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1.  Endothelial cell markers reflecting endothelial cell dysfunction in patients with mixed connective tissue disease 
The aim of the present study was to investigate the association between cardiovascular risk factors and endothelial dysfunction in patients with mixed connective tissue disease (MCTD) and to determine which biomarkers are associated with atherosclerotic complications, such as cardiovascular disease.
Fifty MCTD patients and 38 healthy age-matched and sex-matched controls were enrolled in this study. In order to describe endothelial dysfunction, we assessed flow-mediated dilation (FMD), nitrate-mediated dilation (NMD) and carotid artery intima-media thickness (IMT). We investigated FMD of the brachial artery after reactive hyperemia and NMD after sublingual nitroglycerin administration, while the IMT of the common carotid artery was determined by ultrasound. Anti-U1 ribonucleoprotein (anti-U1RNP) antibodies, anti-cardiolipin (anti-CL) antibodies, anti-endothelial cell antibody (AECA) and endothelial cell markers, such as soluble thrombomodulin (TM) and von Willebrand factor antigen (vWFAg), were assessed.
The endothelium-dependent vasodilation (FMD) was significantly impaired in patients with MCTD, as compared with controls (%FMD: 4.7 ± 4.2% vs. 8.7 ± 5.0%; P < 0.001), while the percentage NMD did not differ (%NMD: 14.3 ± 6.6% vs. 17.1 ± 6.7%; P = 0.073). Mean carotid IMT values were higher in patients than in controls (IMT: MCTD, 0.64 ± 0.13 mm vs. controls, 0.53 ± 0.14 mm; P < 0.001). FMD negatively correlated with disease duration, the levels of apolipoprotein A1, the paraoxonase-1 activity, and systolic blood pressure in MCTD patients. The percentage FMD was significantly lower in MCTD patients with cardiovascular diseases (CVD), than in those without CVD (%FMD: 3.5 ± 2.9 vs. 5.8 ± 4.8, P < 0.0002), while percentage NMD did not differ between patients with and without CVDs. Serum levels of autoantibodies (anti-U1RNP, AECA and anti-CL) were significantly higher in MCTD patients and differed between MCTD patients with and without CVD. Endothelial cell markers such as soluble TM (12.2 ± 8.1 ng/ml vs. 3.2 ± 1.3 ng/ml; P < 0.001) and vWFAg (224.1 ± 115% vs. 89.4 ± 27.1%, P < 0.001) were the highest in MCTD patients with CVD.
FMD is a reliable sensitive marker of endothelial cell dysfunction in MCTD. Beside the traditional risk factors, anti-U1RNP, AECA and anti-CL antibodies may be important not only in the pathogenesis of MCTD but in the induction of endothelial cell activation, and may play crucial roles in the development of early atherosclerosis in MCTD.
PMCID: PMC2911856  PMID: 20459625
2.  Forearm Vascular Reactivity and Arterial Stiffness in Asymptomatic Subjects from the Community 
Hypertension  2008;51(6):1512-1518.
Vascular reactivity may affect the stiffness characteristics of the arterial wall. We investigated the association between forearm microcirculatory and conduit artery function and measures of arterial stiffness in 527 asymptomatic non-Hispanic white adults without known cardiovascular disease. High-resolution ultrasonography of the brachial artery (ba) was performed to assess forearm microcirculatory function (ba blood flow velocity, local shear stress, and forearm vascular resistance at rest and during reactive hyperemia) and conduit artery function (ba flow-mediated dilatation baFMD and ba nitroglycerin-mediated dilatation baNMD). Arterial stiffness was assessed by cuff-derived brachial pulse pressure and aortic pulse wave velocity (aPWV) measured by applanation tonometry. In regression analyses that adjusted for heart rate, mean arterial pressure, height, cardiovascular risk factors, and hypertension medication and statin use, higher baseline ba systolic velocity and systolic shear stress were associated with greater pulse pressure (P=0.0002 and P=0.006, respectively) and higher aPWV (each P<0.0001). During hyperemia, lower ba mean velocity and lower mean shear stress were associated with higher pulse pressure (P=0.045 and P=0.036, respectively) while both systolic and mean velocity (P<0.0001 and P=0.002, respectively) and systolic and mean shear stress (P<0.0001 and P=0.003, respectively) were inversely associated with aPWV. baFMD was not associated with pulse pressure but was inversely associated with aPWV (P=0.011). baNMD was inversely associated with pulse pressure (P=0.0002) and aPWV (P=0.008). Our findings demonstrate that impaired forearm microvascular function (in the form of elevated resting blood flow velocity and impaired flow reserve) and impaired brachial artery reactivity are associated with increased arterial stiffness.
PMCID: PMC2869626  PMID: 18426995
microvascular function; flow-mediated dilatation; nitroglycerin-mediated dilatation; arterial stiffness; pulse pressure; pulse wave velocity
3.  Vascular remodeling in adults after coarctation repair: impact of descending aorta stenosis and age at surgery 
Clinical Research in Cardiology  2010;100(5):447-455.
Patients after successful repair of coarctation of aorta (CoAo) are at risk of hypertension at rest and associated end-organ damage. The aim of the study was to assess arterial stiffness and function in adults after coarctation repair in relation to descending aorta (AoD) residual coarctation and patient’s age at operation.
85 patients after CoAo repair (53 males) aged 34.6 ± 10.3 years; median age at operation 0.9 ± 8.2 years. The control group—30 individuals (18 males) at mean age 33.6 ± 8.2 years. The following central parameters: augmentation pressure (AP) and augmentation index (AI) as well as peripheral vascular parameters: flow-mediated dilatation (FMD), nitroglycerin-mediated vasodilatation (NMD), intima-media thickness (IMT) and pulse wave velocity (PWV) were measured.
47 CoAo-repaired patients were normotensive, and compared to control, they presented higher values of central parameters AP (7.3 ± 4.6 vs. 4.4 ± 3.6 mmHg; p = 0.002) and AI (18.6 ± 10.4 vs. 13.5 ± 4.3%; p = 0.03); as well as the increased PWV (6.8 ± 1.2 vs. 5.4 ± 0.9 m/s; p = 0.003), while IMT was comparable (0.53 ± 0.01 vs. 0.51 ± 0.01 mm; p = 0.06). The vasodilatation was impaired in the normotensive patients: FMD (4.8 ± 2.8 vs. 8.5 ± 2.3%; p = 0.00003) and NMD (11.3 ± 4.6 vs. 19.8 ± 7.2%; p = 0.00001). The comparison of recoarctation (46, 54%) to non-recoarctation (39, 46%) patients did not reveal any significant differences in resting systolic and diastolic pressures, as well as the values of AI and the peripheral vascular parameters; the value of AP was higher in the recoarctation patients (10.5 ± 6.9 vs. 7.5 ± 4.1; p = 0.02) and correlated positively with the gradient across AoD (r = 0.295, p = 0.01). There was no significant linear correlation between age at the time of surgery and any of peripheral arterial parameters.
Residual stenosis in AoD does not affect the arterial vasodilatation nor stiffness in patients after CoAo repair. Early operation has no impact on peripheral vascular remodeling or central pressure which supports the claim that coarctation of the aorta is a systemic vascular disorder which leads to progressive vascular and end-organ damage despite early correction.
PMCID: PMC3079825  PMID: 21161708
Adult congenital heart disease; Flow mediated dilatation (FMD); Pulse wave velocity (PWV); Intima-media thickness (IMT); Augmentation index (AI); Coarctation of aorta (CoAo)
4.  Relation of Cumulative Weight Burden to Vascular Endothelial Dysfunction in Obesity 
Although excess fat mass is broadly linked to increased cardiovascular risk, the relation between vascular phenotype and degree of obesity in extreme weight categories is unknown. We examined brachial artery vasomotor responses using ultrasound in 203 consecutive patients mainly afflicted with severe obesity (mean age 44 ± 11 yr; body mass index (BMI) 46 ± 9 kg/m2, range 30–72 kg/m2; and body weight 128 ± 29kg, range 69–207 kg). We studied a unique population with >70% of subjects characterized as morbidly obese (BMI ≥ 40) including a 31% group of super-obese individuals (BMI ≥ 50). Brachial artery flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) were examined as measures of endothelium-dependent and -independent dilation, respectively, in relation to clinical, hemodynamic, and metabolic parameters. Endothelial function was significantly impaired in the highest as compared to lowest tertile of body weight (FMD 6.5 ± 4.6 vs. 9.8 ± 4.8%, p<0.001), whereas NMD was similar in all groups. Univariate correlates of FMD were gender, weight, waist circumference, BMI, diastolic blood pressure, and creatinine. In multivariate analysis, weight was a strong independent significant predictor of FMD (β= −0.23, p=0.005) in addition to gender. Within an overweight population, cumulative weight burden remains strongly linked to progressive arterial dysfunction. In conclusion, these results suggest that cardiovascular risks intensify with escalating obesity, and underscore the importance of therapeutic weight loss interventions in the context of the expanding obesity epidemic.
PMCID: PMC2199378  PMID: 18157973
endothelium; obesity; vasculature
5.  Combined examination of glyceryl trinitrate‐mediated vascular dilation with flow‐mediated vascular dilation is essential for assessment of vascular function in type 2 diabetes 
In order to characterize the impaired vascular function in type 2 diabetes (DM) patients, we evaluated the flow‐mediated vascular dilation (FMD) with glyceryl trinitrate‐mediated vascular dilation (NMD) using ultrasonography.
Materials and Methods
A total of 111 DM patients and 42 healthy control participants were studied. The maximal dilatation of FMD and NMD (%FMD and %NMD, respectively), the beginning time (T) of dilatation after stimulation and the velocity (V) of the vascular dilatation were also measured.
Among DM patients, 49% had impaired %NMD, which affects the results of %FMD. In DM patients with normal %NMD, the %FMD was also significantly lower than that in control participants, although the T and the V were not impaired. In contrast, both the T and the V were disturbed in the DM patients with low %NMD. Multiple linear regression analysis showed that %NMD was independently correlated with albuminuria. Our results indicate that the impaired FMD in DM is be affected by low NMD, and impaired endothelial function already exists even in DM patients whose vascular smooth muscle function is still retained, and also albuminuria is the clinical feature of DM with low %NMD.
Examination of NMD, not only FMD, should be carried out as it offers the possibility of clarifying vascular function in DM patients.
PMCID: PMC4015668  PMID: 24843670
Flow‐mediated vascular dilatation; Glyceryl trinitrate‐mediated vascular dilatation; Type 2 diabetes
6.  Relationship of visit-to-visit and ambulatory blood pressure variability to vascular function in African Americans 
Visit-to-visit clinic blood pressure variability (BPV) and 24-hour BPV have both been identified as independent risk factors for cardiovascular (CV) morbidity and mortality; however the mechanisms contributing to the increased CV risk as yet are unclear. The purpose of this study was to assess the relationship between BPV and endothelial function in a cohort of putatively healthy African Americans.
36 African Americans who were sedentary, non-diabetic, non-smoking, free of cardiovascular and renal disease and not on antihypertensive medication followed an American Heart Association low fat, low salt diet for 6 weeks. Upon completion of the 6-week dietary stabilization period, participants underwent 24-hour ambulatory BP monitoring and had their office BP measured on three separate days. Right brachial artery diameter was assessed at rest, during reactive hyperemia (flow-mediated dilation: FMD), and after nitroglycerin administration (nitroglycerin-mediated dilation: NMD).
Participants classified as having decreased endothelial function according to either %FMD or the FMD/NMD ratio had significantly higher 24-hour BPV and a trend for higher visit-to-visit BPV when compared to participants with normal endothelial function. Continuous variable analyses revealed a significant positive association between NMD and 24-hour diastolic BPV (DBPV). Visit-to-visit systolic BPV (SBPV), 24-hour SBPV, and 24-hour DBPV were all negatively associated with the FMD/NMD ratio. All relationships remained significant after adjustment for age, BMI, and mean BP levels.
These results may suggest that BPV is in increased in African Americans with decreased endothelial function and is associated with the vascular smooth muscle response to nitric oxide.
PMCID: PMC3629695  PMID: 21814215
African Americans; ambulatory blood pressure monitoring; blood pressure variability; endothelial function
7.  Alterations in arterial function after high-voltage electrical injury 
Critical Care  2012;16(1):R25.
The aim of this study was to evaluate the functional changes of the arterial endothelium and smooth muscle after a high-voltage electrical injury (HVEI), using flow-mediated dilation (FMD) and nitrate-mediated dilation (NMD).
Twenty-five male patients injured in the upper extremities by current due to contact with more than 20,000 volts were enrolled in the study. FMD and NMD were measured on the brachial artery within 48 hours after HVEI, and follow-up FMD and NMD were evaluated six weeks later. In addition, we enrolled an age, sex and body mass index matched healthy control group consisting of 25 individuals. Including FMD and NMD, all the variables of the control group were investigated one time and compared with the initial and six week follow-up data of the HVEI group.
A significantly lower initial FMD was seen in the HVEI group compared with the control group (2.1 ± 1.2% versus 13.6 ± 3.4%, P < 0.01). At the six week follow-up, the FMD of the HVEI group had significantly improved compared to the initial FMD (2.1 ± 1.2% versus 5.1 ± 2.1%, P < 0.01), but it was still lower than the FMD of the control group (5.1 ± 2.1% versus 13.6 ± 3.4%, P < 0.01). A significantly lower NMD was seen both initially and at the six week follow-up compared with the NMD of the control group (7.3 ± 4.7% versus 20.4 ± 4.1%, P < 0.01 and 11.4 ± 6.7% versus 20.4 ± 4.1%, P < 0.01, respectively). The FMD study of the contralateral arm which was uninjured by HVEI was available in six patients. In those patients, the six week follow-up FMD was significantly improved in the HVEI arm compared with the initial FMD (1.8 ± 0.6% versus 4.4 ± 1.6%, P < 0.01). However, in the contralateral uninjured arm, there was no difference between the initial and the six week follow-up FMDs (5.5 ± 1.4% versus 6.9 ± 2.2%, P = 0.26).
After HVEI, the endothelial and smooth muscle functions of the brachial artery were significantly decreased for at least six weeks. Long term cautious care might be needed for all victims of HVEI, because there is a chance of increased risk of thrombosis or stenosis in the injured arm.
PMCID: PMC3396269  PMID: 22326053
high-voltage electrical injury; endothelium; smooth muscle; arterial function; flow-mediated dilation; nitrate-mediated dilation
8.  The Peroxisome Proliferator Activated Receptor‐γ Pioglitazone Improves Vascular Function and Decreases Disease Activity in Patients With Rheumatoid Arthritis 
Rheumatoid arthritis (RA) is associated with heightened mortality due to atherosclerotic cardiovascular disease (CVD). Inflammatory pathways in RA negatively affect vascular physiology and promote metabolic disturbances that contribute to CVD. We hypothesized that the peroxisome proliferator activated receptor‐γ (PPAR‐γ) pioglitazone could promote potent vasculoprotective and anti‐inflammatory effects in RA.
Methods and Results
One hundred forty‐three non‐diabetic adult RA patients (76.2% female, age 55.2±12.1 [mean±SD]) on stable RA standard of care treatment were enrolled in a randomized, double‐blind placebo controlled crossover trial of 45 mg daily pioglitazone versus placebo, with a 3‐month duration/arm and a 2‐month washout period. Pulse wave velocity of the aorta (PWV), brachial artery flow mediated dilatation (FMD), nitroglycerin mediated dilatation (NMD), microvascular endothelial function (reactive hyperemia index [RHI]), and circulating biomarkers of inflammation, insulin resistance, and atherosclerosis risk all were quantified. RA disease activity was assessed with the 28‐Joint Count Disease Activity Score (DAS‐28) C‐reactive protein (CRP) and the Short Form (36) Health Survey quality of life questionnaire. When added to standard of care RA treatment, pioglitazone significantly decreased pulse wave velocity (ie, aortic stiffness) (P=0.01), while FMD and RHI remained unchanged when compared to treatment with placebo. Further, pioglitazone significantly reduced RA disease activity (P=0.02) and CRP levels (P=0.001), while improving lipid profiles. The drug was well tolerated.
Addition of pioglitazone to RA standard of care significantly improves aortic elasticity and decreases inflammation and disease activity with minimal safety issues. The clinical implications of these findings remain to be established.
Clinical Trial Registration
URL: Unique Identifier: NCT00554853.
PMCID: PMC3886758  PMID: 24252844
drugs; inflammation; rheumatoid arthritis; vasodilation
9.  Erosive Hand Osteoarthritis is Associated with Subclinical Atherosclerosis and Endothelial Dysfunction 
Chronic inflammatory disorders have been associated with accelerated atherosclerosis and increased cardiovascular (CV) risk. Recent evidence suggests that erosive hand osteoarthritis (EOA) has considerable inflammation; therefore, we examined the presence of subclinical atherosclerosis and endothelial dysfunction in EOA. Twenty-four patients with EOA and 24 age- and sex-matched healthy individuals without clinical OA were included in the study. No subject had a history of CV disease. Intima-media thickness (IMT) and atheromatous plaques in the common carotid and common femoral arteries were measured by Doppler ultrasonography. The endothelium-dependent, flow-mediated dilatation (FMD) and endothelium-independent, sublingual glyceryl trinitrate (NTG)-induced dilatation (NMD) of the brachial artery were assessed. The EOA patients had significantly elevated systolic and diastolic blood pressure (p<0.001 for both). The 10-year risk of general CV disease, as predicted with the Framingham Risk Score, was similar in patients and controls (p=0.18). IMT of both common carotid and common femoral artery were increased in EOA (p=0.01 and p<0.01, respectively), but the frequency of atherosclerotic plaques was not increased. There was no difference in FMD and NMD between the two groups, but the difference between FMD and NMD was increased in EOA. In conclusion, this small controlled study showed an association between EOA and subclinical atherosclerosis that cannot be fully attributed to traditional CV risk factors, as assessed by the Framingham score. These results suggest that chronic, low-grade inflammation is implicated in atherosclerosis in EOA.
PMCID: PMC3884791  PMID: 24711757
atherosclerosis; Doppler ultrasonography; dilatation; endothelium; erosive osteoarthritis; Framingham risk score
10.  Cardiovascular Risk Assessment with Vascular Function, Carotid Atherosclerosis and the UKPDS Risk Engine in Korean Patients with Newly Diagnosed Type 2 Diabetes 
Diabetes & Metabolism Journal  2011;35(6):619-627.
Patients with type 2 diabetes have an increased risk of cardiovascular disease. Few studies have evaluated the cardiovascular disease (CVD) risk simultaneously using the United Kingdom Prospective Diabetes Study (UKPDS) risk engine and non-invasive vascular tests in patients with newly diagnosed type 2 diabetes.
Participants (n=380; aged 20 to 81 years) with newly diagnosed type 2 diabetes were free of clinical evidence of CVD. The 10-year coronary heart disease (CHD) and stroke risks were calculated for each patient using the UKPDS risk engine. Carotid intima media thickness (CIMT), flow mediated dilation (FMD), pulse wave velocity (PWV) and augmentation index (AI) were measured. The correlations between the UKPDS risk engine and the non-invasive vascular tests were assessed using partial correlation analysis, after adjusting for age, and multiple regression analysis.
The mean 10-year CHD and 10-year stroke risks were 14.92±11.53% and 4.03±3.95%, respectively. The 10-year CHD risk correlated with CIMT (P<0.001), FMD (P=0.017), and PWV (P=0.35) after adjusting for age. The 10-year stroke risk correlated only with the mean CIMT (P<0.001) after adjusting for age. FMD correlated with age (P<0.01) and systolic blood pressure (P=0.09). CIMT correlated with age (P<0.01), HbA1c (P=0.05), and gender (P<0.01).
The CVD risk is increased at the onset of type 2 diabetes. CIMT, FMD, and PWV along with the UKPDS risk engine should be considered to evaluate cardiovascular disease risk in patients with newly diagnosed type 2 diabetes.
PMCID: PMC3253973  PMID: 22247905
Atherosclerosis; Cardiovascular risk; Diabetes mellitus, type 2; United Kingdom Prospective Diabetes Study risk engine; Vascular function
11.  Endothelial function and left ventricular remodeling in diabetic and non-diabetic patients after acute coronary syndrome 
Endothelial dysfunction is an independent predictor of future cardiac events.
We evaluated the relationship between flow-mediated dilation (FMD) in brachial artery and coronary risk factors in 93 patients (70 males, mean age: 62±8 years) with ACS treated with primary angioplasty (PCI). The patients were divided into 2 subgroups: 43 patients with diabetes mellitus type 2 (DM) and 50 non-diabetics (non-DM). Patients were examined on the 3rd day after ACS and after 6 months. FMD on the 3rd day were significantly lower in DM than in non-DM (5.8±2.2% vs. 8.8±4.9%, p=0.0007) and after 6 months (6.2±2.6% vs. 9.4±4.4%, p<0.0001). It was also observed that the improvement of FMD in both groups after a 6-month follow-up inversely correlated with the increase of left ventricular end-diastolic volume (LVEDV) (r=−0.41, p<0.001).
There was an inverse relationship between FMD and age (r=−0.26, p<0.01), BMI (r=−0.26, p<0,005), total cholesterol (r=−0.56, p<0.001) and LDL cholesterol (r=−0.53, p<0.001). There was no relationship between triglycerides, hypertension and history of smoking. In the DM group, FMD negatively correlated with HbA1c (r=−0.68, p<0.001). Restenosis rate was significantly higher in the DM group (19% vs. 6%, p<0.001) but there was no relationship between FMD and restenosis.
Impaired FMD is more significant in diabetics than in non-diabetic patients with ACS. Lack of improvement of FMD after acute coronary syndrome can be a predictor of detrimental left ventricular remodeling in patients with ACS.
PMCID: PMC3524697  PMID: 21278691
flow-mediated dilatation; endothelium; diabetes mellitus; acute coronary syndrome; left ventricular remodeling
12.  Denture-Related Stomatitis Is Associated with Endothelial Dysfunction 
BioMed Research International  2014;2014:474016.
Oral inflammation, such as periodontitis, can lead to endothelial dysfunction, accelerated atherosclerosis, and vascular dysfunction. The relationship between vascular dysfunction and other common forms of oral infections such as denture-related stomatitis (DRS) is unknown. Similar risk factors predispose to both conditions including smoking, diabetes, age, and obesity. Accordingly, we aimed to investigate endothelial function and major vascular disease risk factors in 44 consecutive patients with dentures with clinical and microbiological features of DRS (n = 20) and without DRS (n = 24). While there was a tendency for higher occurrence of diabetes and smoking, groups did not differ significantly in respect to major vascular disease risk factors. Groups did not differ in main ambulatory blood pressure, total cholesterol, or even CRP. Importantly, flow mediated dilatation (FMD) was significantly lower in DRS than in non-DRS subjects, while nitroglycerin induced vasorelaxation (NMD) or intima-media thickness (IMT) was similar. Interestingly, while triglyceride levels were normal in both groups, they were higher in DRS subjects, although they did not correlate with either FMD or NMD. Conclusions. Denture related stomatitis is associated with endothelial dysfunction in elderly patients with dentures. This is in part related to the fact that diabetes and smoking increase risk of both DRS and cardiovascular disease.
PMCID: PMC4090512  PMID: 25045683
13.  The Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Improves Vascular Endothelial Function in Type 2 Diabetes 
Journal of Korean Medical Science  2012;27(11):1364-1370.
The vascular endothelial function is impaired in the very early stage of atherosclerosis in diabetic patients. The goal of this study was to identify the mechanism underlying the improvement in vascular endothelial function by sitagliptin in type 2 diabetes mellitus patients. This study was an open-labeled prospective observational single arm trial. Forty patients were treated with 50 mg of sitagliptin once daily for 12-weeks. The flow-mediated dilation (FMD) and plasma adiponectin were measured at baseline and 12 weeks after initiating treatment. The %FMD was significantly increased after treatment (4.13 ± 1.59 vs 5.12 ± 1.55, P < 0.001), whereas the nitroglycerin-mediated dilation (NMD) did not change. The plasma adiponectin levels significantly increased (13.0 ± 11.3 vs 14.3 ± 12.8, P < 0.001). The changes in the FMD were significantly correlated with those of the plasma adiponectin (r = 0.322, P < 0.05). A multivariate linear regression analysis demonstrated that the improvement in the FMD is associated with the plasma adiponectin (P < 0.05). The treatment of type 2 diabetes mellitus patients with sitagliptin reverses vascular endothelial dysfunction, as evidenced by increase in the FMD, and improvement of the adiponectin levels (UMIN Clinical Trials Registry System as trial ID UMIN000004236).
PMCID: PMC3492672  PMID: 23166419
Endothelial Function; Dipeptidyl Peptidase-4 Inhibitor; Adiponectin; Type 2 Diabetes Mellitus
14.  The Impact of Blood Pressure Variability on Subclinical Ventricular, Renal and Vascular Dysfunction, in Patients with Hypertension and Diabetes 
Mædica  2013;8(2):129-136.
Background: Blood pressure variability (BPV) was proved as a cardiovascular risk factor. One of its mechanisms is related to arterial stiffness and ventriculo-arterial coupling; however its impact on subclinical cardiovascular dysfunction has not been evaluated yet.
Objectives: To assess the relationship between BPV on 24 hours, and subclinical left ventricle (LV), renal, and vascular dysfunction in diabetic and hypertensive patients. Material and methods: We studied 56 patients (57±9 years, 29 men) with mild-to-moderate hypertension and type 2 diabetes, no cardiovascular disease, normal ejection fraction and normal renal function. 24 hours ambulatory blood pressure monitoring (ABPM) was used to assess BPV, daytime (d) and night time (n), by: 1. mean (M); 2. standard deviation of mean (SD); 3. variance (Vr); 4. coefficient of variation (CV); 5. day/night variation: reverse dippers, non-dippers, dippers and extreme dippers; conventional and 2D speckle tracking echo to assess LV function; myocardial deformation was measured as global longitudinal strain (GLS). Endothelial (flow mediated dilation, FMD) and arterial function (intima media-thickness, IMT; pulse wave velocity, PWV), microalbuminuria were tested.
Outcomes: Daytime BPV correlates inversely with subclinical myocardial function evaluated through GLS. Daytime systolic BPV correlates positively with IMT (all rho > 0.30, all p < 0.05). Also, there is a significantly inverse correlation between mean BP and GLS. We found a direct correlation between mean BP, but not BPV, and microalbuminuria (all rho > - 0.30 and all p < 0.05). We found no correlation between BPV and FMD, PWV. There were no differences for GLS, microalbuminuria and FMD between dipper groups.
Conclusions: In diabetic patients with mild-to-moderate hypertension, increased daytime blood pressure variability correlates with subclinical left ventricular dysfunction and arterial function (IMT), while microalbuminuria correlates with elevated blood pressure, but not with blood pressure variability.
PMCID: PMC3865121  PMID: 24371476
blood pressure variability; ventricular dysfunction; diabetes; hypertension
15.  Endothelial dysfunction is associated with left ventricular mass (assessed using MRI) in an adult population (MESA) 
Journal of human hypertension  2010;25(1):25-31.
Brachial flow-mediated dilation (FMD) is a measure of endothelial nitric oxide bioavailability. Endothelial nitric oxide controls vascular tone and is likely to modify the ventricular muscle coupling mechanism. The association between left ventricular mass and FMD is not well understood. We assessed the association between left ventricular mass index (LVMI) and FMD in participants of the Multi-Ethnic Study of Atherosclerosis (MESA). MESA is a population-based study of 6814 adults free of clinical cardiovascular disease at baseline who were recruited from six US clinics. LVMI (left ventricular mass per body surface area) and FMD were measured in 2447 subjects. Linear regression analysis was used to evaluate the association. The subjects had a mean age of 61.2 ± 9.9 years, 51.2% females with 34.3% Caucasians, 21.6% Chinese, 19.4% African Americans and 24.7% Hispanics. The mean body mass index (BMI) was 27.4 ± 4.8 kg m−2, 9.4% had diabetes, 11% were current smokers and 38% hypertensives. The mean ± s.d. LVMI was 78.1 ± 15.9 g m−2 and mean ± s.d. FMD was 4.4% ± 2.8%. In univariate analysis, LVMI was inversely correlated with FMD (r = −0.20, P < 0.0001). In the multivariable analysis, LVMI was associated with FMD (β coefficient (se) = −0.50 (0.11), P < 0.001 (0.5 g m−2 reduction in LVMI per 1% increase in FMD)) after adjusting for age, gender, race/ethnicity, systolic blood pressure, diabetes mellitus, smoking, weight, statin use, antihypertensive medication use, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol. The association between brachial flow mediated dilation and LVMI maybe independent of traditional CV risk factors in population based adults.
PMCID: PMC3037860  PMID: 20237502
left ventricular mass; endothelial function; brachial flow-mediated dilation; population
16.  Impact of Framingham Risk Score, Flow-Mediated Dilation, Pulse Wave Velocity, and Biomarkers for Cardiovascular Events in Stable Angina 
Journal of Korean Medical Science  2014;29(10):1391-1397.
Although the age-adjusted Framingham risk score (AFRS), flow-mediated dilation (FMD), brachial-ankle pulse wave velocity (baPWV), high-sensitivity C-reactive protein (hsCRP), fibrinogen, homocysteine, and free fatty acid (FFA) can predict future cardiovascular events (CVEs), a comparison of these risk assessments for patients with stable angina has not been reported. We enrolled 203 patients with stable angina who had been scheduled for coronary angiography (CAG). After CAG, 134 patients showed significant coronary artery disease. During 4.2 yr follow-up, 36 patients (18%) showed CVEs, including myocardial infarction, de-novo coronary artery revascularization, in-stent restenosis, stroke, and cardiovascular death. ROC analysis showed that AFRS, FMD, baPWV, and hsCRP could predict CVEs (with AUC values of 0.752, 0.707, 0.659, and 0.702, respectively, all P<0.001 except baPWV P=0.003). A Cox proportional hazard analysis showed that AFRS and FMD were independent predictors of CVEs (HR, 2.945; 95% CI, 1.572-5.522; P=0.001 and HR, 0.914; 95% CI, 0.826-0.989; P=0.008, respectively). However, there was no difference in predictive power between combining AFRS plus FMD and AFRS alone (AUC 0.752 vs. 0.763; z=1.358, P=0.175). In patients with stable angina, AFRS and FMD are independent predictors of CVEs. However, there is no additive value of FMD on the AFRS in predicting CVEs.
Graphical Abstract
PMCID: PMC4214940  PMID: 25368493
Framingham Risk Score; Flow-Mediated Dilation; Cardiovascular Event
17.  Retinal Vascular Caliber and Brachial Flow-Mediated Dilation 
Background and Purpose
Retinal vascular caliber changes have been shown to predict stroke, but the underlying mechanism of this association is unknown. We examined the relationship between retinal vascular caliber with brachial flow-mediated dilation (FMD), a measure of systemic endothelial function.
The Multi-Ethnic Study of Atherosclerosis (MESA) is a population-based study of persons 45 to 84 years of age residing in 6 US communities free of clinical cardiovascular disease at baseline. Brachial FMD data were collected at baseline (July 2000 to June 2002), and retinal vascular caliber was measured from digital retinal photographs at the second examination, immediately after the first (August 2002 to January 2004). Data were available for 2851 participants for analysis.
The mean brachial FMD was 4.39±2.79%. After adjusting for age and gender, brachial FMD was reduced in persons with wider retinal venular caliber (changes in FMD −0.25, 95% CI, −0.36, − 0.13; P<0.001, per SD increase in venular caliber). This relationship persists after adjusting for systolic blood pressure, serum total cholesterol, use of lipid-lowering and antihypertensive medication, body mass index, current smoking status, and hemoglobinA1C (−0.18; 95% CI −0.30, − 0.06; P=0.004, per SD increase in venular caliber). Brachial FMD was not associated with retinal arteriolar caliber.
Persons with wider retinal venules have reduced brachial FMD, independent of other vascular risk factors. This suggests that retinal venular caliber, previously shown to predict stroke, may be a marker of underlying systemic endothelial dysfunction.
PMCID: PMC2945294  PMID: 20508189
epidemiology; vasodilation; imaging; endothelial function
18.  Targeting Inflammation Using Salsalate in Patients With Type 2 Diabetes: Effects on Flow-Mediated Dilation (TINSAL-FMD) 
Diabetes Care  2013;36(12):4132-4139.
To test whether inhibiting inflammation with salsalate improves endothelial function in patients with type 2 diabetes (T2D).
We conducted an ancillary study to the National Institutes of Health–sponsored, multicenter, randomized, double-masked, placebo-controlled trial evaluating the safety and efficacy of salsalate in targeting inflammation to improve glycemia in patients with T2D. Flow-mediated, endothelium-dependent dilation (FMD) and endothelium-independent, nitroglycerin-mediated dilation (NMD) of the brachial artery were assessed at baseline and 3 and 6 months following randomization to either salsalate 3.5 g/day or placebo. The primary end point was change in FMD at 6 months.
A total of 88 participants were enrolled in the study, and data after randomization were available for 75. Patients in the treatment and control groups had similar ages (56 years), BMI (33 kg/m2), sex (64% male), ethnicity, current treatment, and baseline HbA1c (7.7% [61 mmol/mol]). In patients treated with salsalate versus placebo, HbA1c was reduced by 0.46% (5.0 mmol/mol; P < 0.001), fasting glucose by 16.1 mg/dL (P < 0.001), and white blood cell count by 430 cells/µL (P < 0.02). There was no difference in the mean change in either FMD (0.70% [95% CI −0.86 to 2.25%]; P = 0.38) or NMD (−0.59% [95% CI −2.70 to 1.51%]; P = 0.57) between the groups treated with salsalate and placebo at 6 months. Total and LDL cholesterol were 11 and 16 mg/dL higher, respectively, and urinary albumin was 2.0 µg/mg creatinine higher in the patients treated with salsalate compared with those treated with placebo (all P < 0.009).
Salsalate does not change FMD in peripheral conduit arteries in patients with T2D despite lowering HbA1c. This finding suggests that salsalate does not have an effect on vascular inflammation, inflammation does not cause endothelial dysfunction in T2D, or confounding effects of salsalate mitigate favorable effects on endothelial function.
PMCID: PMC3836144  PMID: 24130358
19.  Impact of Vitamin D Supplementation on Arterial Vasomotion, Stiffness and Endothelial Biomarkers in Chronic Kidney Disease Patients 
PLoS ONE  2014;9(3):e91363.
Cardiovascular events are frequent and vascular endothelial function is abnormal in patients with chronic kidney disease (CKD). We demonstrated endothelial dysfunction with vitamin D deficiency in CKD patients; however the impact of cholecalciferol supplementation on vascular stiffness and vasomotor function, endothelial and bone biomarkers in CKD patients with low 25-hydroxy vitamin D [25(OH)D] is unknown, which this study investigated.
We assessed non-diabetic patients with CKD stage 3/4, age 17–80 years and serum 25(OH)D <75 nmol/L. Brachial artery Flow Mediated Dilation (FMD), Pulse Wave Velocity (PWV), Augmentation Index (AI) and circulating blood biomarkers were evaluated at baseline and at 16 weeks. Oral 300,000 units cholecalciferol was administered at baseline and 8-weeks.
Clinical characteristics of 26 patients were: age 50±14 (mean±1SD) years, eGFR 41±11 ml/min/1.73 m2, males 73%, dyslipidaemia 36%, smokers 23% and hypertensives 87%.
At 16-week serum 25(OH)D and calcium increased (43±16 to 84±29 nmol/L, p<0.001 and 2.37±0.09 to 2.42±0.09 mmol/L; p = 0.004, respectively) and parathyroid hormone decreased (10.8±8.6 to 7.4±4.4; p = 0.001). FMD improved from 3.1±3.3% to 6.1±3.7%, p = 0.001.
Endothelial biomarker concentrations decreased: E-Selectin from 5666±2123 to 5256±2058 pg/mL; p = 0.032, ICAM-1, 3.45±0.01 to 3.10±1.04 ng/mL; p = 0.038 and VCAM-1, 54±33 to 42±33 ng/mL; p = 0.006. eGFR, BP, PWV, AI, hsCRP, von Willebrand factor and Fibroblast Growth Factor-23, remained unchanged.
This study demonstrates for the first time improvement of endothelial vasomotor and secretory functions with vitamin D in CKD patients without significant adverse effects on arterial stiffness, serum calcium or FGF-23.
Trial Registration NCT02005718
PMCID: PMC3960127  PMID: 24646518
20.  Impact of diabetes mellitus on arterial stiffness in a representative sample of an urban Brazilian population 
Independent of other cardiovascular (CV) risk factors, increased arterial stiffness has been established as a predictor of morbidity and mortality. The main aim of this study was to investigate the impact of diabetes on arterial stiffness in a representative sample of an urban Brazilian population plus Amerindians.
A total of 1,415 individuals from the general population were randomly selected plus 588 Amerindians from a native community in Brazil. In addition, a sub-sample of 380 individuals from the general population had 5-year follow-up data. Pulse wave velocity (PWV) was measured with a non-invasive automatic device (Complior, Colson; Garges les Gonesses, France) and increased arterial stiffness was defined as PWV ≥ 12 m/s.
In the overall group, diabetic individuals had higher frequencies of increased arterial stiffness and hypertension. They also had higher values of PWV, body mass index, total cholesterol, triglycerides, systolic and diastolic blood pressures compared to non-diabetic individuals (p < 0.01). In an analysis stratified by hypertension, PWV values and increased arterial stiffness frequency were higher in diabetic individuals in both groups (hypertensive and non-hypertensive) (p < 0.05). Furthermore, higher risk for increased arterial stiffness was observed in the diabetic individuals from the overall group (OR = 2.27; CI = 1.47-3.52, p < 0.001) and from the hypertensive group (OR = 2.70; CI = 1.58-4.75, p < 0.001), adjusted for covariates. Regarding the ethnic stratification, diabetic individuals from Amerindian, White, and Mulatto (mixed-race) groups had higher PWV values and a greater frequency of increased arterial stiffness compared to non-diabetic individuals. Both diabetic and non-diabetic individuals had higher PWV values after 5 years. There was no significant difference in the 5-year PWV progression in diabetic compared to non-diabetic individuals.
These results confirm, in a sample of Brazilian population, that the presence of diabetes is associated with increased arterial stiffness and it may contribute in part to increased cardiovascular risk in diabetic patients.
PMCID: PMC3765236  PMID: 23965633
Arterial stiffness; Diabetes mellitus; Hypertension; Brazilian population
21.  Interleukin-17 as a novel predictor of vascular function in rheumatoid arthritis 
Annals of the rheumatic diseases  2011;70(9):1550-1555.
Rheumatoid arthritis (RA) is associated with enhanced cardiovascular (CV) risk and subclinical vascular disease. The proinflammatory milieu has been linked to premature atherosclerosis and endothelial dysfunction in RA. While IL-17 is considered pathogenic in RA, its role in determining vascular dysfunction in this disease has not been systematically assessed. We analyzed candidate variables that could determine endothelial function in various vascular territories in a cohort of RA patients on biologic therapy, with minimal traditional CV risk factors and low disease activity score.
RA patients (n=51) on stable biologic therapy underwent measurement of conduit artery endothelial function by brachial artery flow-mediated dilatation (FMD); arterial compliance by pulse wave velocity (PWV) assessment; and endothelium-dependent microvascular testing with Endo-PAT2000 device to assess reactive hyperemia index (RHI). IL-17 was quantified by ELISA and disease activity was assessed by DAS-28.
IL-17 and high sensitivity CRP were the main determinants of lower RHI in univariate (p=0.004, <0.001) and multivariate (p=0.004, <0.0001) analysis, respectively. Traditional and non-traditional CV risk variables determined PWV, with a significant positive association with IL-17 in univariate and multivariate analysis (p=0.02, 0.01, respectively). In contrast, conduit endothelial function was mainly determined by rheumatoid factor titers (p=0.003). Anti-CCP titers and disease activity did not determine vascular function.
In RA patients treated with biologics, IL-17 is a main predictor of microvascular function and arterial compliance. This study suggests IL-17 may play a significant role in development of endothelial dysfunction and CVD in RA.
PMCID: PMC3151670  PMID: 21727237
22.  Impact of hypertension on various markers of subclinical atherosclerosis in early type 2 diabetes 
Presence of Diabetes Mellitus increases the risk of subclinical atherosclerosis. In this study was aimed to determine the influence of hypertension (HTN) on surrogate markers of atherosclerosis in a population of patients with early type 2 diabetes.
125 diabetic subjects drawn from Dr. Shariati outpatient’s clinic list and 153 non- diabetic subjects who were the relatives in law of diabetic participants were recruited. Participants with type 2 diabetes were free of clinical evidence of cardiovascular disease and renal involvement. Two groups of diabetic and control were further divided into two subgroups of hypertensive (known case of HTN or blood pressure ≥140/90 mmHg) and normotensive, and anthropometric characteristics, metabolic biomarkers as well as markers of subclinical atherosclerosis including Carotid intima media thickness (CIMT), flow mediated dilation (FMD) and Ankle Brachial Index (ABI) were measured.
Diabetic group with a mean age of 49.9 ± 7.5 years had significantly higher CIMT (0.64 ± 0.14 vs 0.76 ± 0.19, p = 0.001) and lower FMD (16.5 ± 8.1 vs 13.3 ± 7.1, p = 0.003) and ABI (1.2 ± 0.1 vs 1.1 ± 0.1, p = 0.01) than control with mean age of 52.9 ± 10.1 years. 34% of control and 59.2% of diabetic were hypertensive. Fasting blood sugar, insulin levels and calculated insulin resistance index of HOMA IR. of hypertensive subjects were higher than normotensive subjects in both groups of diabetic and non-diabetic. Similar pattern was presented for measured inflammatory mediators of hs-CRP and IL-6. Among subclinical atherosclerosis markers, only CIMT was significantly different between hypertensive and normotensive subjects in both groups. In adjusted linear regression analysis, a constant significant association existed between age and CIMT, ABI and FMD in non-diabetic, while in diabetic, age only correlated with CIMT and not the other two markers. In multiple regression model, HTN was recognized as a risk factor for increasing CIMT (OR = 2.93, 95% CI = 1.03-8.33, p = 0.04) but not attenuating FMD or ABI.
Since FMD and CIMT may measure a different stage of subclinical atherosclerosis in diabetic patients, influence of HTN on these markers might be different.
PMCID: PMC3933380  PMID: 24476202
Diabetes melitus; Subclinical atherosclerosis; CIMT; FMD; ABI; Hypertension
23.  Hypoglycemia, but Not Glucose Variability, Relates to Vascular Function in Children with Type 1 Diabetes 
Chronic sustained hyperglycemia unequivocally predicts vascular disease in diabetes. However, the vascular risk of glucose variability, including hypoglycemia, is uncertain. Vascular dysfunction is present in children with type 1 diabetes and is a critical precursor of atherosclerosis. We aimed to evaluate the relationship between glucose variability and vascular function in children with type 1 diabetes.
Subjects and Methods
Fifty-two type 1 diabetes subjects (14 [SD 2.7] years old, 25 males) had continuous glucose monitoring that included 48 h of data used to evaluate glucose variability (mean amplitude of glycemic excursions [MAGE] and other measurements) and hypoglycemia indices (glycemic risk assessment diabetes equation [GRADE] hypoglycemia, Low Blood Glucose Index [LBGI], and observed duration of hypoglycemia). Children with type 1 diabetes and 50 age- and gender-matched controls had assessments of vascular function (flow-mediated dilatation [FMD] and glyceryl trinitrate–mediated dilatation [GTN]).
Children with type 1 diabetes had lower FMD and GTN than controls (P=0.02 and P<0.001, respectively). GRADE hypoglycemia and LBGI were inversely related to FMD (r=−0.36, P=0.009 and r=−0.302, P=0.03, respectively) but did not relate to GTN. GRADE hypoglycemia was independently related to FMD (regression coefficient=−0.25±0.09, P=0.006). MAGE and other measurements of glucose variability measurements did not relate to FMD or GTN.
Hypoglycemia, but not glucose variability, during continuous glucose monitoring relates to impaired vascular endothelial function in children with type 1 diabetes. Hypoglycemia may be an additional risk factor for early cardiovascular disease, but the effect of glucose variability, independent of glycosylated hemoglobin, on vascular function remains uncertain.
PMCID: PMC3359626  PMID: 22313018
24.  Idiopathic deep venous thrombosis and arterial endothelial dysfunction in the elderly 
Age  2011;34(3):751-760.
Arterial and venous thrombosis have always been regarded as different pathologies and epidemiological studies have examined the association between venous thrombosis and indicators of atherosclerosis and/or arterial thromboembolic events. We measured the flow-mediated dilation (FMD), a well-known marker of arterial endothelial dysfunction, in young–middle-aged and old-aged patients with and without unprovoked deep venous thrombosis (DVT). The aim of this study was to investigate whether DVT was a significant predictor for impaired FMD, considering all the patients and young–middle-aged (age < 65 years) and old-aged (age ≥ 65 years) patients separately. FMD was measured in the brachial artery on a population of 120 subjects with the same atherosclerosis risk factors, 68 male and 52 female, 70 young–middle-aged subjects (mean age ± SD 49.5 ± 10.5 years) and 50 old-aged subjects (76.2 ± 7.7 years). Patients with DVT showed a significant decrease of FMD compared to patients without DVT (6.8 ± 5.5% vs. 10.9 ± 3.5%, p < 0.001). Moreover, old-aged patients showed a significant decrease of FMD compared to the young–middle-aged subjects (7.4 ± 4.1% vs. 9.8 ± 5.3%, p = 0.005). In the whole study population, DVT was strongly associated with FMD (risk factors adjusted β = −4.14, p < 0.001). A significant interaction between age and the presence of DVT on predicting FMD was found (p = 0.003) suggesting a differential behavior of DVT as predictor of FMD. In young–middle-aged group, multivariate model confirmed that DVT was the most significant predictor of continuous FMD (β = −6.06, p < 0.001). On the contrary, DVT was no more a predictor of FMD in the old age group (β = −0.73, p=0.556). Furthermore, old-aged patients without DVT showed a statistically significant decrease of FMD compared to the young–middle-aged subjects without DVT (8.2±2.1% vs. 12.6±2.7%, p<0.001) and old-aged patients with DVT showed a not statistically significant decrease of the FMD compared to the young–middle-aged patients with DVT (6.7±5.3% vs. 6.8±5.7%, p = 0.932). In conclusion, young–middle-aged patients with spontaneous DVT show an impaired FMD, whereas this impairment in old-aged subjects is evident independently from the presence or absence of DVT. Aging per se may be associated with physiologic abnormalities in the systemic arteries and with endothelial dysfunction.
PMCID: PMC3337930  PMID: 21598017
Endothelial dysfunction; Venous thrombosis; Atherosclerosis; Flow-mediated dilation; Aging; Life Sciences; Molecular Medicine; Geriatrics/Gerontology; Cell Biology
25.  Descriptive study of possible link between cardioankle vascular index and homocysteine in vascular-related diseases 
BMJ Open  2013;3(3):e002483.
Cardioankle vascular index (CAVI) is a new index of arterial stiffness independent of immediate blood pressure. Homocysteine (Hcy) is an independent risk factor for vascular diseases. The aim of this study was to investigate the relationship between Hcy and CAVI in the vascular-related diseases.
Descriptive research.
88 patients (M/F 46/42) with or without hypertension, coronary artery disease or arteriosclerosis obliterans were enrolled to our study. They were divided into two groups according to the level of Hcy.
CAVI, carotid-femoral pulse wave velocity (CF-PWV) and carotid-radial pulse wave velocity (CR-PWV) were measured by VS-1000 and Complior apparatus.
There was significant correlation between Hcy and CF-PWV, CR-PWV, CAVI in the entire group (r=0.33, p=0.002; r=0.51, p<0.001; r=0.42, p<0.001, respectively). And there was significant correlation between Hcy and CF-PWV, CR-PWV, CAVI in the vascular-related disease group (r=0.23, p=0.048; r=0.51, p<0.001; r=0.392, p=0.001, respectively). The level of Hcy was significantly higher in patients with one or more vascular diseases than in patients without vascular diseases. The levels of CF-PWV, CR-PWV and CAVI were significantly higher in Hcy ≥15 μmol/l group than in Hcy <5 μmol/l group (13.7±3.0 vs 10.8±2.5, p < 0.001; 10.6±2.1 vs 9.2±1.6, p=0.001; 9.30±2.1 vs 7.79±2.1, p=0.001, respectively). Multiple linear regression showed that Hcy, body mass index (BMI) and age were independent associating factors of CAVI in the entire study group (β=0.421, p=0.001; β=−0.309, p=0.006; β=0.297, p=0.012, respectively). And Hcy, BMI and age were independent influencing factors of CAVI in the vascular-related disease group (β=0.434, p=0.001; β=−0.331, p=0.009; β=0.288, p=0.022, respectively).
CAVI was positively correlated with Hcy in the vascular-related diseases.
PMCID: PMC3612818  PMID: 23533216
Vascular medicine

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