Endothelial dysfunction precedes atherosclerosis and the development of cardiovascular disease

Studies have long demonstrated a correlation between endothelial dysfunction and conditions predisposing to CVD, including: arterial hypertension, normotensive subjects with a family history of hypertension, smoking, dyslipidemia, aging, diabetes mellitus, and obesity.

Publications & Other Studies

Endothelial dysfunction predicts early-stage CVD

Table 1 highlights some of the most significant studies from the last twenty years.publication-tables-1

Flow-mediated dilation accurately measures endothelial dysfunction

Table 2 summarizes longitudinal studies using the gold standard — brachial artery ultrasound imaging — to measure %FMD. In these large population studies, the correlation between overall CVD risk and %FMD is apparent.
publication-tables-prov

Studies That Utilize The AngioDefender System

Rosuvastatin improves endothelial dysfunction in RA

A Syngle1, N Garg2, P Krishan2

1Cardio Rheuma, Healing Touch City Clinic and Fortis Hospital, Chandigarh, India,

2Department of Pharmaceutical Sciences & Drug Research, Punjabi University, Patiala, India

 

Objective: Inflammation in rheumatoid arthritis (RA) is associated with endothelial dysfunction (ED), which leads to accelerated atherosclerosis. Rosuvastatin improves the ED in non-rheumatic diseases but it has not yet been investigated in rheumatic diseases. We aimed to investigate the effect of rosuvastatin on ED in RA.

 

Methods: Forty RA patients were randomized to receive 6 months of treatment with rosuvastatin (10 mg/day, n = 20) or placebo (n = 20) as an adjunct to existing anti-rheumatic drug treatment. Inflammatory disease activity measures included Disease activity score of 28 joints (DAS28); CRP and ESR were measured at baseline and after treatment. Flow mediated dilatation (FMD) was assessed by AngioDefenderTM (Everist Health, Ann Arbor, MI, United States). Pro-inflammatory cytokines (TNF-a, IL-6 and IL-1) were measured by ELISA.

 

Results: At baseline, inflammatory measures and pro-inflammatory cytokines were elevated among both groups. At baseline, significant correlation was found between FMD and CRP and IL-6 in the rosuvastatin group while significant correlation was found between FMD and CRP in the placebo group. After treatment with rosuvastatin, FMD improved significantly from 3.82 ± 1.4% to 9.84 ± 1.10% (P < 0.01). After treatment with rosuvastatin, levels of inflammatory measures (Fig. 2), low-density lipoprotein cholesterol and pro-inflammatory cytokines decreased significantly. There was no significant change in the placebo group. Significant negative correlation was observed between FMD and IL-1, TNF-a (Fig. 1), disease activity measures like DAS28, and CRP after treatment with rosuvastatin.

 

Figure 1. FMD negatively correlated with IL-1 and TNF-a.

 

Figure 2. Effect of rosuvastatin on inflammatory measures

 

Conclusion: First study to show that rosuvastatin improves inflammatory disease activity and ED in patients with RA. Beneficial effect of rosuvastatin may be attributed to lowering inflammatory disease activity measures and pro-inflammatory cytokines. Improvement in ED in RA occurs through both cholesterol-independent and -dependent pathways.

 

Acknowledgement: This study has been supported by APLAR 2012 Research Grant.

APLAR-0348. International Journal of Rheumatic Diseases 2014; 17 (Suppl. 1): 55. http://onlinelibrary.wiley.com/doi/10.1111/1756-185x.12344/abstract

 

Update: Rosuvastatin Improves Inflammation and Vascular Function in Rheumatoid Arthritis

A Syngle1, N Garg2, P Krishan2

1Cardio Rheuma, Cardio Rheuma & Healing Touch City Clinic, Chandigarh and Senior Consultant Physician and Rheumatologist Fortis Multi-Specialty Hospital Hospital, Mohali, India

2Department of Pharmaceutical Sciences & Drug Research, Punjabi University, Patiala, India

 

Background: Increased cardiovascular risk in patients with rheumatoid arthritis (RA) provides a strong rationale for early therapeutical interventions. In view of the similarities between atherosclerosis and RA1 and the proven benefit of statins in atherosclerotic vascular disease, rosuvastatin is being investigated in RA. 

 

Objectives: To delineate the impact of rosuvastatin on endothelial function and adhesion molecules as well as on markers of inflammation in patients with RA. 

 

Methods: 76 RA patients were randomized to receive 6 months of treatment with rosuvastatin (10 mg/day, n=38) or placebo (n=38) as an adjunct to existing stable antirheumatic drugs. Flow mediated dilatation (FMD) was assessed by AngioDefender™ (Everist Health, Ann Arbor, MI, United States). Inflammatory measures included Disease Activity Score of 28 joints (DAS28), CRP and ESR were measured at baseline and after treatment. Estimation of serum nitrite, lipids, pro-inflammatory cytokines (TNF-α, IL-6 and IL-1) and adhesion molecules (ICAM-1 and VCAM-1) was done at baseline and after treatment. 

 

Results: At baseline, inflammatory measures, pro-inflammatory cytokines and adhesion molecules were elevated among both groups. At baseline, significant correlation was found between FMD and CRP and ICAM-1 in the rosuvastatin group while significant correlation was found between FMD and CRP in the placebo group. FMD increased significantly (p<0.01) after treatment with rosuvastatin but did not show significant change with placebo. After treatment, rosuvastatin exerted positive effect on lipid spectrum: lowering concentration of total cholesterol, LDL, elevation of HDL as compared with placebo. At 6 months, DAS28, ESR, CRP, TNF-α and IL-6 improved significantly on rosuvastatin as compared with placebo (Fig.1). Furthermore, concentrations of serum nitrite and ICAM-1 were significantly lower in the rosuvastatin group compared with the placebo group. There was no significant improvement in IL-1 and VCAM-1 in both groups. Significant negative correlation was observed between FMD and IL-6, ICAM-1, CRP and LDL after treatment with rosuvastatin.

 

Figure 1. Percentage change in inflammatory markers after treatment with rosuvastatin compared to placebo

 

Conclusions: First study to show that rosuvastatin improves inflammatory disease activity and endothelial dysfunction in RA. Rosuvastatin lowers the proinflammatory cytokines, especially IL-6 and TNF-α, which down regulates adhesion molecules and CRP production and thus the production of NO. Reduction of cytokines and CRP favorably impacts the inflammatory disease activity. Rosuvastatin also favorably improved the lipid levels through HMG-CoA reductase inhibition and possibly through cytokine reduction. These factors, in turn, improve the endothelial dysfunction. The anti-inflammatory and vasculoprotective effects of rosuvastatin in RA appear to be due to its anti-proinflammatory cytokine effect and HMG-CoA reduction. Rosuvastatin can mediate modest but clinically apparent anti-inflammatory effects with modification of vascular risk factors in the context of high-grade autoimmune inflammation of RA. These findings suggest that vascular effects of rosuvastatin may provide a novel strategy to prevent cardiovascular events in these patients. 

 

References: [1] Kaplan, M.J. Curr. Opin. Rheumatol. 2006; 18:289-297 

 

Acknowledgements: This study was supported by APLAR Research Grant. 

 

Disclosure of Interest: None declared 

 

THU0113 

A. Syngle, N. Garg, P. Krishan. Rosuvastatin Improves Inflammation and Vascular Function in Rheumatoid Arthritis. Ann Rheum Dis. 2014; (suppl.2):1-1332 (217). [DOI: 10.1136/annrheumdis-2014-eular.5290] 

http://ard.bmj.com/content/73/Suppl_2/217.1.full.pdf+html?sid=d36e52aa-541c-4961-af7f-e31354fbe7c8

Rosuvastatin and Olmesarta Improve Inflammation and Endothelial Function in Rheumatoid Arthritis

A Syngle1, N Garg2, P Krishan2

1Cardio Rheuma, Cardio Rheuma & Healing Touch City Clinic, Chandigarh and Senior Consultant Physician and Rheumatologist Fortis Multi-Specialty Hospital Hospital, Mohali, India

2Department of Pharmaceutical Sciences & Drug Research, Punjabi University, Patiala, India

 

Background: Cardiovascular disease remains the leading cause of excessive morbidity and mortality in rheumatoid arthritis (RA). Atherosclerosis and RA share similar pathogenetic mechanisms1. Rosuvastatin and olmesartan improve inflammation and endothelial dysfunction in non-rheumatic patients but it has not yet been investigated in rheumatic patients. 

 

Objectives: To investigate the effects of rosuvastatin and olmesartan on inflammation and endothelial function in patients with rheumatoid arthritis 

 

Methods: Forty-five RA patients fulfilling the 2010 Rheumatoid Arthritis classification criteria were randomized into 3 groups to receive 6 months treatment with rosuvastatin (10 mg/day, n=15), olmesartan (10 mg/day, n=15) and placebo (n=15) as an adjunct to existing stable antirheumatic drugs. Flow mediated dilatation (FMD) was assessed by AngioDefender™ (Everist Health, Ann Arbor, MI, United States). Inflammatory measures, including Disease Activity Score of 28 joints (DAS28), CRP and ESR, pro-inflammatory cytokines (TNF-α, IL-6 and IL-1), serum nitrite and adhesion molecules (ICAM-1 and VCAM-1), and levels of lipids were measured at baseline and after treatment.

 

Results: At baseline, all inflammatory measures, pro-inflammatory cytokines and adhesion molecules were elevated and endothelial function impaired among all the three groups. After 6 months of therapy, FMD increased by 67.1%, 44.1% and 6.1%, in the rosuvastatin, olmesartan and placebo groups respectively (Fig.1A) and DAS28 significantly reduced by 55.2%, 25% and 7.5%, in the rosuvastatin, olmesartan and placebo groups respectively (Fig.1B). 

 

 

 

Both rosuvastatin and olmesartan significantly decreased serum CRP and TNF-α as compared with placebo. Rosuvastatin also significantly improved ESR, IL-6, ICAM-1and serum nitrite concentration after 6 months but olmesartan and placebo had no significant change in these measures. IL-1 showed insignificant changes in both the drug groups and placebo. Rosuvastatin produced significant reductions in total cholesterol and LDL cholesterol but there were no significant changes in the lipid profile in recipients of olmesartan and placebo. Olmesartan significantly reduced blood pressure compared with rosuvastatin and placebo. Significant negative correlation was observed between FMD and IL-6 and TNF-α after treatment with rosuvastatin whereas a significant inverse correlation was found between FMD and TNF-α after treatment with olmesartan. 

 

Conclusions: First study to show that rosuvastatin and olmesartan improve inflammation and endothelial dysfunction in RA. Both rosuvastatin and olmesartan lowers the pro-inflammatory cytokines, especially IL-6 and TNF-α which down regulates the production of CRP and NO and improves the inflammation and endothelial dysfunction. However, rosuvastatin, in addition, also favourably impacted ICAM-1 and lipid abnormalities. In contrast, olmesartan has beneficial effect on blood pressure. Thus both rosuvastatin and olmesartan have anti-inflammatory and vasculoprotective effects in RA mediated through anti-proinflammatory cytokine action. 

 

References: 

[1] Sattar N et al., Circulation. 2003; 108:2957-63. 

 

Acknowledgements: This study was supported by Research Grant from Universal Grant Commission, New Delhi [F. No.41-725/2012 (SR)]. 

 

Disclosure of Interest: None declared 

 

THU0112 

A. Syngle, N. Garg, P. Krishan. Rosuvastatin and Olmesartan Improve Inflammation and Endothelial Dysfunction in Rheumatoid Arthritis. Ann Rheum Dis. 2014; (suppl.2):1-1332 (216). [DOI: 10.1136/annrheumdis-2014-eular.5272]

 

 

Adhesion Molecules and Brachial Artery Vasodilator Function in RA

A Syngle1, N Garg2, P Krishan2
1Cardio Rheuma, Healing Touch City Clinic and Fortis Hospital, Chandigarh, India,
2Department of Pharmaceutical Sciences & Drug Research, Punjabi University, Patiala, India

 

Objective: We aimed to investigate the relationship between biomarkers of endothelial dysfunction, inflammation and vascular function in rheumatoid arthritis (RA) patients.

 

Methods: Thirty adult RA patients (4 male, 26 female) and 30 age and sex matched healthy controls (6 male, 24 female) were enrolled in the study. Assessment of FMD was done by AngioDefender (Everist Health, Ann Arbor, MI, United States). Soluble adhesion molecules (sICAM-1 and sVCAM-1) and pro-inflammatory cytokines (TNF-α, IL-6 and IL-1) were measured using standard ELISA kits. As surrogates for disease activity, DAS28, C-reactive protein and ESR levels were determined.

 

Results: Compared with healthy controls, RA patients had significantly (P < 0.05) increased basal concentrations of soluble intracellular adhesion molecules (sICAM-1), soluble vascular cell adhesion molecule (sVCAM-1), tumour necrosis factor-a (TNF-α), interleukin-6 (IL-6) and interleukin-1 (IL-1). Concentrations of sVCAM-1 related to TNF- α and FMD (P < 0.05) while sICAM-1 related to IL-1 (P < 0.05). sVCAM-1 related to DAS28 and CRP revealed a significant (P = 0.01) positive correlation in RA patients.

 

Conclusion: In RA, endothelial activation correlates with FMD, through inappropriate secretion of cytokines. Our observations are consistent with the hypothesis that upregulation of adhesion molecules by inflammatory cytokines impairs vascular function. This suggests that strategies to decrease inflammatory activity in RA patients should focus not only on the treatment of conventional risk factors, but also on the improvement of endothelial function.

 

Acknowledgement: This study has been supported by APLAR 2012 Research Grant.

APLAR-0302. International Journal of Rheumatic Diseases 2014; 17 (Suppl. 1): 54. http://onlinelibrary.wiley.com/doi/10.1111/1756-185x.12344/abstract

 

 

E.P.C.s are a Determinant of Vascular Function & Atherosclerosis in A.S.

A Syngle1, I Verma2N Garg2, P Krishan2

1Cardio Rheuma, Healing Touch City Clinic and Fortis Hospital, Chandigarh, India,

2Department of Pharmaceutical Sciences & Drug Research, Punjabi University, Patiala, India

 

Objectives: Ankylosing spondylitis (AS) is an inflammatory disease associated with premature atherosclerosis. We hypothesized that depleted endothelial progenitor cells (EPCs), mediators of inflammation and carotid intima media thickness (cIMT) are associated with atherosclerosis in other populations and would be increased and associated with the severity of coronary atherosclerosis in patients with AS. 

 

Methods: We compared 30 patients of AS with 22 healthy controls. CD34+, CD133+, were used to quantify EPCs using flow cytometry. Flow-mediated dilatation (FMD) was assessed by using AngioDefenderTM (Everist Health, Ann Arbor, MI, United States). CIMT was measured using ultrasonography. Pro-inflammatory cytokines and inflammatory disease activity measures, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Functional ability, as monitored by using Bath Ankylosing Spondylitis Functional Index (BASFI), were also assessed. 

 

Results: EPCs were significantly decreased in AS patients as compared to healthy controls (P = 0.01). We also found significantly increased CIMT in AS group compared with controls (P = 0.01). FMD was significantly impaired and inflammatory disease activity measures i.e. BASDAI, BASFI and serum concentrations of IL-6, TNF-α and IL-6 were higher in AS patients than controls (all P < 0.05). We also found significantly increased CIMT in the AS group compared with controls (P = 0.01). Total cholesterol and high density lipoprotein cholesterol levels were significantly impaired in AS patients compared with controls (P < 0.05). A significant positive correlation was observed between the percentage of EPCs, FMD and HDL cholesterol (P < 0.05) and a negative correlation was found between EPC and CIMT, IL-6, and BASDAI. 

 

Conclusion: EPCs are significantly associated with the severity of subclinical atherosclerosis in AS. Higher CV risk in AS is possibly also contributed by reduced EPCs, altered lipid profile and higher levels of pro-inflammatory cytokines. Impaired EPC may lead to accelerated vascular remodeling due to chronic impairment of endothelial function. 

 

APLAR-0337. International Journal of Rheumatic Diseases 2014; 17 (Suppl. 1): 75-76. http://onlinelibrary.wiley.com/doi/10.1111/1756-185x.12344/abstract

 

 

FEASIBILITY OFANGIODEFENDERASSESSMENTIN CARDIAC REHABILITATION

J.Wulffhart,T.Hartley, K.Unsworth, D.Humen, N.Suskin

St.Joseph’sHospitalCardiac Rehabilitation andSecondaryPrevention Program,London,ON

Rationale:AngioDefender(AD)isanon-ultrasound tool developed byEveristHealth(Ann Arbor,MI,USA) toassessFlowMediated Dilation(FMD)in thebrachialartery,usinga proprietaryalgorithmicanalysisofupperarmpulse waves.The Everist VascularAgeCalculator (VAC)combinesFMD withtraditionalFraminghamRiskcomponentstoscale chronologicalage to“risk-adjusted age” (VA).PreviousAD studieshaveassessed FMD in presumedhealthy populations;we wereinterestedin thefeasibilityofusingADandthe VACtocalculateFMD andVA,respectively,in patientswith establishedcardiovasculardisease.

Objectives:To better understandtheparticipantexperience,interestand reactiontoAD assessment ofFMD and VA.

Methods:Twenty-seven patientsfrom atertiarycentreCardiac Rehabilitation(CR)Program participatedin thisstudy. ParticipantsunderwenttwoAD assessmentsofFMDatentryintoCR, on separate days(Pre-1,Pre-2), atthe sametimeofday,undersimilarfasting andresting conditions,nomorethana weekapart.Briefly,the ADprocedure includeda 10-minuterest; baseline assessment;5-minute upperarmocclusion atSBP+30mmHg;and recovery assessmentpost-occlusion tocalculate%FMD.Thisisan identical procedure tothatroutinely used when measuring FMD usingvascularultrasound.Aftereachtest,participants wereasked toratetheircomfort,willingnesstoundergo additional tests,and interestinresults,using a5- pointLikertscale.AfterPre-2,VA was calculated,and participant reactionto theirVA wasalso evaluated.

Results:Ofthe 26patientswho initiatedPre-1testing,median comfort was“high”,although 6/26respondentsratedthetest“low”or“verylow”comfortafter Pre-1.Thisimprovedto only one ratingof“low”comfortafterPre-2.Participantwillingnessto undergo additionaltests and interestintheirtestresultshadmedianandmode valuesof“veryhigh”.Participantfeedback wasmainlyaboutdiscomfortduring theocclusionphaseofFMD,noise ofthedevice pump, and perceptionsofcooltemperaturein thetestingroom.Therewas no significantdifferencein chronological ageversusVA (65±10vs.62±10years,respectively;p=0.19).

Conclusions:CRP participants tolerateAD assessment ofFMD well and are interested in knowing theirVA.Largerandlonger-term studiesareneededtoadequatelyassesswhether knowledge ofone’srisk-adjustedageusing theVACiseffectivein enhancingengagementand motivationforriskreduction strategiesinCR patients.

 

 

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American Heart Association

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References

  1. Michael E. Widlansky, MD et al. The Clinical Implications of Endothelial Dysfunction. Journal of the American College of Cardiology Vol. 42, No. 7, 2003. http://www.ncbi.nlm.nih.gov/pubmed/14522472.
  2. Halcox et al. Endothelial function predicts progression of CIMT. Circulation. 2009. http://www.ncbi.nlm.nih.gov/pubmed/1920430
  3. McEniery et al--Endothelial function is associated with pulse pressure, pulse wave velocity, and augmentation index in health humans. Hypertension. 2006. http://www.ncbi.nlm.nih.gov/pubmed/16940223.
  4. Panza JA, et al. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Eng J Med 1990; 323:22-27.
  5. Taddei S, et al. Defective L-arginine-nitric oxide pathway in offspring of essential hypertensive patients. Circulation 1996; 94(6):1298-303.
  6. Celermajer DS, et al. Cigarette smoking is associated with dose related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation 1993; 88:2149 –2155.
  7. Spieker LE, et al. High-density lipoprotein restores endothelial function in hypercholesterolemic men. Circulation 2002; 105:1399 –1402.
  8. Linder L, et al. Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo: blunted response in essential hypertension. Circulation 1990; 81:1762–1767.
  9. Steinberg HO, et al. Obesity/insulin resistance is associated with endothelial dysfunction: implications for the syndrome of insulin resistance. J Clin Invest 1996; 97:2601–2610.

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