 (3.9, 8.6) mg/mg creatinine at diagnosis, and in remission after 6 months of steroid therapy. Patients with SRNS had Up: Uc of 5.5 (3.1, 10.8) at diagnosis. Height and body mass index (BMI) differed significantly between cases and controls, and BMI SDS did not differ from baseline to 6 months later among children with FRNS/SDNS (P = 0.80). Children with FRNS/SDNS and SRNS had high serum cholesterol, Up: Uc, and low albumin (P < 0.05) at diagnosis. Serum cholesterol and triglyceride levels in FRNS/SDNS declined from 406 (359,444) mg/dl and 343 (280,430) mg/dl, respectively, at diagnosis, to 198 (189.5, 238) mg/dl and 189 (167.5, 206.5) mg/dl at 6-month follow-up (in remission). Serum cholesterol and triglyceride levels in children with SRNS were 360.5 (260, 463.2) mg/sdl and 242 (174.5, 323) mg/dl, respectively.
Levels of endothelial biomarkers
The levels of vWF, sTM, and PAI-1 were significantly higher in patients with FRNS/SDNS and SRNS at diagnosis, as compared to controls [Table 2]. The levels of sTM and PAI-1 fell significantly after 6 months of corticosteroid therapy in patients with FRNS/SDNS [Table 3]. However, levels of vWF did not differ significantly between the two time points [Table 3]. Levels of vWF, but not sTM or PAI-1, were significantly higher at onset of SRNS as compared with children with FRNS/SDNS at onset.
|Table 2: Levels of markers of endothelial dysfunction at enrollment in patients and controls|
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|Table 3: Plasma levels of markers of endothelial dysfunction in frequently relapsing nephrotic syndrome|
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Association of endothelial markers to biochemical characteristics
Total cholesterol was correlated positively to PAI-1 (r = 0.643; P < 0.001), sTM (r = 0.531; P < 0.001), vWF (r = 0.265; P = 0.027), and Up: Uc (r = 0.577; P < 0.001) and negatively with serum albumin (r = −0.603; P < 0.001). Multiple regression analysis, using levels of PAI-1, sTM, vWF, spot Up: Uc, and serum albumin, to predict serum total cholesterol levels, indicated that the model explained 62% of the variance, and was a significant predictor of hypercholesterolemia (F (3, 50) =27.34; P < 0.001). Levels of sTM (β = 2.624; P < 0.001), Up: Uc (β = 7.629; P = 0.004), and serum albumin (β = −63.45;β < 0.001) contributed significantly to the model.
| Discussion|| |
Endothelial dysfunction is deemed as the “risk of the risk factors.” Specific atherogenic risk factors in patients of NS might result in endothelial dysfunction, which is associated with future cardiovascular events. Endothelial markers are released secondary to endothelial injury; hence, their increased levels are consistent with endothelial dysfunction. Our study revealed that levels of vWF, sTM, and PAI-1 were significantly increased in patients with FRNS/SDNS and SRNS at diagnosis [Table 2]. Despite remission of disease, some endothelial markers continued to be high, indicating persistent risk of atherosclerosis.
Sharma et al. and Tkaczyk, et al. observed that the levels of vWF, sTM, and PAI-1 were elevated in patients with first episode of NS , and that endothelial dysfunction was most pronounced in relapse. Arumugam et al. demonstrated increased plasma levels of endothelin-1 at onset of NS, indicating a proinflammatory and prothrombotic state of the endothelium., Endothelial dysfunction was demonstrated in FSGS patients by increased levels of endothelial markers, including vWF, circulating endothelial cells (CECs), soluble vascular cell adhesion molecule-1 (sVCAM-1), sTM, and soluble e-selectin. Patients with thromboembolism had raised levels of CECs and vWF than those without thromboembolism. Zhang et al. reported increased levels of vWF and sTM and Malyszko et al. found higher levels of sTM in NS cases as compared to controls., Therefore, overwhelming evidence supports the role of endothelial dysfunction even at the onset of NS. However, previous studies have not examined endothelial dysfunction in children with FRNS/SDNS.
Previous reports of endothelial injury at onset of NS improved during remission., Our study showed that the markers of endothelial dysfunction were significantly elevated in patients with FRNS/SDNS at diagnosis and the levels declined with remission, except vWF which continued to be elevated at 6 months of steroid therapy. This suggests that some amount of endothelial damage persists even at remission. As vWF is deemed a marker of endothelial activation, its persistent high levels indicate a chronic activation of the endothelium in patients with FRNS/SDNS. Plausible mechanisms for its elevation in patients with FRNS/SDNS and SRNS are unremitting proteinuria, chronic exposure to steroids, and persistent hypoalbuminemia. These results are consistent with observations by Tkaczyk et al., who found that the endothelial markers sTM and PAI-1 decreased gradually over several months, but vWF activity increased in patients with NS, regardless of disease stage. Sharma et al. illustrated that the levels of endothelial dysfunction markers fall after 12 weeks of remission of first episode of NS. Zhang et al. showed that adults with FSGS have high levels of CECs, vascular cell adhesion molecule (VCAM-1), and sTM, that decline significantly after nonsteroidal immunosuppressive therapy, but vWF and sVCAM-1 persisted at high levels for a year despite complete remission. In our study, we found significantly higher levels of vWF, sTM, and PAI-1 in patients with SRNS as compared to controls, and significantly elevated levels of vWF in patients with SRNS as compared to those with FRNS/SDNS, indicating an increased risk of endothelial injury in patients with steroid resistance as compared to steroid sensitive NS, suggesting a higher risk of accelerated atherosclerosis and perfusion abnormalities. Findings of the present work are consistent with our previous study, which found that the levels of tPA, vWF, and sTM were significantly raised in patients with SRNS compared to infrequently relapsing steroid sensitive NS.
Hypercholesterolemia and hypoalbuminemia are reported to be associated with endothelial injury, and the present study suggests similar correlations. Previous studies in patients at onset of steroid sensitive NS and adults with FSGS suggest similar correlation., Some other published studies, however, show inconsistent relationships between these markers and biochemical parameters in NS.,
Other endothelial markers that have been studied in NS recently include endothelin-1, asymmetric dimethylarginine, CECs, soluble e-selectin, VCAM, thrombomodulin, CD146, syndecan-1, intercellular adhesion molecule-1, and free homocysteine.,,,,, Increasingly, reports emphasize the role of studying carotid intima-media thickness (cIMT) as a predictor of atherosclerosis.,, A systematic review indicated an association between cIMT and coronary atherosclerosis or cardiovascular events., Flow-mediated dilatation (FMD) is another surrogate of endothelial function. Overall, endothelial dysfunction has emerged as a critical concept and is understood as progressing continuously from reversible (Type I and II endothelial activation) to irreversible (endothelial apoptosis and necrosis) endothelial dysfunction.
The reversible phase of endothelial dysfunction might be a target of interventional strategies. Clarkson et al. showed that L-arginine boosts endothelium-dependent dilatation. Mancini et al. studied the impact of ACE inhibitors on reversible endothelial dysfunction in patients with coronary artery disease in the Trial on Reversing Endothelial Dysfunction (TREND) study. A meta-analysis established that treatment with niacin improves endothelial function. Other drugs studied for their role in endothelial dysfunction include atenolol, lacidipine, irbesartan, and valsartan., HMG-CoA reductase inhibitors (statins, e.g., atorvastatin, cervistatin, and simvastatin) have gained popularity in NS due to their proven role in hypercholesterolemia which correlates with endothelial dysfunction. Statins are shown to reduce PAI-1 and significantly improve FMD., Therapy with statins lead to substantial improvement in dyslipidemia in adult patients with NS, but have unproven value in changing long-term cardiovascular outcomes for pediatric patients. A well-designed longitudinal study is required to understand the role of early treatment with statins in pediatric patients with FRNS/SDNS and SRNS with significant endothelial dysfunction.
| Conclusion|| |
Children with FRNS/SDNS and SRNS have significant endothelial dysfunction in all stages of disease in varying severity as reflected by the levels of endothelial markers. Our study was limited by its small sample size and lack of long-term follow-up for cardiovascular outcomes. We did not assess FMD, cIMT, and markers of cardiovascular morbidity to assess the functional impact of the elevated endothelial markers.
We acknowledge the contribution of Professor Vineeta Batra, GB Pant Hospital, New Delhi, in histopathological examination of the samples.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Zhao Y, Su W, Liu S, Huo Q, Zhang H. Acute myocardial infarction in a young girl with nephrotic syndrome: A case report and literature review. Can J Cardiol 2017;33:950.e15-9.
Suryawanshi SP, Das B, Patnaik AN. Myocardial infarction in children: Two interesting cases. Ann Pediatr Cardiol 2011;4:81-3.
Nandi M, Mondal R. Nephrotic syndrome with atherosclerosis. Indian Pediatr 2011;48:907-8.
Youssef DM, Gomaa MA, El-Akhras A, Tolba SA, Abd Allah GM, Daoud O, et al
. Brachial artery flow-mediated dilatation and carotid intima-media thickness in children with idiopathic nephrotic syndrome. Iran J Kidney Dis 2018;12:331-40.
Skrzypczyk P, Kuźma-Mroczkowska E, Kułagowska J, Brzewski M, Okarska-Napierała M, Pańczyk-Tomaszewska M. Carotid intima-media thickness in children with idiopathic nephrotic syndrome: A single center cross-sectional study. Clin Nephrol 2019;91:353-62.
Hari P, Khandelwal P, Smoyer WE. Dyslipidemia and cardiovascular health in childhood nephrotic syndrome. Pediatr Nephrol 2019. doi: 10.1007/s00467-019-04301-y.
Patnaik SK, Kumar P, Bamal M, Patel S, Yadav MP, Kumar V, et al
. Cardiovascular outcomes of Nephrotic syndrome in childhood (CVONS) study: A protocol for prospective cohort study. BMC Nephrol 2018;19:81.
Lechner BL, Bockenhauer D, Iragorri S, Kennedy TL, Siegel NJ. The risk of cardiovascular disease in adults who have had childhood nephrotic syndrome. Pediatr Nephrol 2004;19:744-8.
Chong AY, Blann AD, Lip GY. Assessment of endothelial damage and dysfunction: Observations in relation to heart failure. QJM 2003;96:253-67.
Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr., Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 2000;101:948-54.
Zhang J, Bottiglieri T, McCullough PA. The central role of endothelial dysfunction in cardiorenal syndrome. Cardiorenal Med 2017;7:104-17.
Lip GY, Blann A. von Willebrand factor: A marker of endothelial dysfunction in vascular disorders? Cardiovasc Res 1997;34:255-65.
Makin AJ, Blann AD, Chung NA, Silverman SH, Lip GY. Assessment of endothelialdamage in atherosclerotic vascular disease by quantification of circulating endothelial cells. Relationship with von Willebrand factor and tissue factor. Eur Heart J 2004;25:371-6.
Blann AD, Taberner DA. A reliable marker of endothelial cell dysfunction: Does it exist? Br J Haematol 1995;90:244-8.
Boehme MW, Deng Y, Raeth U, Bierhaus A, Ziegler R, Stremmel W, et al
. Release of thrombomodulin from endothelial cells by concerted action of TNF-alpha and neutrophils:In vivo
and in vitro
studies. Immunology 1996;87:134-40.
Tohda G, Oida K, Okada Y, Kosaka S, Okada E, Takahashi S, et al
. Expression of thrombomodulin in atherosclerotic lesions and mitogenic activity of recombinant thrombomodulin in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1998;18:1861-9.
Quyyumi AA, Dakak N, Andrews NP, Husain S, Arora S, Gilligan DM, et al
. Nitric oxide activity in the human coronary circulation. Impact of risk factors for coronary atherosclerosis. J Clin Invest 1995;95:1747-55.
Sharma B, Saha A, Dubey NK, Kapoor K, Anubhuti, Batra VV, et al
. Endothelial dysfuntion in children with idiopathic nephrotic syndrome. Atherosclerosis 2014;233:704-6.
Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: A marker of atherosclerotic risk. Arterioscler Thromb Vasc Biol 2003;23:168-75.
Tkaczyk M, Czupryniak A, Owczarek D, Lukamowicz J, Nowicki M. Markers of endothelial dysfunction in children with idiopathic nephrotic syndrome. Am J Nephrol 2008;28:197-202.
Arumugam V, Saha A, Kaur M, Basak T, Sengupta S, Batra V, et al
. Endothelin 1 and endothelial dysfunction in children with idiopathic nephrotic syndrome. Artery Res 2017;18:36-40.
Zhang Q, Zeng C, Fu Y, Cheng Z, Zhang J, Liu Z. Biomarkers of endothelial dysfunction in patients with primary focal segmental glomerulosclerosis. Nephrology (Carlton) 2012;17:338-45.
Malyszko J, Malyszko JS, Mysliwiec M. Markers of endothelial cell injury and thrombin activatable fibrinolysis inhibitor in nephrotic syndrome. Blood Coagul Fibrinolysis 2002;13:615-21.
Shouman M, Abdallah N, Tablawy NE, Rashed L. Biochemical markers of endothelial dysfunction in pediatric nephrotic syndrome. Arch Med Sci 2009;5:415-21.
Kniazewska MH, Obuchowicz AK, Wielkoszyński T, Zmudzińska-Kitczak J, Urban K, Marek M, et al
. Atherosclerosis risk factors in young patients formerly treated for idiopathic nephrotic syndrome. Pediatr Nephrol 2009;24:549-54.
Arumugam V, Saha A, Kaur M, Deepthi B, Basak T, Sengupta S, et al
. Plasma free homocysteine levels in children with idiopathic nephrotic syndrome. Indian J Nephrol 2019;29:186-90.
] [Full text]
Hyla-Klekot L, Bryniarski P, Pulcer B, Ziora K, Paradysz A. Dimethylarginines as risk markers of atherosclerosis and chronic kidney disease in children with nephrotic syndrome. Adv Clin Exp Med 2015;24:307-14.
Kundal M, Saha A, Dubey NK, Kapoor K, Basak T, Bhardwaj G, et al
. Homocysteine metabolism in children with idiopathic nephrotic syndrome. Clin Transl Sci 2014;7:132-6.
Małyszko J, Małyszko JS, Myśliwiec M. Is there a link between CD146, a novel adhesion molecule and other markers of endothelial dysfunction in nephrotic syndrome and continuous ambulatory peritoneal dialysis? Thromb Res 2005;115:19-24.
Litwin M, Niemirska A. Intima-media thickness measurements in children with cardiovascular risk factors. Pediatr Nephrol 2009;24:707-19.
Hooman N, Isa-Tafreshi R, Otukesh H, Mostafavi SH, Hallaji F. Carotidartery function in children with idiopathic nephrotic syndrome. Nefrologia 2013;33:650-6.
Ksiazek J, Niemirska A, Lipka M, Grenda R. Evaluation of arterial intima-media thickness (IMT) in children with idiopathic nephrotic syndrome–preliminary report. Przegl Lek 2006;63 Suppl 3:205-7.
Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: A systematic review and meta-analysis. Circulation 2007;115:459-67.
Wang JG, Staessen JA, Li Y, Van Bortel LM, Nawrot T, Fagard R, et al
. Carotid intima-media thickness and antihypertensive treatment: A meta-analysis of randomized controlled trials. Stroke 2006;37:1933-40.
Rahul I, Krishnamurthy S, Satheesh S, Biswal N, Bobby Z, Lakshminarayanan S. Brachial artery flow-mediated dilatation and carotid intimal medial thickness in pediatric nephrotic syndrome: A cross-sectional case–control study. Clin Exp Nephrol 2015;19:125-32.
Clarkson P, Adams MR, Powe AJ, Donald AE, McCredie R, Robinson J, et al
. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest 1996;97:1989-94.
Mancini GB, Henry GC, Macaya C, O'Neill BJ, Pucillo AL, Carere RG, et al
. Angiotensin-converting enzyme inhibition with quinapril improves endothelial vasomotor dysfunction in patients with coronary artery disease. The TREND (Trial on Reversing ENdothelial Dysfunction) study. Circulation 1996;94:258-65.
Sahebkar A. Effect of niacin on endothelial function: A systematic review and meta-analysis of randomized controlled trials. Vasc Med 2014;19:54-66.
Taddei S, Virdis A, Ghiadoni L, Magagna A, Pasini AF, Garbin U, et al
. Effect of calcium antagonist or beta blockade treatment on nitric oxide-dependent vasodilation and oxidative stress in essential hypertensive patients. J Hypertens 2001;19:1379-86.
Sozen AB, Kayacan MS, Tansel T, Celebi A, Kudat H, Akkaya V, et al
. Drugs with blocking effects on the renin-angiotensin-aldosterone system do not improve endothelial dysfunction long-term in hypertensive patients. J Int Med Res 2009;37:996-1002.
Konduracka E, Galicka-Latala D, Cieslik G, Rostoff P, Fedak D, Sieradzki J, et al
. Effect of atorvastatin on endothelial function and inflammation in long-duration type 1 diabetic patients without coronary heart disease and arterial hypertension. Diabetes Obes Metab 2008;10:719-25.
Zhang L, Gong D, Li S, Zhou X. Meta-analysis of the effects of statin therapy on endothelial function in patients with diabetes mellitus. Atherosclerosis 2012;223:78-85.
Dogra GK, Watts GF, Herrmann S, Thomas MA, Irish AB. Statin therapy improves brachial artery endothelial function in nephrotic syndrome. Kidney Int 2002;62:550-7.
[Table 1], [Table 2], [Table 3]