2011

Itamar Medical Ltd.

EndoPAT Publications

[BOOKLET OF ARTICLES]
Summarized version of the body of publication up to date.

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Table of Content:
Scientific Statements, Reviews, Reproducibility, comparison with other tests. Population based studies. Risk Factors and bio-markers. Endothelial function in CVD patients. Heart failure, AF, other heart conditions. Female's Health. Erectile Dysfunction and Men's Health. Diabetes. Inflammatory diseases/ Sepsis. Sleep Apnea. Intervention studies. Nutrition Tx or challenge, Therapeutic medical devices, exercise and life style. Pediatric/adolescents. pages 2-6

pages 7-9 pages 10-14 pages 15-19 pages 20-24 pages 25-27 pages 28-29 pages 30-33 pages 34-40 pages 41-42 pages 43-49 pages 50-61

pages 62-65

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Scientific Statements, Reviews, Reproducibility, comparison with other tests.

1) Methods for evaluating endothelial function: a position statement from the European Society of Cardiology Working Group on Peripheral Circulation. Lekakis J, Abraham P, Balbarini A, Blann A, Boulanger CM, Cockcroft J, Cosentino F, Deanfield J, Gallino A, Ikonomidis I, Kremastinos D, Landmesser U, Protogerou A, Stefanadis C, Tousoulis D, Vassalli G, Vink H, Werner N, Wilkinson I, Vlachopoulos C. Eur J Cardiovasc Prev Rehabil 2011 Mar 11. An ESC position paper on available in-vivo and ex-vivo methods for evaluating endothelial function emphasizing more recent ones, including diagnostic modalities such as epicardial and microvascular coronary endothelial function, local vasodilation by venous occlusion plethysmography and flow-mediated dilatation, arterial pulse wave analysis, pulse amplitude tonometry (EndoPAT), laser Doppler flowmetry, and biochemical markers and bioassays. Results: In relation to the EndoPAT, the authors cited the findings that: a) patients with low Framingham Risk Score risk but with endothelial dysfunction were at a higher actual risk than patients with high Framingham Risk Score but normal endothelial function, and b) that endothelial dysfunction was found to be an independent risk factor for a future major adverse cardiovascular event. Conclusions: Evaluation of endothelial function appears as an appealing adjunct for risk stratification, prevention and rehabilitation. http://www.ncbi.nlm.nih.gov/pubmed/21450600 2) Assessing endothelial vasodilator function with the Endo-PAT 2000. Axtell AL, Gomari FA, Cooke JP. J Vis Exp. 2010 Oct 15 ;( 44).

P age |3 This article and video demonstrate how to use the Endo-PAT2000 to assess endothelial vasodilator function. There are a number of methods to assess endothelial vasodilator function. The Endo-PAT2000 is highlighted as being a rapid and non-invasive technique. Unlike the commonly used technique of duplex ultra-sonography to assess flow mediated vasodilation, it is totally operator-independent, and the equipment is an order of magnitude less expensive. Other merits are also discussed and shown. http://www.ncbi.nlm.nih.gov/pubmed/20972417 3) Endothelial Function as a functional Expression of Cardiovascular Risk Factors. Reriani M, Lerman L O, Lerman A. Biomarkers in Medicine 2010; 4(3):351-360(10) Review of the role of endothelial function, (EF), in aiding in future the prediction of future CV events with special attention on the EndoPAT2000 assessment of EF. Traditional CV risk factors fail in predicting the development of Ischemic Heart Disease in 25-50% of cases, underscoring a complex interplay between traditional risk factors, (Framingham Risk Scores) risk factors, genetic disposition and newer athero-protective risk factors. Conclusions: EF represents the sum of all athero-protective mechanisms, and the integrated overall CV risk factor burden. It may be regarded as the missing link between CV risk factors and atherosclerotic disease. http://www.ncbi.nlm.nih.gov/pubmed/20550469 4) Diagnosis and treatment of endothelial dysfunction in cardiovascular disease. Hirata Y, Nagata D, Suzuki E, Nishimatsu H, Suzuki J, Nagai R. Int Heart J. 2010 Jan; 51(1):1-6. Review examining the diagnosis and treatment of cardiovascular disease from the viewpoint of endothelial function. Author s basic tenet is that vascular endothelial dysfunction is the causative factor or promoting mechanism of arteriosclerosis. In reviewing endothelial function diagnostic methods, the role of the EndoPAT in the Framingham Heart Study is highlighted. Conclusion: It is essential to consider the improvement and repair of endothelial function when treating arteriosclerotic disease and there is a need to having simple methods to measure it. http://www.ncbi.nlm.nih.gov/pubmed/20145343 5) Pulse wave amplitude is associated with brachial artery diameter: implications for gender differences in microvascular function.

P age |4 Heffernan KS, Karas RH, Mooney PJ, Patel AR, Kuvin JT. Vasc Med. 2010 Feb; 15(1):39-45. Assessed whether brachial artery diameter (BAD) affects downstream resistance vessel PWA in 115 patients varying in cardiovascular risk profiles, and hypothesized that (A) finger PWA is influenced by BAD, and (B) that this influences RHI difference between genders. There was a negative association between BAD and PWA-RHI (r = -0.34, p < 0.05). Women had greater RHI and smaller BAD compared with men (p < 0.05). Conclusion: RHI is negatively associated with BAD. Studies examining gender differences with PAT may need to correct for BAD as a potential confounder. http://www.ncbi.nlm.nih.gov/pubmed/20026517 6) Muscle sympathetic nerve activity is related to a surrogate marker of endothelial function in healthy individuals. Sverrisdttir YB, Jansson LM, Hgg U, Gan LM. PLoS One. 2010 Feb 17;5(2):e9257 Investigated whether directly recorded sympathetic vasoconstrictor outflow, (MSNA) is related to endothelial function, (EndoPAT), in 10 healthy normotensive subjects. Findings and Conclusion: EndoPAT index was inversely related to MSNA (r = -0.8, p = 0.005), indicating that sympathetic outflow may be modulated by changes in endothelial function and also stressed the importance of routine exercise in maintaining CV health. http://www.ncbi.nlm.nih.gov/pubmed/20174639 7) Variability of peripheral arterial tonometry in the measurement of endothelial function in healthy men. Liu J, Wang J, Jin Y, Roethig HJ, Unverdorben M. Clin Cardiol. 2009 Dec; 32(12):700-4. The authors examined inter/intraday reproducibility and variability of the reactive hyperemia index (RHI) in 22 healthy males at intervals of 0.5 hours (7/day), 1 hour (5/day), and at 2 hour intervals (7/day, n=10), over 3 consecutive days. RHI values at the same time points on each of the 3 days were not statistically significantly different. The authors noted that while repetitive EndoPAT measurements have no carryover effect on RHI at 1or 2 hour intervals, 0.5 hour intervals show a trend of increase, and that intra subject RHI variability is similar to flowmediated dilation using brachial artery ultrasound scanning.

P age |5 http://www.ncbi.nlm.nih.gov/pubmed/20027662 8) Assessment of Vascular Endothelial Function With Peripheral Arterial Tonometry Information at Your Fingertips? Patvardhan EA, Heffernan KS, Ruan JM, Soffler MI, Karas RH, Kuvin JT Cardiol Rev. 2010 Jan-Feb; 18(1):20-8. Comprehensively reviews endothelial function assessment techniques, particularly EndoPAT technology. Since endothelial dysfunction is firmly established in the pathogenesis of atherosclerosis, its accurate assessment as a gauge of vascular health has long been intensively investigated. It is emerging as a useful tool for predicting cardiovascular risk, and as a surrogate outcome measure for cardiovascular event reduction in intervention studies. Conclusion: EndoPAT has facilitated noninvasive assessment of endothelial function in the clinical arena, in various disease states, helped define pathophysiology, and response to interventions. http://www.ncbi.nlm.nih.gov/pubmed/20010335 9) Noninvasive Assessment of Subclinical Atherosclerosis in Children and Adolescents Recommendations for Standard Assessment for Clinical Research. A Scientific Statement from the American Heart Association. Urbina EM, Williams RV, Alpert BS, Collins RT, Daniels SR, Hayman L, Jacobson M, Mahoney L, Mietus-Snyder M, Rocchini A, Steinberger J, McCrindle B Hypertension 2009; 54(5):919-50. A landmark AHA Scientific Statement reviewing literature on noninvasive assessment of atherosclerosis in children and adolescents. It recommended the standardization of these tools for research, and called for developing valid and reliable techniques with normative data for clinical evaluation of atherosclerosis in pediatric patients, since precise and reliable noninvasive tests for atherosclerosis in youth will improve estimation of future risk for heart attack and stroke. In relating to endothelial assessment, the EndoPAT was singled out as an operator independent device showing promise, with good reproducibility in children. http://www.ncbi.nlm.nih.gov/pubmed/19729599 10) Endothelial pulse amplitude testing: feasibility and reproducibility in adolescents. Selamet Tierney ES, Newburger JW, Gauvreau K, Geva J, Coogan E, Colan SD, de Ferranti SD J Pediatr. 2009 Jun;154(6):901-5

P age |6 Evaluated the feasibility and intra-subject reproducibility of the EndoPAT in 30 healthy adolescents aged 13 to 19 years on different days. A very high intra-class correlation coefficient for day-today reproducibility (R=0.78, p< .000001) was reported. The authors concluded that, in healthy adolescents, EndoPAT is feasible and highly reproducible, which may provide an easy and reliable means for assessing endothelial function. http://www.ncbi.nlm.nih.gov/pubmed/19217124 11) Role of nitric oxide in the regulation of digital pulse volume amplitude in humans. Nohria A, Gerhard-Herman M, Creager MA, Hurley S, Mitra D, Ganz P. J Appl Physiol. 2006 Aug; 101(2):545-8. Aimed to investigate whether nitric oxide (NO) is a major component accounting for endothelial dependent vasodilatation measured with the EndoPAT device. The role of NO was investigated in 33 healthy subjects (19 men, aged 19 53 years) by inhibiting nitric oxide synthesis with NGnitro-L-arginine methyl ester (L-NAME). As a control served 10 subjects that underwent an identical protocol with saline and 5 subjects with phenylephrine, a nonspecific vasoconstrictor. The change in digital PAT signal amplitude response to reactive hyperemia before and during intra-radial administration was compared between the three groups. Results: PAT response was significantly blunted by LNAME administration (-46 21%, p = 0.002), was unchanged with saline and relatively insignificantly increased with phenylephrine (20 9%, p=NS). Conclusions: The authors stated that we demonstrate that nitric oxide is the mediator responsible for the marked increase in digital PVA-RH and added that measurement of digital PVA-RH may indeed provide a simple means of assessing endothelial function in humans. http://www.ncbi.nlm.nih.gov/pubmed/16614356

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Population based studies

1)

Noninvasive vascular function measurement in the community: cross sectional relations and comparison of methods. Schnabel RB, Schulz A, Wild PS, Sinning CR, Wilde S, Eleftheriadis M, Herkenhoff S, Zeller T, Lubos E, Lackner KJ, Warnholtz A, Gori T, Blankenberg S, Mnzel T. CircCardiovasc Imaging. 2011 Jul 1; 4(4):371-80. Simultaneously compared associations amongst flow-mediated dilation (FMD), peripheral arterial volume pulse determined by infrared photo reflection index, and EndoPAT index, in relation to classical cardiovascular risk factors in an unselected cohort of 5000 participants. Results: The strongest association for hyperemic response variables was between EndoPAT index and FMD. Classical risk factors explained between 15.8% (reflection index) and 58.4% (brachial artery diameter) of the baseline values and 3.2% (reflection index), 15.4% (FMD), and 13.9% (EndoPAT index) of the variability of hyperemic responses. Regression models of the vascular function measures varied in relation to classical risk factors, but were consistently associated with age, sex, body mass index, and indicators of hypertension. EndoPAT index also showed a relation to fasting glucose concentrations. Conclusions: Noninvasive measures of conduit artery (by FMD) and microvascular peripheral arterial function (by EndoPAT) are modestly correlated, differ in their relation to classical cardiovascular risk factors, and may thus reflect different pathologies. http://www.ncbi.nlm.nih.gov/pubmed/21551420

2)

Relation of brachial and digital measures of vascular function in the community: the Framingham heart study. Hamburg NM, Palmisano J, Larson MG, Sullivan LM, Lehman BT, Vasan RS, Levy D, Mitchell GF, Vita JA, Benjamin EJ. Hypertension. 2011 Mar; 57(3):390-6 Noninvasively compared vasodilator function in the brachial artery - (FMD, n=7031; age 48 13, 54% women), and digital arteries using EndoPAT- (PAT ratio , n=4352; age 55

P age |8 16, 51% women), in Framingham Offspring, Third Generation and Omni Cohorts. Abnormality thresholds were defined respectively as the sex-specific fifth percentile in a reference group free of conventional cardiovascular risk factors. Results: Abnormal FMD but not PAT ratio prevalence increased with age and higher systolic blood pressure. Higher BMI was associated with increased abnormality prevalence in both. Abnormal PAT ratio correlates included lower systolic blood pressure, increasing total/highdensity lipoprotein cholesterol ratio, diabetes, smoking, and lipidlowering medication. In 1,843 concurrent tests, PAT ratio and FMD were not significantly associated. Conclusions: FMD and PAT ratio might provide distinct information regarding vascular function in conduit versus smaller digital vessels. http://www.ncbi.nlm.nih.gov/pubmed/21263120 3) Black race is associated with digital artery endothelial dysfunction: Results from the Heart SCORE study. SR Mulukutla, L Venkitachalam, C Bambs, KE Kip, A Aiyer, OC Marroquin, SE Reis. Eur Heart J. 2010 Aug 24. Examined relationship between race and endothelial dysfunction in 1377 subjects (41% black; 58.5 7.5 years; 67% female). Results: EndoPAT ratio (natural logarithm) was significantly lower in blacks vs. whites (0.67 0.44 vs. 0.80 0.46, P < 0.001). Black race independently correlated with lower PAT ratio across all Framingham risk strata. With white women as a reference parameter estimates for lower PAT ratio in ascending order were: black males (t = 6.93, P < 0.0001); white males (t = 3.31, P = 0.001); and black females (t = 1.12, P = 0.26). Conclusion: Black race is independently associated with arterial endothelial dysfunction. http://www.ncbi.nlm.nih.gov/pubmed/20736241 4) Assessment of endothelial function using digital pulse amplitude tonometry. Hamburg NM, Benjamin EJ. Trends Cardiovasc Med. 2009 Jan; 19(1):6-11. Reviews recent studies that support the utility of EndoPAT as a relevant test of peripheral endothelial function, pointing that there is abundant evidence linking

P age |9 endothelial dysfunction to atherosclerosis and to an increased risk of cardiovascular events. Since a simple and accurate endothelial function test is an attractive, noninvasive addition to cardiovascular risk stratification tools, there is considerable interest in developing the test of digital vascular function using PAT as a method for evaluating endothelial function. The advantages of the technique include its ease of administration, and an automated analysis program facilitating the acquisition of reliable data. http://www.ncbi.nlm.nih.gov/pubmed/19467447 5) Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Hamburg NM, Keyes MJ, Larson MG, Vasan RS, Schnabel R, Pryde MM, Mitchell GF, Sheffy J, Vita JA, Benjamin EJ. Circulation. 2008 May 13; 117(19):2467-74. Examined the relation of digital pulse amplitude and digital hyperemic response to cardiovascular risk factors in the community by measuring the EndoPAT index in Framingham Third Generation Cohort participants (n=1957; mean age= 40+/- 9 years; 49% women). Results: expressing the PAT ratio as the natural logarithm of the ratio of post deflation to baseline pulse amplitude in the hyperemic finger divided by the same ratio in the contralateral finger that served as control. The relation of the PAT ratio to cardiovascular risk factors was strongest in the 90- to 120-second post deflation interval. In stepwise multivariable linear regression models, male sex, body mass index, ratio of total to high-density lipoprotein cholesterol, diabetes mellitus, smoking, and lipidlowering treatment were inversely related to PAT ratio, whereas increasing age was positively related to PAT ratio (all P<0.01). Conclusions: Reactive hyperemia produced a time-dependent increase in fingertip pulse amplitude. Digital vasodilator function is related to multiple traditional and metabolic cardiovascular risk factors. http://www.ncbi.nlm.nih.gov/pubmed/18458169

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Risk Factors and bio-markers

1) Comparing EndoPAT and BIOPAC measurement of vascular responses to mental stress. Martin EA, Nelson RE, Felmlee-Devine MD, Brown TE, Lerman A. Cell Biochem Funct. 2011 Jun; 29(4):272-8. Compared stress-induced changes in vascular function during acute mental stress tests using the EndoPAT2000, to a standard polygraph device (BIOPAC MP150), in 25 healthy subjects. Reactive hyperemia was compared at baseline and following three acute mental stress tests using both methods. Results: There was no difference in vascular hyperemic reactivity at baseline and following acute mental stress, as measured by both systems (P > 0.05), however, mental stress ratios measured by EndoPAT were significantly different than those measured by BIOPAC (P < 0.01). Conclusions: Data suggest that EndoPAT measurements of vascular responses to acute mental stress may be more specific and sensitive than measurements using the BIOPAC system. http://www.ncbi.nlm.nih.gov/pubmed/21671245 2) Plasma leptin levels and digital pulse volume in obese patients without metabolic syndrome - A pilot study. Lin YH, Ho YL, Lee JK, Huang HL, Huang KC, Chen MF. Clin Chim Acta. 2011 Apr 11; 412(9-10):730-4. Assessed the relationship among endothelial dysfunction (EndoPAT2000), anthropometric indices, adipokines and inflammatory cytokines in 35 obese patients without metabolic syndrome, 11 of whom had been diagnosed with endothelial dysfunction. Results: There was a significant difference of ln leptin (p=0.007), ln [leptin/visceral fat thickness] (p=0.004) and ln [leptin/subcutaneous fat thickness] (p<0.001) between patients with and without endothelial dysfunction. ln [leptin/subcutaneous fat thickness] was significantly related to the ln (PAT ratio) (p=0.002). Using ln

P a g e | 11 [leptin/subcutaneous fat thickness] to detect endothelial dysfunction provided area under ROC curve of 0.843 (p=0.002). Conclusions: Abnormal digital vascular function occurs in obese patients without metabolic syndrome. Low plasma leptin/subcutaneous fat ratio is associated with endothelial dysfunction in this population. http://www.ncbi.nlm.nih.gov/pubmed/21195702 3) High-density lipoprotein cholesterol and apolipoprotein A1 levels strongly influence the reactivity of small peripheral arteries. Ferr R, Aragons G, Plana N, Merino J, Heras M, Buixadera C, Masana L. Atherosclerosis. 2011 Feb 2. Assessed EndoPAT index in the acral arteries, and the associations between clinical, anthropometric and biochemical factors in 816 subjects at intermediate to high cardiovascular risk. Results: HDL cholesterol and apolipoprotein A1 levels were strongly and positively correlated with an increased EndoPAT index. Metabolic syndrome components, (increased waist circumference, hypertriglyceridaemia and smoking), and serum markers of inflammation were inversely associated with EndoPAT index. Predictors of EndoPAT index were HDL cholesterol, (protective effect), and smoking, (negative impact). Conclusions: HDL cholesterol and apolipoprotein A1 levels have a strong, positive correlation with small artery reactive hyperemia, whereas smoking, waist circumference and triglyceride levels were inversely associated. http://www.ncbi.nlm.nih.gov/pubmed/21367423 4) Endothelial function in a cardiovascular risk population with borderline anklebrachial index. Syvnen K, Korhonen P, Partanen A, Aarnio P. Vascular Health and Risk Management 2011 7 Feb. Assessed endothelial function using EndoPAT2000 in 66 individuals with cardiovascular risk, borderline Ankle-Brachial Index (ABI), and hypertension, newly diagnosed glucose disorder, metabolic syndrome, obesity, or a ten year risk of cardiovascular disease death of 5% (Systematic Coronary Risk Evaluation System).

P a g e | 12 Results: Mean ABI was 0.95 and mean RHI 2.11. Endothelial dysfunction, (RHI < 1.67), was detected in 15/66 subjects. Subjects with impaired fasting glucose (IFG) had lower RHI (1.91) than non IFG (2.24) (P = 0.02). Conclusions: In a cardiovascular risk population with borderline ABI nearly a quarter had endothelial dysfunction, indicating an elevated risk of cardiovascular events and possible need for more aggressive treatment for their risk factors. http://www.ncbi.nlm.nih.gov/pubmed/21415923 5) Effect of Brief Secondhand Smoke Exposure on Endothelial Function and Circulating Markers of Inflammation. P O. Bonetti, E Lardi, C Geissmann, M U. Kuhn, H Bruesch, W H. Reinhart. Atherosclerosis 2010 Dec 22. Assessed the acute effects of short-term secondhand smoking (SHS) on endothelial function and circulating markers of inflammation in 18 non-smoking males before and 12 hours after a one-hour SHS exposure. EndoPAT2000, circulating markers of endothelial function and circulating inflammatory markers were measured. Results: Twelve hours after SHS, average EndoPAT index was significantly lower than before SHS exposure (1.54 0.49 vs. 2.01 0.55, p=0.01), whereas inflammatory markers remained unchanged. Conclusions: Short-term SHS exposure leads to a measurable disturbance of endothelial function, but not to inflammatory changes. http://www.ncbi.nlm.nih.gov/pubmed/21215401 6) Is Acute High-Dose Secondhand Smoke Exposure Always Harmful to Microvascular Function in Healthy Adults? Bard RL, Dvonch JT, Kaciroti N, Lustig SA, Brook RD. Prev Cardiol. 2010 Fall; 13(4):175-9. Investigated vascular and blood pressure (BP) reactions to 1- hour second hand smoking (SHS) exposure in 25 healthy nonsmoking adults. EndoPAT response and aortic hemodynamic compliance were assessed before and after SHS and BP were measured every 15 minutes during and 24-hours before and after SHS.

P a g e | 13 Results: SHS did not change endothelial function, aortic hemodynamic, arterial compliance, or 24-hour systolic BP. However, diastolic BP significantly increased during SHS by 3.4 +/- 5.6 mm Hg. Conclusion: Brief SHS exposure did not impair microvascular endothelial function or arterial compliance in healthy nonsmoking adults, but brachial diastolic BP increased. http://www.ncbi.nlm.nih.gov/pubmed/20860641 7) No Evidence of Impaired Endothelial Function or Altered Inflammatory State in Patients with Familial Hypercholesterolemia Treated with Statins. A Hovland, I Aagnes, OL Brekke,JH Flage, KT Lappegard. Journal of Clinical Lipidology. 2010 Jul-Aug; 4(4):288-92. Evaluated endothelial function (using EndoPAT2000) and inflammatory cytokines in patients with Familial Hypercholesterolemia (FH) treated with statins (n=14) vs. matched healthy controls (n=11). Results: No differences between the groups in any of the inflammatory markers tested, nor in HDL-cholesterol, LDL-cholesterol, triglycerides, APO A, APO B, Lp, homocysteine, HbA1c, platelets and fibrinogen. EndoPAT index was 1.58 in FH and 1.93 in controls (p=n.s). Conclusions: Neither Endothelial function, nor inflammatory states were different in FH patients on statins compared with healthy controls. http://www.ncbi.nlm.nih.gov/pubmed/21122661 8) High-throughput ambulatory assessment of digital reactive hyperemia: Concurrent validity with known cardiovascular risk factors and potential confounding. Truschel E, Jarczok MN, Fischer JE, Terris DD. Prev Med. 2009 Dec; 49(6):468-72. Evaluated the concurrent validity between EndoPAT determined RHI, with CVD risk factors and biomarkers in a high-throughput ambulatory setting (2007 EADS/Augsburg, Germany, cohort follow-up). In 603 subjects RHI values were significantly related to several known risk factors for CVD, including subject's sex, LDL cholesterol level, systolic BP, and WHR.

P a g e | 14 Conclusion: Further study needed to directly compare the use of EndoPAT in controlled and less-controlled settings and assess predictive validity of RHI in CVD primary prevention. http://www.ncbi.nlm.nih.gov/pubmed/19804795 9) Endothelial dysfunction and specific inflammation in obesity hypoventilation syndrome. Borel JC, Roux-Lombard P, Tamisier R, Arnaud C, Monneret D, Arnol N, Baguet JP, Levy P, Pepin JL. PLoS One. 2009; 24; 4(8):e6733. Investigated the additive role of moderate chronic hypoventilation to obesity in systemic inflammation and endothelial dysfunction in 14 OHS versus 39 eucapnic obese patients matched for BMI and age. Diurnal blood gases, overnight polysomnography and EndoPAT determined endothelial function were assessed. Inflammatory and antiinflammatory cytokines were measured by multiplex beads immunoassays. Among other things the authors found that endothelial function was significantly more impaired in OHS, thus explaining OHS strong association with increased cardiovascular risk. http://www.ncbi.nlm.nih.gov/pubmed/19701463

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Endothelial function in CVD patients.

1) Small artery dilation and endothelial markers in cardiovascular risk patients. Aragons G, Ferr R, Girona J, Plana N, Merino J, Heras M, Masana L. Eur J Clin Invest. 2011. Studied the correlations between the hyperemia reactivity of small peripheral arteries determined by EndoPAT and the levels of serum biomarkers of EF (endothelial function), inflammation and oxidation in patients with cardiovascular (CV) risk factors (N=407). Results: A significant correlation was found between EndoPAT index and concentration of soluble E-selectin (sE-selectin) and soluble vascular cell adhesion molecule 1 (sVCAM1). In non-metabolic syndrome patients (46%), these correlations were stronger, and oxidized low-density lipoprotein/LDL (oxLDL/LDL) was also correlated with EndoPAT index. Conclusions: Elevated levels of sE-selectin and, to a smaller degree, sVCAM-1 and oxLDL/LDL are associated with lower EndoPAT index. sE-selectin is the main determinant biomarker of EndoPAT index as assessed by regression analysis. http://www.ncbi.nlm.nih.gov/pubmed/21631467 2) Associations of cardiovascular risk factors with two surrogate markers of subclinical atherosclerosis: Endothelial function and carotid intima media thickness. Fitch KV, Stavrou E, Looby SE, Hemphill L, Jaff MR, Grinspoon SK. Atherosclerosis. 2011 Aug; 217(2):437-40. Examined the correlation between endothelial function assessment, (EndoPAT), and carotid Intima Media Thickness (cIMT) in 54 healthy subjects. Results: cIMT and EndoPAT index were significantly associated (r=0.35, P = 0.02) in univariate analysis. EndoPAT index was significantly associated with age, triglycerides, fasting glucose, HDL, WHR, waist circumference and VAT (visceral adipose tissue). cIMT was associated with other risk factors. In multivariate regression analyses, triglyceride level (P = 0.04) remained a significant determinant of EndoPAT index.

P a g e | 16 Conclusions: Determinants of cIMT and EndoPAT index were different, dominated by triglyceride and abdominal adiposity measures for EndoPAT index. http://www.ncbi.nlm.nih.gov/pubmed/21570076 3) The Prevalence of Endothelial Dysfunction in Patients With and Without Coronary Artery Disease. S Toggweiler, A Schoenenberger, N Urbanek, P Erne. Clin Cardiol. 2010; 33(12):746-52. Examined whether cardiovascular (CV) risk factors are correlated with endothelial dysfunction (ED) even in patients without CAD, in 341 patients referred for coronary angiography. Results: The EndoPAT index, was significantly higher in patients without CAD (2.02 0.52) vs. chronic CAD (1.81 +/- 0.44, P = 0.001) or acute CAD (1.74 0.49, P < 0.001). In multivariate analysis, CAD, diabetes, smoking, and number of risk factors, were strong predictors of ED. ED was also present in 67% of patients without CAD but with 3 CV risk factors. Conclusions: Prevalence of ED in patients with chest pain depends on the presence of CAD and CV risk factors. Non-CAD patients with 3 risk factors frequently have ED, increased risk for future CV events, and may profit from intensified therapy to control CV risk factors. http://www.ncbi.nlm.nih.gov/pubmed/21184558 4) T-cadherin is present on endothelial microparticles and is elevated in plasma in early atherosclerosis. Philippova M, Suter Y, Toggweiler S, Schoenenberger AW, Joshi MB, Kyriakakis E, Erne P, Resink TJ. Eur Heart J. 2010. Since up regulation of T-cadherin on the surface of Endothelial Cells (EC) may be a characteristic marker of EC activation and stress, this study investigated whether Tcadherin might also be shed from ECs, and reflect the extent of their activation or damage. Results: Plasma T-cadherin was 0.900.90 ng/mL in 30 healthy volunteers, 9.232.61 in 63 patients with non-significant atherosclerosis and 6.931.31 in 162 chronic coronary artery disease patients. Both patient groups had a significant dependency between T-

P a g e | 17 cadherin levels and the degree of endothelial dysfunction as measured by EndoPAT, (P = 0.043) Conclusions: Plasma T-cadherin is increased in early atherosclerosis and correlates with endothelial dysfunction. http://www.ncbi.nlm.nih.gov/pubmed/20584775 5) Assessment of Endothelial Function by Noninvasive Peripheral Arterial Tonometry Predicts Late Cardiovascular Adverse Events. R Rubinshtein, J T. Kuvin, M Soffler, R J. Lennon, S Lavi, R E. Nelson, G M. Pumper L O. Lerman, A Lerman. EHJ 2010; 31(9):1142-8. First outcome study. Examining EndoPAT predictive value of late Major Adverse Cardiovascular Events (MACE) in 270 outpatients (5412 years, 48% female). Natural logarithmic RH index (L_RHI) was determined, and then patients were followed for MACE (cardiac death, MI, revascularization or cardiac hospitalization) during a mean 5.8 years. Results: MACE occurred in 86 patients (31%). 7 years MACE rate was 48% in patients with L_RHI < 0.4 vs. 28% with L_RHI > 0.4 (P = 0.03). Framingham risk score was not higher in patients with MACE. Multivariate analysis identified L_RHI <0.4 as an independent predictor of MACE (P = 0.03). Conclusions: Low L_RHI was shown to be an independent predictor of MACE, thus may be useful in identifying CV risk. http://www.ncbi.nlm.nih.gov/pubmed/20181680 6) Digital Assessment of Endothelial Function and Ischemic Heart Disease in women. Y Matsuzawa, S Sugiyama, K Sugamura ,T Nozaki, K Ohba, M Konishi, J Matsubara, H Sumida, K Kaikita, S Kojima, Y Nagayoshi, M Yamamuro, Y Izumiya, S Iwashita, K Matsui, H Jinnouchi, K Kimura, S Umemura, H Ogawa. JACC 2010; 55(16):1688-1696. Evaluated EndoPAT for predicting ischemic heart disease (IHD) relative to angiography. Subjects, 140 stable women with chest pain, comprising: obstructive coronary artery disease (CAD - 49%), non-obstructive coronary artery disease (NOCAD 30%) and non-

P a g e | 18 IHD (21%). NOCAD was diagnosed by angiography plus coronary blood flow using intracoronary acetylcholine provocation and stress test with cardiac scintigraphy. Results: Median EndoPAT RHI ; CAD = 1.57 and NOCAD = 1.58, vs. 2.15 in non-IHD. (p < 0.001). RHI was significantly associated with IHD in multivariate analysis, and by ROC (AUC = 0.86; p < 0.001). RHI prediction of NOCAD, after excluding obstructive CAD (AUC 0.85; p <0.001; (81% sensitivity and 80% specificity at RHI>1.81)). Conclusions: EndoPAT2000 RHI can predict angiographically confirmed IHD, both obstructive and non-obstructive CAD, hence useful for identifying high-risk women for IHD. http://www.ncbi.nlm.nih.gov/pubmed/20394872 7) Peripheral Arterial Tonometry for Risk Stratification in Men With Coronary Artery Disease. Heffernan KS, Karas RH, Patvardhan EA, Jafri H, Kuvin JT. Clin Cardiol. 2010 Feb; 33(2):94-8. Assessed EndoPAT suitability for detecting high risk CAD patients in large and clinically varied populations. In 42 men with stable CAD and well controlled LDL cholesterol levels, plasma levels of: (A), hs-CRP and (B), Lp-PLA2, defined risk groups (High; A & B elevated, Moderate; A or B elevated, Low; A & B low). Results: PAT was significantly lower in high-risk (1.3 +/- 0.04) versus moderate (1.6 +/0.07, P < 0.05) and low-risk (2.0 +/- 0.1, P < 0.05) groups, and was a significant predictor of high risk (binary logistic regression, P < 0.05). Conclusion: EndoPAT distinguished high from moderate and low risk men with stable CAD and well controlled LDL-C levels, aiding in residual risk stratification in at risk cohorts. http://www.ncbi.nlm.nih.gov/pubmed/20186990 8) Comparison of peripheral arterial response to mental stress in men versus women with coronary artery disease. Hassan M, Li Q, Brumback B, Lucey DG, Bestland M, Eubanks G, Fillingim RB, Sheps DS. Am J Cardiol. 2008 Oct 15; 102(8):970-4.

P a g e | 19 Determined gender-related differences in peripheral arterial response to induced mental stress, (public speaking task), in 211 patients with CAD, using the EndoPAT. Hemodynamic and PAT measurements were recorded during rest and mental stress. Results: The PAT stress to rest ratio was significantly higher in women (0.80 0.72) vs. men (0.59 0.48) (p = 0.032). This finding remained significant after controlling for possible confounding factors (p =0.037). Conclusions: Peripheral vasoconstrictive response to mental stress was more pronounced in men compared with women, suggesting that men have higher susceptibility to mental stress-related adverse effects. http://www.ncbi.nlm.nih.gov/pubmed/18929695 9) Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr, Kuvin JT, Lerman A. J Am Coll Cardiol. 2004 Dec 7; 44(11):2137-41. Evaluated the EndoPAT as a noninvasive tool to identify coronary microvascular endothelial dysfunction by comparing it to intra-coronary response to Ach in 94 consecutive patients (39 males; age 50 2), who were referred for coronary angiography to exclude CAD and were found to have normal or near normal coronary stenosis (<30% diameter). Intra-coronary assessment of endothelial dysfunction was normal (n = 39) and abnormal (n =55) and when using this as a "gold standard" the EndoPAT response was shown to have 80% sensitivity and 85% specificity to identify patients with coronary endothelial dysfunction. In conclusion the authors wrote that these Results are suggesting a role for RH-PAT as a noninvasive test to identify patients during the early stage of CAD. http://www.ncbi.nlm.nih.gov/pubmed/15582310

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Heart failure, AF, other heart conditions.

1) Usefulness of peripheral vascular function to predict functional health status in patients with fontan circulation. Goldstein BH, Golbus JR, Sandelin AM, Warnke N, Gooding L, King KK, Donohue JE, Gurney JG, Goldberg CS, Rocchini AP, Charpie JR. Am J Cardiol. 2011 Aug 1; 108(3):428-34. Assessed the association between peripheral vascular function and functional health status in Fontan-palliated patients using the EndoPAT and Cardiopulmonary exercise testing in 51 Asymptomatic Fontan patients (94% New York Heart Association functional class I and 88% B-type natriuretic peptide level <50 pg/ml), and 22 matched healthy controls. Results: The Fontan EndoPAT baseline pulse amplitude was greater than controls (median 2.74, vs. median 1.86, p=0.03). EndoPAT index was lower in Fontan patients (median 0.17, vs. median 0.50, p=0.002). Key parameters of exercise performance were lower in Fontan patients than in the controls, and the EndoPAT index correlated with measurements of exercise performance. Conclusions: In an asymptomatic Fontan population there is evidence suggesting dysfunction of the endothelium-derived nitric oxide pathway. Vasodilator function appears to correlate with exercise performance. http://www.ncbi.nlm.nih.gov/pubmed/21600541 2) Improvement effect on endothelial function in patients with congestive heart failure treated with cardiac resynchronization therapy. Enomoto K, Yamabe H, Toyama K, Matsuzawa Y, Yamamuro M, Uemura T, Morihisa K, Iwashita S, Kaikita K, Sugiyama S, Ogawa H. J Cardiol. 2011 Jul; 58(1):69-73. Investigated the relationship between CRT (cardiac resynchronization therapy) and vascular endothelia lfunction (EndoPAT), in 22 consecutive severe CHF patients with

P a g e | 21 dilated cardiomyopathy, receiving optimal medical therapy alone (medical therapy group: n=10) or CRT group (n=12) at enrolment, and after 12 weeks. Also analyzed the association between EndoPAT index and cardiac function. Results: Both therapies significantly and equally improved functional class, LVEF, end-diastolic left ventricular dimension and plasma levels of brain natriuretic peptide (BNP). Only CRT significantly increased cardiac output and EndoPAT index (medical therapy group: 1.50.2 to 1.50.3, p=0.824; CRT group: 1.40.2 to 1.70.4, p=0.003). There was significant positive correlation between changes in EndoPAT index and cardiac output (r=0.600, p=0.003). Conclusions: CRT significantly improved endothelial function through the improvement of cardiac output in CHF patients, compared to optimal medical therapy. http://www.ncbi.nlm.nih.gov/pubmed/21493043

3) Endothelial Dysfunction in Paroxysmal Atrial Fibrillation as a Prothrombotic State: Comparison with Permanent/Persistent Atrial Fibrillation. Matsue Y, Suzuki M, Abe M, Ono M, Seya M, Nakamura T, Iwatuka R, Mizukami A, Toyama K, Kumasaka L, Handa K, Nagahori W, Ohno M, Matsumura A, Hashimoto Y. J Atheroscler Thromb. 2011 Jan 6. Examined the relation between paroxysmal atrial fibrillation (PAF) and endothelial function in100 consecutive Atrial Fibrillation (AF) outpatients and 21 matched controls. The AF group was further divided into PAF and persistent AF (PeAF). Results: EndoPAT index was significantly lower in both AF groups compared to controls; PAF and PeAF were both significant independent predictors of endothelial dysfunction. Conclusions: PAF is an independent predictor of endothelial dysfunction regardless of any other concomitant comorbidity, thus may explain the equal risk of thromboembolism in PAF and PeAF groups. http://www.ncbi.nlm.nih.gov/pubmed/21224522 4) Inflammation and reduced endothelial function in the course of severe acute heart failure. Hermansen SE, Kalstad T, How OJ, Myrmel T.

P a g e | 22 Transl Res.2011 Mar; 157(3):117-27. Assessed over 4 consecutive days the changes and associations between vascular function (EndoPAT2000), markers of inflammation, and circulating ADMA levels in patients with cardiogenic shock (CS, n=12) and post cardiotomy heart failure (PC-HF, n=12). Results: Baseline EndoPAT index was significantly attenuated for both CS and PC-HF (1.35 and 1.45, respectively, P = .001), compared to healthy controls (2.28). Inflammatory markers were markedly elevated, and improved EndoPAT index was associated with decrease in inflammatory markers in PC-HF. ADMA was related to organ dysfunction and degree of hypoperfusion during CS, but showed no correlation to inflammation or impaired vasodilator function. Conclusions: The pathogenic significance of these responses needs clarification. http://www.ncbi.nlm.nih.gov/pubmed/21316028 5) Right ventricular pacing impairs endothelial function in man. Choy AM, Su HH, Elder DH, Noman A, Pauriah M, Struthers AD, Lang CC. Europace. 2011 Feb 22. Examined the effects of right ventricular pacing (RVP-min vs. RVPmax) on cardiac measures of vascular health (endothelial function using the EndoPAT2000), ventricular wall stress (B-type natriuretic peptide), and cardiac reserve (cardiac output response to exercise) in 22 subjects with dual-chamber pacemakers. Results: EndoPAT index was significantly lower after RVP-max vs. RVP-min (1.73+0.33 vs. 1.96+0.37, P<0.05). B-type natriuretic peptide was not significantly different between pacing modes. Cardiac output at peak exercise was significantly lower during RVP-max. Conclusions: Right ventricular pacing is associated with worsened endothelial function and cardiac reserve. http://www.ncbi.nlm.nih.gov/pubmed/21343239

6) Endothelial Function and Vascular Response to Mental Stress Are Impaired in Patients With Apical Ballooning Syndrome. E A. Martin, A Prasad, C S. Rihal, L O. Lerman, A Lerman.

P a g e | 23 JACC 2010; 56: 1840-1846. Examined endothelial function and vascular responses to acute mental stress in 28 females, 12 with apical ballooning syndrome (ABS), 12 postmenopausal controls (C), and 4 with myocardial infarction (MI). EndoPAT2000 and Plasma catecholamine levels were tested at baseline and following 3 acute mental stress tests. Results: Following mental stress, EndoPAT indexes were significantly lower and catecholamine levels significantly increased in ABS vs. C. PAT scores during mental stress were significantly lower in ABS vs. MI and C. Conclusions: Increased vascular reactivity and decreased endothelial function in response to acute mental stress in ABS may implicate vasomotor dysfunction as a potential mechanism in the pathogenesis of ABS. http://www.ncbi.nlm.nih.gov/pubmed/21087714 7) Global Cardiovascular Reserve Dysfunction in Heart Failure With Preserved Ejection Fraction. BA Borlaug, TP Olson, CSP Lam, KS Flood, A Lerman, BD Johnson, MM Redfield. J Am Coll Cardiol. 2010 Sep 7; 56(11):845-54. Examined cardiovascular function in 21 patients with heart failure and preserved ejection fraction (HFpEF), as compared to 19 patients with hypertension without heart failure, and 10 healthy controls before and during exercise with Doppler echocardiography, Peripheral Arterial Tonometry (EndoPAT), and gas exchange. Results: Exercise capacity and tolerance was reduced in HFpEF compared with hypertensives and controls. Endothelial function was impaired in HFpEF and hypertensives compared with controls. Conclusion: HFpEF is characterized by depressed reserve capacity involving both cardiac and vascular function, which both contributes to produce exercise limitation. http://www.ncbi.nlm.nih.gov/pubmed/20813282

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Women's Health

1)

Alterations in Platelet Function and Cell-Derived Microvesicles in Recently Menopausal Women: Relationship to Metabolic Syndrome and Atherogenic Risk. Jayachandran M, Litwiller RD, Lahr BD, Bailey KR, Owen WG, Mulvagh SL, Heit JA, Hodis HN, Harman SM, Miller VM. J CardiovascTransl Res. 2011 Jul 24. Correlated platelet functions and cellular origin of blood-borne microvesicles, and noninvasive measures of cardiovascular disease [carotid artery intima medial thickness (CIMT), coronary artery calcium (CAC) score, and endothelial reactive hyperemia measured with EndoPAT] in 118 recently menopausal women with components of MS. Results: Platelet number increased with increasing waist circumference, platelet secretion of ATP and expression of P-selectin decreased with increasing blood glucose (p = 0.005) and blood pressure (p < 0.05). Waist circumference and systolic blood pressure were independently associated with monocyte- and endothelium-derived microvesicles (p < 0.05). Platelet-derived and total procoagulant phosphatidylserinepositive microvesicles, and systolic blood pressure correlated with CIMT (p < 0.05), but not with CAC or EndoPAT index. Conclusions: Among recently menopausal women, specific platelet functions and concentrations of circulating activated cell membrane-derived procoagulant microvesicles change with individual components of MS. http://www.ncbi.nlm.nih.gov/pubmed/21786187

2)

Multiwave associations between depressive symptoms and endothelial function in adolescent and young adult females. Tomfohr LM, Murphy ML, Miller GE, Puterman E. Psychosom Med. 2011 Jul; 73(6):456-61. Examined whether symptoms of depression have a lasting negative influence on endothelial function in 135 adolescent and young adult females, without known or suspected major health problems, followed for 2.5 years. Endothelial function was

P a g e | 25 measured thrice throughout the study using EndoPAT, and Beck Depression Inventory was administered. Results: Intra-subject self-reported depressive symptoms covaried with endothelial function ( = -0.23, p< .05). As depression symptoms rose beyond typical levels, endothelial function declined commensurately even after controlling for health practices and adiposity. There was no evidence that depressive symptoms predicted future endothelial function. Conclusions: Depressive symptoms were concurrently associated with endothelial function, but no observation was made of a lasting negative effect. http://www.ncbi.nlm.nih.gov/pubmed/21715299 3) Vascular function in the diagnostic categories of polycystic ovary syndrome. Moran LJ, Cameron JD, Strauss BJ, Teede HJ. Hum Reprod. 2011 May 25. Assessed whether milder phenotypes of PCOS (polycystic ovary syndrome) have elevated CVD risk compared with controls in 54 overweight premenopausal women with either NIH PCOS (n = 29) or milder non-NIH PCOS (n = 25) and 27 controls without PCOS. Primary outcomes were endothelial function [EndoPAT2000, ADMA and plasminogen activator inhibitor-1 (PAI-1)] and arterial stiffness (PWVc). Secondary outcomes were insulin resistance, glucose tolerance and C-reactive protein. Results: PAI-1 (P = 0.20), PAT (P = 0.95) and PWVc (P = 0.67) were similar for the three groups. ADMA was higher in both groups of PCOS vs. controls. Conclusions: Women with NIH and non-NIH PCOS have elevated ADMA compared with controls independent of age and adiposity, suggesting that CVD risk, reflected by endothelial dysfunction, is increased in both traditional NIH and new milder non-NIH PCOS phenotypes. http://www.ncbi.nlm.nih.gov/pubmed/21616917 4) Endothelial function and cardiovascular risk stratification in menopausal women. Mulvagh SL, Behrenbeck T, Lahr BA, Bailey KR, Zais TG, Araoz PA, Miller VM. Climacteric 2009.

P a g e | 26 A report from KEEPS study examining whether EndoPAT is useful in stratifying cardiovascular risk in recently menopausal women asymptomatic for cardiovascular disease. RHI was not associated with standard risk assessment algorithms, CAC or CIMT. The authors stated that RHI may provide an additional independent factor and noninvasive tool to further stratify cardiovascular risk in recently menopausal women. As KEEPS continues, data on RHI will provide information regarding hormonal therapy, endovascular biology and atherosclerotic risk. http://www.ncbi.nlm.nih.gov/pubmed/19657788 5) Evaluation of endothelial function in women with polycystic ovary syndrome. Lowenstein L, Damti A, Pillar G, Shott S, Blumenfeld Z. Eur J ObstetGynecolReprod Biol. 2007 Oct;134(2):208-12. Determined the EndoPAT index in 33 healthy control women vs. 31 women with PCOS, and the effect of metformin in PCOS. RESULTS: Average EndoPAT index in PCOS was 1.480.32 vs. 2.000.51 in controls (P<0.001), with no significant changes in the 18 PCOS patients treated with metformin. CONCLUSIONS: Endothelial dysfunction is more likely among PCOS patients than in healthy controls. Metformin treatment for 3 months in PCOS patients did not improve endothelial function. http://www.ncbi.nlm.nih.gov/pubmed/17374431 6) Pre-eclampsia is associated with sleep-disordered breathing and endothelial dysfunction. Yinon D, Lowenstein L, Suraya S, Beloosesky R, Zmora O, Malhotra A, Pillar G. EurRespir J. 2006 Feb; 27(2):328-33. Assessed endothelial function (EF) using the EndoPAT, and sleep-disordered breathing (SDB) in 17 Pre-eclamptic toxemia (PET) patients, and 25 uncomplicated pregnancy controls. Results: PET patients had a significantly higher respiratory disturbance index (RDI) (18.48.4 vs. 8.31.3) and lower EndoPAT index than controls (1.50.1 vs. 1.80.1). EndoPAT index tended to correlate with RDI.

P a g e | 27 Conclusions: Both SDB and endothelial dysfunction are more likely to occur in females with pre-eclamptic toxemia than in uncomplicated pregnancies. http://www.ncbi.nlm.nih.gov/pubmed/16452588

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Erectile Dysfunction and Men's Health

1) Greater Endothelial Dysfunction and Arterial Stiffness in Men With Chronic Prostatitis/Chronic Pelvic Pain Syndrome-A Possible Link to Cardiovascular Disease. Shoskes DA, Prots D, Karns J, Horhn J, Shoskes AC. J Urol. 2011 Sep; 186(3):907-10. Studied vascular dysfunction in patients with chronic prostatitis/chronic pelvic pain syndrome (N=21) and controls (N=14) using EndoPAT for endothelial function assessment and arterial stiffness. Symptoms were measured with the National Institutes of Health Chronic Prostatitis Symptom Index and patient phenotype was characterized by the UPOINT system. Results: In patients with chronic pelvic pain syndrome, EndoPAT index was significantly lower vs. controls, (1.76 1.2 vs. 2.21 1.7, p = 0.03), and augmentation index was significantly higher (5.0% 2.3 vs. -6.0% 3.0, p = 0.006). Conclusions: Men with chronic prostatitis/chronic pelvic pain syndrome have evidence of increased arterial stiffness and vascular endothelial dysfunction and can be risk stratified using EndoPAT testing. http://www.ncbi.nlm.nih.gov/pubmed/21791354 2) The Application of Digital Pulse Amplitude Tonometry to the Diagnostic Investigation of Endothelial Dysfunction in Men with Erectile Dysfunction. A. Aversa, D. Francomano, R. Bruzziches, M. Pili, M. Natali & G. Spera Andrologia. 2011 Feb; 43(1):9-15. Examined the diagnostic value of RHI and augmentation index (AI) determined using EndoPAT, in 70 men, 40 with Erectile Dysfunction (ED) of any origin, and 30 controls without ED. ED patients underwent diagnostic investigation including dynamic penile duplex ultrasound (PDU) to assess ED etiology. Results: Average RHI was not different between groups. AI was higher in ED vs. controls (P < 0.0001), and likewise when controlled for vascular risk factors (P < 0.0001). AI and duplex measurement were inversely correlated (r2 = -0.72, P < 0.0001). Conclusions: Increased AI may represent an early detection of vascular impairment, preceding endothelial dysfunction in populations at low risk for developing vascular ED.

P a g e | 29 http://www.ncbi.nlm.nih.gov/pubmed/21219376 3) The endothelial-erectile dysfunction connection: an essential update. Costa C, Virag R. J Sex Med. 2009 Sep; 6(9):2390-404. Reviews the most recent knowledge on basic and clinical mechanisms underlying loss of cavernosal endothelial function, and discusses local and systemic methods for endothelial function assessment in ED individuals. RESULTS: Risk factor-associated cavernosal endothelial dysfunction is mostly induced by unifying mechanisms, including oxidative stress and impaired endothelial nitric oxide functional activities, which present clinically as ED. CONCLUSIONS: The established endothelial-erectile dysfunction connection was thoroughly revised, from basic mechanisms to the clinical importance of endothelial dysfunction assessment as diagnosis for generalized vascular disease. Further studies are required to disclose efficient approaches to repair disabled endothelium and both restore and prevent endothelial dysfunction. http://www.ncbi.nlm.nih.gov/pubmed/19523038 4) Assessment of endothelial function in the patient with erectile dysfunction: an opportunity for the urologist. Tamler R, Bar-Chama N. Int J Impot Res. 2008 Jul-Aug; 20(4):370-7. Review exploring how urologists and others may utilize the link between erectile dysfunction and endothelial dysfunction in clinical practice, comparing methods of assessing endothelial dysfunction and , speculating on how this information might impact treatment plans. The authors conclude by supporting the demand for a greater involvement of the urology community in screening for cardiovascular disease; and suggest in-office assessment for endothelial dysfunction in the ED population with possibly more aggressive cardiologic evaluation. Urologists should consider offering their patients treatment of both ED and endothelial dysfunction with daily PDE-5 therapy. http://www.ncbi.nlm.nih.gov/pubmed/18463666

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Diabetes
1) NT-proBNP levels, atherosclerosis and vascular function in asymptomatic type 2 diabetic patients with microalbuminuria: peripheral reactive hyperaemia index but not NT-proBNP is an independent predictor of coronary atherosclerosis. Reinhard H, Wiinberg N, Hansen PR, Kjaer A, Petersen CL, Winther K, Parving HH, Rossing P, Jacobsen PK. CardiovascDiabetol. 2011 Aug 3; 10(1):71. Examined interrelationships amongst P-NT-proBNP, atherosclerosis and/or vascular dysfunction in the coronary, carotid and peripheral arteries using coronary calcium score, carotid intimamedia thickness, ankle-brachial index, and/or toe-brachial index,in 200 asymptomatic type 2 diabetic patients with microalbuminuria receiving intensive multifactorial treatment, using EndoPAT as a marker for endothelial function. RESULTS: P-NT-proBNP was not associated with vascular dysfunction but was associated with atherosclerosis in unadjusted analysis, but not after adjustment for conventional risk factors. In total, 49% of the patients had atherosclerosis in one territory. Low EndoPAT index was an independent predictor of coronary atherosclerosis (odds ratio [CI], 2.60 [1.15-5.88]. CONCLUSIONS: Half of asymptomatic patients with type 2 diabetes and microalbuminuria had significant atherosclerosis in at least one vascular territory despite intensive treatment. Coronary atherosclerosis was most prevalent, whereas carotid disease was more rarely observed. EndoPAT but not plasma NT-proBNP was predictive of coronary atherosclerosis. http://www.ncbi.nlm.nih.gov/pubmed/21812947 2) Fatty acid-binding protein 4 is associated with endothelial dysfunction in patients with type 2 diabetes. G Aragonesa, R Ferrea, I Lazaroa, A Cabrea, N Planaa, J Merinoa, M Herasa, J Gironaa, L Masana. Atherosclerosis. 2010 Nov; 213(1):329-31. Investigated the relationship between circulating FABP4 level, (Adipocyte fatty acid-binding protein), and endothelial function in Type II diabetics (T2D).

P a g e | 31 257 patients (105 T2D and 152 non-diabetics) at increased risk of cardiovascular disease, were tested for circulating FABP4, endothelial function assessed by EndoPAT (RHI), IMT and markers of inflammation and oxidation. RESULTS: FABP4 was negatively associated with RHI (r = -0.226, P = 0.05). In a stepwise multivariate analysis, FABP4 was a predictor of RHI (P = 0.04). CONCLUSION: EndoPAT confirmed a direct effect of plasma FABP4 on endothelial function in T2D. http://www.ncbi.nlm.nih.gov/pubmed/20723896 3) Impaired vascular function in obese adolescents with insulin resistance. Mahmud FH, Hill DJ, Cuerden MS, Clarson CL. J Pediatr. 2009 Nov; 155(5):678-82. Evaluated endothelial function (EF), cardiovascular risk factors and adipocytokines in 77obese adolescents with impaired insulin sensitivity (IR), and 51 matched controls. Results: The obese subjects had IR and significantly greater body mass index (BMI), higher waist circumference (WC), elevated low-density lipoprotein cholesterol (LDL-C), triglyceride and highsensitivity C-reactive protein levels. The mean PAT ratio was significantly lower in obese adolescents vs. controls (1.510.4 vs 2.060.4; P=.002). Linear regression demonstrated associations between PAT ratio and BMI, WC, age, and LDL-C but not between PAT and leptin, resistin, or adiponectin levels or IR. Conclusions: Obese adolescents with IR exhibited significantly worse EF compared with healthy, nonobese controls, and EF showed a significant association with measures of adiposity and other cardiovascular risk factors. http://www.ncbi.nlm.nih.gov/pubmed/19595374 4) Post-challenge hyperglycemia in older adults is associated with increased cardiovascular risk profile. Crandall JP, Shamoon H, Cohen HW, Reid M, Gajavelli S, Trandafirescu G, Tabatabaie V, Barzilai N. J Clin Endocrinol Metab. 2009 May; 94(5):1595-601. Characterized metabolic and CVD risk profile of elderly subjects with Post-challenge hyperglycemia (PCH) and to determine the effect of acute postprandial metabolic changes on vascular biomarkers. This was a cross sectional study, standard meal challenge protocol. 58 Subjects age 65 and older were recruited for the study; elderly with PCH (fasting plasma glucose <126 mg/dl and 2 hr OGTT glucose >170 mg/dl, n=28) and a control group of matching (for age,

P a g e | 32 sex, BMI, and ethnicity) elderly with normal glucose tolerance (FPG <100 mg/dl and 2hr glucose <140 mg/dl, n=30). Results: Fasting glucose (1023 vs. 93 2mg/dl, p<0.001) and HbA1c (5.7% vs. 5.4%, p=0.01) were modestly higher in the PCH group, which was also more insulin resistant; RH-PAT declined postprandially only in PCH (post-meal delta -0.280.01 vs. 0.040.04, p=0.05 in the PCH and NGT groups respectively). Conclusions: The authors concluded that older adults with PCH experience significant fasting and postprandial metabolic dysregulation which is accompanied by a pro-atherosclerotic and pro-thrombotic vascular profile. http://www.ncbi.nlm.nih.gov/pubmed/19208733 5) Peripheral artery tonometry demonstrates altered endothelial function in children with type 1 diabetes. Haller MJ, Stein J, Shuster J, Theriaque D, Silverstein J, Schatz DA, Earing MG, Lerman A, Mahmud FH. Pediatr Diabetes. 2007 Aug; 8(4):193-8. Assessed the EndoPAT index as a marker of endothelial dysfunction in 64 children with type 1 diabetes (T1D), and 20 controls. RESULTS: Children with T1D had greater endothelial dysfunction compared to controls (EndoPAT index 1.63 0.5, vs.1.95 0.3, p = 0.01). Repeat EndoPAT indices were predicted by initial values (p = 0.0025). Mean intrapatient standard deviation of EndoPAT index was 0.261 and mean coefficient of variation was 14.8. Variations in EndoPAT index were not explained by differences in glucose, HbA1c, BMI, systolic BP, diastolic BP, or lipids. CONCLUSIONS: EndoPAT index is a promising non-invasive technique to assess endothelial function in children with T1D. http://www.ncbi.nlm.nih.gov/pubmed/17659060 6) Correlation between radial artery tonometry- and fingertip tonometry-derived augmentation index in children with type 1 diabetes. Haller MJ, Silverstein JH, Shuster JJ. DiabVasc Dis Res. 2007 Mar; 4(1):66. Determined whether there was a correlation between augmentation index (AI) values generated by radial tonometry (SphygmoCor) and those generated by the EndoPAT, in 53 T1d patients.

P a g e | 33 RESULTS: The R value was 0.68 (p<0.00001). AI generated by radial tonometry explains 46% of the variation in peripheral tonometry-generated AI values. Using the least squares equation, Endo-PAT AI = -8.25 + 0.608 (Sphygmocor AI), the standard error of predicting EndoPAT AI by radial tonometry AI was 8.5. CONCLUSIONS: Non-invasive techniques like EndoPAT and radial artery tonometry may provide cardiovascular risk stratification information needed to determine which pediatric T1d patients require early initiation of drug therapy to reduce long-term risk for CVD events. http://www.ncbi.nlm.nih.gov/pubmed/17469047 7) Altered endothelial function in asymptomatic male adolescents with type 1 diabetes. Mahmud FH, Earing MG, Lee RA, Lteif AN, Driscoll DJ, Lerman A. Congenit Heart Dis. 2006 May; 1(3):98-103. Investigated whether a gender contrast in a preclinical stage of atherosclerosis, or endothelial dysfunction (ED), is present in pediatric diabetic patients (N=40, 20 diabetic subjects and 20 age/gender-matched non diabetics, aged 12-16 years). RESULTS: EndoPAT index was lower for male diabetic subjects vs. controls (1.60 0.32 vs. 1.92 0.28, P < .001), but similar in female diabetic patients vs. controls. CONCLUSIONS: Endothelial dysfunction was present in adolescent male diabetics. Since ED is reversible, early detection of this process may have therapeutic and prognostic implications in this young age group. http://www.ncbi.nlm.nih.gov/pubmed/18377552

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Inflammatory diseases/ Sepsis

1) An observational cohort study of the kynurenine to tryptophan ratio in sepsis: association with impaired immune and microvascular function. Darcy CJ, Davis JS, Woodberry T, McNeil YR, Stephens DP, Yeo TW, Anstey NM. PLoS One. 2011; 6(6):e21185. Examined the relation between IDO (indoleamine 2,3-dioxygenase) activity (measured as kynurenine to tryptophan [KT] ratio), in sepsis to plasma interferon-c, interleukin-10, T cell lymphopenia and impairment of microvascular reactivity assessed by EndoPAT, in 80 sepsis patients and 40 controls. Results: Plasma KT ratio was increased in sepsis (median 141 [IQR 64 235]) compared to controls (36 [28 52]); p< 0.0001), and correlated with plasma interferon-c and interleukin-10, and inversely with total lymphocyte count, CD8+ and CD4+ T-lymphocytes, systolic blood pressure and microvascular reactivity. In response to treatment of severe sepsis, the median KT ratio decreased. Conclusions: IDO-mediated tryptophan catabolism is associated with dysregulated immune responses and impaired microvascular reactivity in sepsis and may link these two fundamental processes in sepsis pathophysiology. http://www.ncbi.nlm.nih.gov/pubmed/21731667 2) Interleukin 17 as a novel predictor of vascular function in rheumatoid arthritis. Marder W, Khalatbari S, Myles JD, Hench R, Yalavarthi S, Lustig S, Brook R, Kaplan MJ. Ann Rheum Dis. 2011 Sep; 70(9):1550-5. Analyzed conduit endothelial function using brachial artery FMD (BAUS); arterial compliance by pulse wave velocity (PWV); and endothelium-dependent microvascular function with EndoPAT in 50 patients with RA having minimal traditional CV risk factors and low disease activity score, receiving treatment with biological agents. IL-17 was quantified and disease activity was assessed by 28-joint count Disease Activity Score. Results: IL-17 was the main determinant of lower EndoPAT index, traditional and non-traditional CV risk variables determined PWV with positive association to IL-17, and BAUS was mainly determined by rheumatoid factor titers.

P a g e | 35 Conclusions: In patients with RA treated with biological agents, IL- 17 is a main predictor of microvascular function and arterial compliance and may play a significant role in development of endothelial dysfunction and cardiovascular disease. http://www.ncbi.nlm.nih.gov/pubmed/21727237 3) Remission is the goal for cardiovascular risk management in patients with rheumatoid arthritis: a cross-sectional comparative study. Provan SA, Semb AG, Hisdal J, Stranden E, Agewall S, Dagfinrud H, Angel K, Atar D, Kvien TK. Ann Rheum Dis. 2011 May; 70(5):812-7. Compared cardiovascular disease (CVD) risk markers amongst patients with rheumatoid arthritis (RA), either active or in remission (N=113), and controls (N=86). A panel of biomarkers, EndoPAT index, pressure measurements, arterial stiffness and intima-media thickness were compared. Results: Active RA had significantly higher levels of NT-proBNP, brachial systolic pressure, augmentation index and central systolic pressure but lower cholesterol than the other 2 groups. Active RA patients also had significantly higher pulse wave velocity and worse EndoPAT index than RA patients in remission. Conclusions: Only Patients with active RA, had significantly increased levels of CVD risk markers, thus linking inflammatory activity to markers of CVD risk in patients with RA and indirectly supporting the notion that remission in RA confers diminished cardiovascular morbidity. http://www.ncbi.nlm.nih.gov/pubmed/21288959 4) Normal Endothelial Function in Patients with Mild-to-Moderate Psoriasis: A Case-control Study. Jensen P, Zachariae C, Hansen P, Skov L. Acta Derm Venereol 2011 May 6. Measured endothelial function (EndoPAT2000), and other cardiovascular risk factors in patients with mild-to-moderate psoriasis (n = 30) and controls (n = 30). Results: No difference in endothelial function between groups, but the patient group exhibited higher levels of certain cardiovascular risk factors compared to controls Conclusions: Even mild-to-moderate psoriasis may be regarded as a systemic inflammatory disease, with an increased cardiovascular risk in the long-term. http://www.ncbi.nlm.nih.gov/pubmed/21547343 5) Modified-release sildenafil reduces Raynaud's phenomenon attack frequency in limited cutaneous systemic sclerosis.

P a g e | 36 Herrick AL, van den Hoogen F, Gabrielli A, Tamimi N, Reid C, O'Connell D, Vazquez-Abad MD, Denton CP. Arthritis Rheum. 2011 Mar; 63(3):775-82. Examined the effect of sildenafil in 57 patients with Raynaud's phenomenon (RP) secondary to limited cutaneous systemic sclerosis (lcSSc), randomized to modified-release sildenafil 100 mg once daily for 3 days followed by modified-release sildenafil 200 mg once daily for 25 days or placebo. Primary end point was percentage change in weekly RP attacks; secondary end points included Raynaud's Condition Score, duration of attacks, RP pain score, endothelial dysfunction (EndoPAT2000), and serum biomarkers. Results: Mean percentage reduction in attacks per week was greater for modified-release sildenafil than for placebo (-44.0% vs. -18.1%, P = 0.034); while secondary end points were similar between groups. Conclusions: Modified-release sildenafil reduced attack frequency in patients with RP secondary to lcSSc and may thus be a treatment option. http://www.ncbi.nlm.nih.gov/pubmed/21360507 6) Angiopoietin-2 is increased in sepsis and inversely associated with nitric oxidedependent microvascular reactivity. Davis JS, Yeo TW, Piera KA, Woodberry T, Celermajer DS, Stephens DP, Anstey NM. Crit Care. 2010; 14(3):R89. Tested endothelial NO bioavailability, vascular endothelial growth factor (VEGF), endothelialactive cytokines and EndoPAT index correlations with ang-2 concentrations in sepsis, (n = 83 early sepsis vs. 41 hospital controls). Results: Plasma Ang-2 increased with sepsis severity (P < 0.0001), and correlated inversely with EndoPAT index (r = -0.38, P < 0.0001), positively with IL-6 (r = 0.57, P < 0.0001) and degree of organ failure (r = 0.58, P < 0.0001). Longitudinal recovery of EndoPAT index was associated with decline in ang-2. Conclusions: Ang-2 is proportional to sepsis severity, and inversely correlated to EndoPAT index. Impaired NO bioavailability may contribute to increased release of ang-2, endothelial activation and capillary leakage. Agents increasing NO bioavailability may have therapeutic potential in sepsis. http://www.ncbi.nlm.nih.gov/pubmed/20482750 7) Asymmetric dimethylarginine, endothelial nitric oxide bioavailability and mortality in sepsis.

P a g e | 37 Davis JS, Darcy CJ, Yeo TW, Jones C, McNeil YR, Stephens DP, Celermajer DS, Anstey NM. PLoS One. 2011 Feb 18; 6(2):e17260. Assessed Plasma concentrations of asymmetric dimethylarginine (ADMA), L-arginine concentrations and Endothelial function (EndoPAT2000) (98 patients, 67 with acute sepsis, and 31 controls). Results: Baseline plasma L-arginine: ADMA ratio was significantly lower in sepsis (median [IQR] 63 [45-103]) than controls (143 [123- 166], p<0.0001) and correlated with EndoPAT index (r = 0.34, p = 0.02). Increase in ADMA correlated with increase in organ failure and decrease in EndoPAT index. Conclusions: Impaired endothelial and microvascular function due to decreased endothelial NO bioavailability is a potential mechanism linking increased plasma ADMA to organ failure and death in sepsis. http://www.ncbi.nlm.nih.gov/pubmed/21364995 8) Increased arterial stiffness in patients with psoriasis is associated with active systemic inflammation. Yiu KH, Yeung CK, Chan HT, Wong RM, Tam S, Lam KF, Yan GH, Yue WS, Chan HH, Tse HF. Br J Dermatol. 2011 Mar; 164(3):514-20. Investigated the relationship between disease activity, systemic inflammation, macrovascular and microvascular function in 52 patients with psoriasis, vs. 50 matched controls. Baseline demographics, hs- CRP, Psoriasis Area and Severity Index (PASI), arterial stiffness and endothelial function were assessed using brachial - ankle pulse wave velocity (baPWV) and EndoPAT index. Results: Patients with psoriasis had significantly higher hs-CRP (P<0.01) and baPWV, (P< 0.01) but did not differ in their EndoPAT index vs. controls. There was significant correlation of hs-CRP with baPWV (r=0.51, P< 0.01) and with PASI (r=0.48, P< 0.01). Conclusions: Young patients with psoriasis have increased arterial stiffness but not microvascular dysfunction compared with healthy controls. http://www.ncbi.nlm.nih.gov/pubmed/21039409 9) Peripheral augmentation index and vascular inflammation in autosomal dominant polycystic kidney disease. Heffernan KS, Kuvin JT, Sarnak MJ, Perrone RD, Miskulin DC, Rudym D, Chandra P, Karas RH, Menon V.

P a g e | 38 Nephrol Dial Transplant. 2011 Feb 3. Assessed peripheral augmentation index (AIx) as a measure of systemic vascular function, using EndoPAT2000, as well as circulating markers of vascular inflammation in autosomal dominant polycystic kidney disease (ADPKD) at various stages (n=144), and 51 healthy controls. Results: AIx was higher in all three ADPKD groups compared to healthy controls (P < 0.05). AIx was similar in normotensive ADPKD with eGFR 60 mL/min/1.73 m2 and hypertensive ADPKD patients with eGFR <60 mL/min/1.73 m2 (P > 0.05), also adhesion molecules as vascular inflammatory markers followed a similar pattern but were not predictors of AIx in ADPKD. Conclusions: Systemic vascular dysfunction, manifesting as increased AIx and vascular inflammation is evident in young normotensive ADPKD patients with preserved renal function. Vascular inflammation is not associated with elevated AIx in ADPKD. http://www.ncbi.nlm.nih.gov/pubmed/21292815 10) Relationship of cell-free hemoglobin to impaired endothelial nitric oxide bioavailability and perfusion in severe falciparum malaria. Yeo TW, Lampah DA, Tjitra E, Gitawati R, Kenangalem E, Piera K, Granger DL, Lopansri BK, Weinberg JB, Price RN, Duffull SB, Celermajer DS, Anstey NM. J Infect Dis. 2009 Nov 15; 200(10):1522-9. Examines the relationship of plasma hemoglobin and myoglobin (due to hemolysis) to endothelial dysfunction and disease severity in adult malaria patients and healthy controls from Papua. Cell-free hemoglobin and reactive RH-PAT, were quantified in moderately severe (78), severe malaria (49) and control subjects (16). Results: Multivariable regression analysis revealed that cell-free hemoglobin remained inversely associated with RH-PAT, and in severe patients, there was a significant longitudinal association between RH-PAT improvement and decreasing levels of cell-free hemoglobin. Conclusion: Hemolysis in falciparum malaria Results in NO quenching by cell-free hemoglobin, and may exacerbate endothelial dysfunction, adhesion receptor expression and impaired tissue perfusion. http://www.ncbi.nlm.nih.gov/pubmed/19803726 11) Sepsis-associated microvascular dysfunction measured by peripheral arterial tonometry: an observational study. Davis JS, Yeo TW, Thomas JH, McMillan M, Darcy CJ, McNeil YR, Cheng AC, Celermajer DS, Stephens DP, Anstey NM. Crit Care 2009 25; 13(5):R155.

P a g e | 39 Endothelial function using EndoPAT, the correlation to sepsis severity, endothelial activity and plasma arginine levels, were assessed in 85 sepsis patients and 45 controls, at baseline and after 2-4 days. Results: Baseline RH-PAT Index (mean [95%CI]) in severe sepsis were (1.57 [1.43-1.70]), in sepsis without organ failure (1.85 [1.67-2.03]), and in controls (2.05 [1.91- 2.19]); p<0.00001. Independent predictors of baseline RH-PAT Index in sepsis were APACH II score and mean arterial pressure, but not plasma L-arginine or markers of endothelial activation. Low baseline RH-PAT Index was significantly correlated with an increase in SOFA score over the first 2-4 days (r=0.37, p<0.02) Conclusion: EndoPAT may have a role for monitoring responses to novel adjunctive therapies targeting the endothelium in sepsis. http://www.ncbi.nlm.nih.gov/pubmed/19778457 12) Peripheral arterial stiffness and endothelial dysfunction in idiopathic and scleroderma associated pulmonary arterial hypertension. Peled N, Shitrit D, Fox BD, Shlomi D, Amital A, Bendayan D, Kramer MR. J Rheumatol. 2009 May; 36(5):970-5. Assessed systemic arterial stiffness and endothelial involvement in 59 subjects; 10 scleroderma & pulmonary arterial hypertension (PAH) patients, 28 idiopathic PAH, and 21 controls (8 scleroderma only and 13 healthy controls). RESULTS: AI was 9.0% 21.5%, in healthy controls, 10.5% 19.6% in scleroderma patients, 20.1% 19.1% in idiopathic-PAH, and 24.4% 18.9% in scleroderma & PAH, (non-significant). EndoPAT index was 1.66 0.66 in idiopathic-PAH & scleroderma, 1.84 0.51 in idiopathic PAH, and 2.20 0.25 in controls; . (p<.05) AI was not correlated to endothelial dysfunction. There were no differences between the 2 PAH t groups clinical parameters. Conclusions: The study shows a trend towards increased arterial stiffness in scleroderma (nonsignificant), and also peripheral endothelial dysfunction in idiopathic-PAH and in scleroderma & PAH. http://www.ncbi.nlm.nih.gov/pubmed/19369472 13) Peripheral endothelial dysfunction in patients with pulmonary arterial hypertension. Peled N, Bendayan D, Shitrit D, Fox B, Yehoshua L, Kramer MR. Respir Med. 2008 Dec; 102(12):1791-6.

P a g e | 40 Examines the association between systemic endothelial dysfunction and Pulmonary Arterial Hypertension (PAH) disease severity. In 54 patients with PAH of varied etiologies (idiopathic, scleroderma, thromboembolic and Eisenmenger) along with 21 controls the EndoPAT response was significantly lower in all PAH groups (p<0.05) except the Eisenmenger group. Interestingly, the EndoPAT response was significantly correlated with multiple indices of disease severity. The authors conclude that a systemic component of endothelial dysfunction might be involved in a dose related manner in idiopathic, scleroderma-associated and chronic thromboembolic PAH. http://www.ncbi.nlm.nih.gov/pubmed/18678478

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Sleep Apnea
1) Endothelial dysfunction in obstructive sleep apnea measured by peripheral arterial tone response in the finger to reactive hyperemia. Itzhaki S, Lavie L, Pillar G, Tal G, Lavie P. Sleep. 2005 May; 28(5):594-600. Assessed endothelial function before sleep (evening), and after waking (morning), in 46 sleep apnea patients, and 17 control subjects without sleep apnea. RESULTS: Morning EndoPAT index was significantly lower in patients with moderate to severe sleep apnea (apnea-hypopnea index - AHI) 30) than in patients with mild sleep apnea (AHI = 10 -29), and controls, and was significantly inversely correlated with AHI. Patients with a history of hypertension or cardiovascular disease had significantly lower morning and evening EndoPAT indices, and AHI and sleep efficiency were significant predictors of morning EndoPAT index. CONCLUSION: The EndoPAT can be used as a substitute for brachial artery ultrasound measurement of endothelial function in patients with sleep apnea. http://www.ncbi.nlm.nih.gov/pubmed/16171272 2) The effects of 1-year treatment with a herbst mandibular advancement splint on obstructive sleep apnea, oxidative stress, and endothelial function. Itzhaki S, Dorchin H, Clark G, Lavie L, Lavie P, Pillar G. Chest. 2007 Mar; 131(3):740-9. Assessed the effect of long-term modified Herbst mandibular advancement splint (MAS) treatment on OSA, oxidative stress markers, and on endothelial function (EF)(N=32; 16 OSA with treatment, 6 OSA without treatment and 10 controls). RESULTS: The mean AHI decreased significantly after 3 months of treatment and also after 1 year (p < 0.005 for both), as did the mean Epworth sleepiness scale score (p < 0.001 for both time epochs). Mean EF improved significantly after 3 months of treatment (p < 0.05) and after 1 year (p = 0.055), to valuessimilar to the reference group.

P a g e | 42 CONCLUSIONS: The Herbst MAS may be a moderately effective long-term treatment for patients with OSA. EF improved to levels that were not significantly different than reference levels, even though apneic events were not completely eliminated. http://www.ncbi.nlm.nih.gov/pubmed/17356088

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Intervention studies:
1) A spontaneous, double-blind, double dummy cross-over study on the Effects of daily vardenafil on arterial stiffness in patients with vasculogenic Erectile dysfunction. Aversa A, Letizia C, Francomano D, Bruzziches R, Natali M, Lenzi A. Int J Cardiol. 2011 May 3. Measured the effects of vardenafil on endothelial function and arterial stiffness in men with erectile dysfunction (ED, N=20) enrolled in a 4-week, randomized, double-blind, double-dummy, crossover study of either daily vardenafil 10mg or 20mg on-demand with a two week washout interval. EndoPAT index, AI, endothelial blood markers and ED questionnaire were assessed. Results: Patients who took daily vardenafil (vs. on-demand) had significant improvements in arterial stiffness as evaluated by the EndoPAT AI (P<0.01), and reduction of plasma ADM levels (p<0.05). Each treatment resulted in significantly greater IIEF5 scores (p<0.001). Conclusions: Daily vardenafil improves arterial stiffness and erectile function measurements in men with severe vasculogenic ED. http://www.ncbi.nlm.nih.gov/pubmed/21546099

2) Effect of Atenolol vs Metoprolol Succinate on Vascular Function in Patients With Hypertension.

Heffernan KS, Suryadevara R, Patvardhan EA, Mooney P, Karas RH, Kuvin JT. Clin Cardiol. 2011 Jan; 34(1):39-44. Compared once daily atenolol vs. metoprolol succinate for 4 weeks on peripheral augmentation index (AIx), EndoPAT index, and brachial artery flow-mediated dilation in 24 patients with essential hypertensionin a randomized, double-blind, and crossover study. Results: Similar reductions in mean arterial pressure and no changes in brachial artery flowmediated dilation or EndoPAT index following either drug, but there was a significant increase in peripheral Aix following atenolol therapy vs. metoprolol (P < 0.05). Conclusions: Compared with metoprolol, atenolol increases peripheral AIx. Neither drug has an effect on vascular endothelial function and both reduce BP. These findings may have clinical implications. http://www.ncbi.nlm.nih.gov/pubmed/21259277

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3) Impairment of endothelial progenitor cell function and vascularization capacity by aldosterone in mice and humans.
Thum T, Schmitter K, Fleissner F, Wiebking V, Dietrich B, Widder JD, Jazbutyte V, Hahner S, Ertl G, Bauersachs J. Eur Heart J. 2011 May; 32(10):1275-86. Assessed the impact of hyperaldosteronism on EPC (endothelial progenitor cells) function and vascularization capacity in mice and humans. Results: Treatment of human EPC with aldosterone induced impaired multiple cellular functions of EPCs. Aldosterone infusion in mice impaired EPC function, EPC homing to vascular structures and vascularization capacity. Endothelial progenitor cells from patients with primary hyperaldosteronism compared with controls of similar age displayed reduced migratory potential. Impaired EPC function was associated with endothelial dysfunction assessed by the EndoPAT2000. MR (mineralocorticoid receptor) blockade in patients with hyperaldosteronism improved EPC function and arterial stiffness assessed by EndoPAT2000. Conclusions: Normalization of EPC function may represent a novel mechanism contributing to the beneficial effects of MR blockade in cardiovascular disease prevention and treatment. http://www.ncbi.nlm.nih.gov/pubmed/20926363

4) Effects of immunoadsorption on endothelial function, circulating endothelial progenitor cells and circulating microparticles in patients With inflammatory dilated cardiomyopathy.
Bulut D, Scheeler M, Niedballa LM, Miebach T, Mgge A. Clin Res Cardiol. 2011 Feb 6. Examined the effects of Immunoadsorption (IA), on endothelial function, circulating endothelial progenitor cells and circulating microparticles (MPs), including endothelial-derived microparticles, in 13 patients with chronic inflammatory dilative cardiomyopathy (iDCM). Blood samples, endothelial function, and arterial stiffness were assessed by EndoPAT2000 before and 6 months after a 5 day course of IA. Results: After 6 months left ventricular systolic function (EF%) improved and LV end-diastolic diameter was reduced. Endothelial function improved from 1.53 0.09 to 1.80 0.12 (p < 0.05), arterial stiffness index and level of circulating EPC remained unchanged and number of MPs decreased by 36.8% (p < 0.05). Conclusions: IA treatment improves endothelial function in chronic iDCM, and is associated with a significant drop in MPs.

P a g e | 45 http://www.ncbi.nlm.nih.gov/pubmed/21298435

5) Relationship between peripheral arterial reactive hyperemia and residual platelet reactivity after 600 mg clopidogrel.
Hamilos M, Muller O, Ntalianis A, Trana C, Bartunek J, Sarno G, Mangiacapra F, Dierickx K, Meeus P, Cuisset T, De Bruyne B, Wijns W, Barbato E. J Thromb Thrombolysis. 2011 Feb 3. Examined whether clopidogrel improvement of peripheral vascular endothelial function (EF) (EndoPAT index), is associated with inhibition of platelet aggregation in 43 stable angina pts. EF and circulating endothelial microparticles (EMPs) were evaluated before and 12 h after 600 mg clopidogrel. Response to clopidogrel expressed as platelet reaction unit (PRU) and percent platelet inhibition (%PI) with high reactivity defined as PRU 240. Results: EF improved after clopidogrel in 20 pts. and was significantly correlated with both PRU (r = -0.61, P < 0.001) and %PI (r = 0.57, P < 0.001). EndoPAT index and EMPs significantly increased after clopidogrel in patients with PRU < 240, but not with PRU 240. Conclusions: Patients with stable CAD improve endothelial function after a single 600 mg clopidogrel loading dose. Improvement was associated with optimal platelet inhibition after clopidogrel. http://www.ncbi.nlm.nih.gov/pubmed/21290254

6) Organic nitrates differentially modulate circulating endothelial progenitor cells and endothelial function in patients with symptomatic coronary artery disease.
Thum T, Wiebking V, Ertl G, Bauersachs J. Antioxid Redox Signal. 2010 Sep 2. Investigated effects of NO donors isosorbide dinitrate (ISDN) and pentaerythritol tetranitrate (PETN) on endothelial progenitor cells (EPC) and EndoPAT response in 36 angiographically proven CAD patients, randomized to treatment for 14 days. Results: PETN treatment - substantially increase in circulating EPC, and 2-fold (P=0.04) increased formation of endothelial colonies, ISDN - no effect detected. Endothelial function - unchanged during PETN treatment, but significantly impaired in ISDN. Conclusion: PETN significantly improved levels of circulating EPC and markers for EPC function, whereas ISDN was without effects on EPCs and worsened endothelial function. http://www.ncbi.nlm.nih.gov/pubmed/20812862

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7) Improvement of Postprandial Endothelial Function after a Single Dose of Exenatide in Individuals with Impaired Glucose Tolerance and Recent Onset Type 2 Diabetes Mellitus.
Koska J, Schwartz EA, Mullin MP, Schwenke DC, Reaven PD. Diabetes Care. 2010 Mar 3. Examined the effects of a single dose of Exenatide or placebo given just prior to a high-fat meal, on postprandial endothelial function (EF) using EndoPAT, in 28 individuals with impaired glucose tolerance or recent onset type 2 diabetes in a double-blinded, randomized cross-over study. Results: Postprandial EF was higher after Exenatide versus placebo (p=0.0002). In the placebo phase, postprandial change in EF was inversely associated with mean postprandial concentrations of triglycerides (r=-0.62, p=0.0004). Changes in postprandial triglyceride concentrations explained 64% of exenatide's effect on postprandial EF. Conclusion: Exenatide ameliorates postprandial endothelial dysfunction after a high-fat meal. http://www.ncbi.nlm.nih.gov/pubmed/20200309

8) Effects of pentaerythritol tetranitrate on endothelial function in coronary artery disease: results of the PENTA study.
Schnorbus B, Schiewe R, Ostad MA, Medler C, Wachtlin D, Wenzel P, Daiber A, Mnzel T, Warnholtz A. Clin Res Cardiol. 2010 Feb; 99(2):115-24. Tested whether treatment with PETN (Pentaerythritol tetranitrate) improves endothelial function in 80 CAD patients randomized to treatment or placebo for 8 weeks. Numerous vascular parameters were assessed including change in brachial artery flow-mediated dilation (FMD) from baseline to follow-up. Results: Changes from baseline to follow up in brachial FMD, EndoPAT index and ALDH-2 activity were no different between the two groups. Relative changes in mean flow volume (P = 0.04) and mean flow velocity (P =0.01) upon ischemia increased in the PETN group versus C. Conclusion: Chronic PETN therapy in patients with CAD may be established for symptomatic treatment without adverse effects on endothelial function and with beneficial effects on the microcirculation. http://www.ncbi.nlm.nih.gov/pubmed/19957087

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9) Relation of Endothelial Function to Residual Platelet Reactivity After Clopidogrel in Patients With Stable Angina Pectoris Undergoing Percutaneous Coronary Intervention.
Muller O, Hamilos M, Bartunek J, Ulrichts H, Mangiacapra F, Holz JB, Ntalianis A, Trana C, Dierickx K, Vercruysse K, De Bruyne B, Wijns W, Barbato E. Am J Cardiol. 2010 Feb 1; 105(3):333-8. Examines if impaired endothelial function, assessed by EndoPAT, correlates with platelet reactivity after clopidogrel, predisposing to unfavorable outcomes after elective percutaneous coronary intervention (PCI). Baseline EndoPAT score, and platelet reactivity were assessed in 52 consecutive stable angina patients, followed by 600-mg clopidogrel >/= 12 hours before PCI. Results: EndoPAT score was inversely correlated with platelet reactivity suggesting greater platelet reactivity with worse endothelial function. Conclusion: Impaired endothelial response before clopidogrel was associated with greater platelet reactivity after clopidogrel, possibly explaining unfavorable PCI outcomes. http://www.ncbi.nlm.nih.gov/pubmed/20102944

10) Effects of ezetimibe add-on therapy for high-risk patients with dyslipidemia.
Yamaoka-Tojo M, Tojo T, Kosugi R, Hatakeyama Y, Yoshida Y, Machida Y, Aoyama N, Masuda T, Izumi T. Lipids Health Dis. 2009 12; 8(1):41. The effect of ezetimibe as an add-on therapy to statin on hypercholesterolemia, biomarkers and endothelial function measured by EndoPAT, was tested in 14 high risk patients with coronary artery disease or other vascular disease treated with statin monotherapy. Results: After 22 weeks of therapy, RHI was improved in patients with hypercholesterolemia (from 1.31 to 1.53; p=0.020). Conclusion: Ezetimibe improves lipid profiles, reduces oxidative stress, and improves endothelial function in high-risk patients with dyslipidemia, which may contribute to atherosclerosis prevention. http://www.ncbi.nlm.nih.gov/pubmed/19821987

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11) Pediatric Atorvastatin in Diabetes Trial (PADIT): a pilot study to determine the effect of atorvastatin on arterial stiffness and endothelial function in children with type 1 diabetes mellitus.
Haller MJ, Stein JM, Shuster JJ, Theriaque D, Samyn MM, Pepine C, Silverstein JH. J Pediatr Endocrinol Metab 2009; 22(1):65-8. This pilot study determined whether 12 weeks of daily atorvastatin (20 mg daily) reduced arterial stiffness and improved endothelial function, in 51 children with type1 diabetes mellitus. No significant differences in either AI75 or EndoPAT score were observed when comparing the groups randomized to atorvastatin then placebo versus placebo then atorvastatin (primary analysis); Secondary analysis demonstrated a potential reduction of arterial stiffness following atorvastatin therapy (p = 0.06). The authors concluded that larger, long-term prospective studies are needed. http://www.ncbi.nlm.nih.gov/pubmed/19344076

12) Ranolazine improves endothelial function in patients with stable coronary artery disease.
Deshmukh SH, Patel SR, Pinassi E, Mindrescu C, Hermance EV, Infantino MN, Coppola JT, Staniloae CS. Coron Artery Dis. 2009 Aug; 20 (5):343-7. Investigated the effect of ranolazine, a novel anti-anginal medication, on endothelial function and on levels of asymmetric dimethylarginine (ADMA), an endogenous NO synthase inhibitor, and C-reactive protein levels. Stable coronary artery disease patients (n=27) were randomly assigned to ranolazine or placebo for 6 weeks then crossed over for 6 weeks in a double-blind manner. Results: EndoPAT response was significantly and rapidly increased after ranolazine (1.850.42 vs. 2.080.57, P = 0.037) but unchanged on placebo (P = 0.29). In parallel ADMA fell significantly with ranolazine vs. placebo (P = 0.02) with a near significant decrease in C-reactive protein levels (P = 0.05). Conclusions: Ranolazine improves endothelial function, asymmetric dimethylarginine, and Creactive protein levels in a group of patients with stable CAD. http://www.ncbi.nlm.nih.gov/pubmed/19444092

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13) Chronic administration of Sildenafil improves markers of endothelial function in men with Type 2 diabetes.
Aversa A, Vitale C, Volterrani M, Fabbri A, Spera G, Fini M, Rosano GM. Diabet Med. 2008 Jan; 25(1):37-44. Determined the effects of chronic therapy with sildenafil on endothelial function in 20 patients with Type 2 diabetes mellitus (DM2) and no erectile dysfunction. Patients randomly received a loading dose of sildenafil (100 mg) for 3 days, followed by either sildenafil 25 mg three times a day for 4 weeks or sildenafil 25 mg for 4 days followed by placebo for 3 weeks. Results: After 1 week, EndoPAT index improved significantly compared with baseline in patients allocated to both sildenafil arms. In patients allocated to chronic sildenafil, a progressive increase in percentage of patients with EndoPAT index improvement was noted while a progressive decrease in the placebo group occurred. At the end of the study, a significant improvement in EndoPAT index compared with baseline was noted after chronic sildenafil. A decrease in endothelin-1 levels and an increase in nitrite/nitrate levels were found after chronic sildenafil; significant changes from baseline in inflammatory biomarkers were also found. Results were the same with BAUS procedure. Conclusions: In DM2 patients, daily sildenafil administration improves endothelial function and reduces markers of vascular inflammation. http://www.ncbi.nlm.nih.gov/pubmed/18199130

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Nutrition Tx or challenge, Therapeutic medical devices, exercise and life style

1) Vitamin D status is associated with arterial stiffness and vascular dysfunction in healthy humans. Al Mheid I, Patel R, Murrow J, Morris A, Rahman A, Fike L, Kavtaradze N, Uphoff I, Hooper C, Tangpricha V, Alexander RW, Brigham K, Quyyumi AA. J Am Coll Cardiol. 2011 Jul 5; 58(2):186-92. Explored the relationship between 25-hydroxyvitamin D (25-OH D), an established marker of vitamin D status, in 554 healthy adults, and endothelial function assessed by both brachial artery flow mediated dilation and by EndoPAT, Carotid-femoral pulse wave velocity, radial tonometry-derived central augmentation index and subendocardial viability ratio. Results: After adjustment for traditional risk markers, 25-OH D remained independently associated with EndoPAT index ( = 0.23, p< 0.001), brachial flow-mediated vasodilation ( = 0.1, p= 0.03), pulse wave velocity, augmentation index, and subendocardial viability ratio. In 42 subjects with vitamin D insufficiency, normalization of 25-OH D at 6 months was associated with increases in EndoPAT index (0.38 +/-0.14, p= 0.009) and subendocardial viability ratio, and a decrease in mean arterial pressure but not with the other measurements. Conclusions: Vitamin D insufficiency is associated with increased arterial stiffness and endothelial dysfunction irrespective of traditional risk burden. http://www.ncbi.nlm.nih.gov/pubmed/217189158 2) CLA Does Not Impair Endothelial Function and Decreases Body Weight as Compared with Safflower Oil in Overweight and Obese Male Subjects. Pfeuffer M, Fielitz K, Laue C, Winkler P, Rubin D, Helwig U, Giller K, Kammann J, Schwedhelm E, Bger RH, Bub A, Bell D, Schrezenmeir J.

P a g e | 51 J Am Coll Nutr. 2011 Feb; 30(1):19-28. Compared the effect of CLA (Conjugated linoleic acid) with safflower oil on endothelial function (EndoPAT index), and markers of cardiovascular risk in overweight and obese men (N=85). Heated safflower oil and olive oil were given for additional descriptive control. Patients were randomized to receive 4.5 g/d of the CLA isomeric mixture, safflower oil, heated safflower oil, or olive oil in a 4-week double-blind study. Endothelial function was assessed in the fasting and postprandial state. Results: CLA did not impair fasting or postprandial PAT index but decreased body weight compared to safflower oil. There were no changes in lipid profile or other inflammatory blood markers. Conclusions: CLA did not impair endothelial function. Other parameters associated with metabolic syndrome and oxidative stress were not changed or were slightly improved. Results suggest that CLA does not increase cardiovascular risk. http://www.ncbi.nlm.nih.gov/pubmed/21697535 3) Postprandial vascular reactivity in obese and normal weight young adults. Ayer JG, Harmer JA, Steinbeck K, Celermajer DS. Obesity (Silver Spring). 2010 May; 18(5):945-51. Compared vascular reactivity after a high-fat meal in 11 obese (median BMI 46.4, age 32.1 6.3 years, 7 men) and 11 normal weight (median BMI 22.6) age- and sex-matched controls. Physiological parameters and blood chemistry were measured at baseline and 1 and 3 h postmeal. Results: At baseline, obese subjects had higher systolic BP, HR, resting FBF, insulin and equivalent FMD, EndoPAT index, hyperemic FBF, AIx75, PWV(b), glucose, total cholesterol, triglycerides, and lower HDL cholesterol. FMD at baseline and 3 h was not significantly different between groups, nor did the meal produce significant changes in EndoPAT index, hyperemic FBF, and PWV(b) in either group. Conclusions: Vascular responses to a high-fat meal are similar in obese and normal weight young adults, and thus unlikely to contribute importantly to the increased cardiovascular risk of obesity. www.ncbi.nlm.nih.gov/pubmed/19834470

P a g e | 52 4) Dietary, lifestyle and pharmacogenetic factors associated with arteriole endothelial-dependent vasodilatation in schizophrenia patients treated with atypical antipsychotics (AAPs). Ellingrod VL, Taylor SF, Brook RD, Evans SJ, Zllner SK, Grove TB, Gardner KM, Bly MJ, Pop-Busui R, Dalack G. Schizophr Res. 2011 Apr 18. Examined endothelial function (EndoPAT Index) in schizophrenic patients (n=83), and determined association with pharmacogenetic, medication, dietary, and lifestyle factors. Subjects were screened for metabolic syndrome, physical activity, smoking, variants related to folate pharmacogenetics, and the influence of N-3 FA dietary intake. Results: EndoPAT Index was positively related to N-3 FA intake (F=17.7(1,16), p=0.0007) in subjects not receiving atypical antipsychotics (AAPs), but not in those treated with AAPs (F=0.25(1,43), p>0.6). Regression analysis confirmed the interaction effect of AAP treatment on the relationship between EndoPAT Index and N-3 FAs (p=0.0105). Endothelial dysfunction was also related to folate pharmacogenetic variants. Conclusions: AAPs may counteract some vascular health benefits of a diet high in N-3 FAs. Pharmacogenetic variants related to folate and homocysteine metabolism may also increase endothelial dysfunction risk. http://www.ncbi.nlm.nih.gov/pubmed/21504842 5) Effects of cranberry juice consumption on vascular function in patients with coronary artery disease. Mustali M Dohadwala, Monika Holbrook, Naomi M Hamburg, Sherene M Shenouda, William B Chung, Megan Titas, Matthew A Kluge, Na Wang, Joseph Palmisano, Paul E Milbury, Jeffrey B Blumberg, and Joseph A Vita. Am J Clin Nutr. 2011 May; 93(5):934-40. Examined the effects of cranberry juice on vascular function in patients with coronary artery disease in an acute pilot study with no placebo (n=15), and in a chronic placebocontrolled crossover study (n=44), before and after active and control beverages, and at 12h after the last beverage. Results: Mean carotid-femoral pulse wave velocity decreased after active juice vs. placebo (P = 0.003), but not Brachial FMD, EndoPAT index, blood pressure, or carotidradial pulse wave velocity. In the pilot study, brachial FMD improved (P=0.01), as did EndoPAT index (P=0.001), 4 h after active juice.

P a g e | 53 Conclusions: Chronic cranberry juice reduced carotid femoral pulse wave velocity. The uncontrolled pilot study suggested an acute but not chronic benefit on endothelial function. http://www.ncbi.nlm.nih.gov/pubmed/21411615 6) Effect of periodontal treatment on circulating CD34(+) cells and peripheral vascular endothelial function: a randomized controlled trial. Li X, Tse HF, Yiu KH, Li LS, Jin L. J Clin Periodontol. 2011 Feb; 38(2):148-56. Investigated the effect of periodontal treatment on circulating progenitor cell (CPC) count and vascular endothelial function in moderate-to-severe chronic Periodontitis in 25 patients assigned to 3 month of treatment, and 25 untreated controls. CPCs and endothelial function using EndoPAT2000 were evaluated at baseline and 3-month follow-up. Results: Periodontal treatment exhibited neutral effects on endothelial function while Circulating CD34(+) cells count significantly decreased in the Treatment group, p=0.011). Conclusions: Treatment of Periodontitis has neutral effects on peripheral endothelial function but significantly decreases circulating CD34(+) cell count. http://www.ncbi.nlm.nih.gov/pubmed/21133981 7) An Air Filter Intervention Study of Endothelial Function Among Healthy Adults in a Woodsmoke-Impacted Community. Allen RW, Carlsten C, Karlen B, Leckie S, van Eeden S, Vedal S, Wong I, Brauer M. Am J Respir Crit Care Med. 2011 Jan 21. Assessed the impact of air filtration on particle exposures and endothelial function in 45 healthy adults in a woodsmoke-impacted community; and also the underlying role of oxidative stress and inflammation in relation to exposure reduction in consecutive 7-day periods of filtered and non-filtered air. Results: Air filtration reduced indoor fine particle concentration and was associated with a 9.4% increase in EndoPAT index and a decrease in C-reactive protein. Conclusions: Systemic inflammation and impaired endothelial function, both predictors of cardiovascular morbidity, can be favorably influenced by reducing indoor particle concentrations.

P a g e | 54 http://www.ncbi.nlm.nih.gov/pubmed/21257787 8) Comparison of Peripheral Endothelial Function in Shift Versus Nonshift Workers. Suessenbacher A, Potocnik M, Drler J, Fluckinger G, Wanitschek M, Pachinger O, Frick M, Alber HF. Am J Cardiol. 2011 Jan 17. Investigated whether shift working is associated with peripheral endothelial dysfunction in 95 workers (48 shift workers (SW), and 47 matched non-shift workers (NSW). Results: SW had lower EndoPAT index compared to NSW on the day shift (1.73 0.4 vs. 1.94 0.5, p = 0.03), no difference in the risk factor profiles between the SW and NSW. In NSW, those with regular physical training had a higher EndoPAT index than those without it. Conclusions: SW had a reduced EndoPAT index compared with NSW, suggesting that endothelial dysfunction might explain the known increased cardiovascular risk in SWs. http://www.ncbi.nlm.nih.gov/pubmed/21247546 9) Endothelial Function is Impaired After a High- Salt Meal in Healthy Subjects. K M Dickinson, P M Clifton, J B Keogh. Am J Clin Nutr 2011. Investigated the postprandial effect of dietary salt on endothelial function, as measured by BAUS and EndoPAT2000, in 16 healthy, normotensive subjects. Subjects received a meal with added salt,- High Salt Meal, (HSM), and a Low Salt Meal, (LSM), on 2 separate occasions in randomized order. Endothelial function was measured while fasting and at 30, 60, 90, and 120 min postprandium. Results: BAUS was significantly more impaired after the HSM than after the LSM at 30 min and at 60 min. No significant differences in BP or RHI were observed between meals. Conclusions: High salt intake significantly suppressed brachial artery FMD, thus having an acute adverse effect on vascular dilatation in the postprandial state. http://www.ncbi.nlm.nih.gov/pubmed/21228265

P a g e | 55 10) Effects of Lycopene Supplementation on Oxidative Stress and Markers of Endothelial Function in Healthy Men. Kim JY, Paik JK, Kim OY, Park HW, Lee JH, Jang Y, Lee JH. Atherosclerosis 2010. Determined the effects of graded lycopene supplementation on endothelial function measured by EndoPAT2000, and measures of oxidative stress in 126 healthy men, receiving graded lycopene 6mg (n = 41), 15mg (n=37), or placebo (n = 38) daily for 8 weeks. Results: In the high dose group after 8 weeks, EndoPAT index increased from 1.45 0.09 to 1.79 0.12; (P = 0.032) and other measurements of oxidative stress, endothelial activation and inflammatory status also improved. Changes were correlated amongst themselves. The beneficial effect of supplementation on endothelial function was remarkable in subjects with initially impaired function. Conclusions: Increase in serum lycopene after supplementation can reduce oxidative stress which may play a role in improving endothelial function. http://www.ncbi.nlm.nih.gov/pubmed/21194693 11) Dose-Response Effects of Omega-3 Fatty Acids on Triglycerides, Inflammation, and Endothelial Function in Healthy Persons with Moderate Hypertriglyceridemia. Skulas-Ray AC, Kris-Etherton PM, Harris WS, Vanden Heuvel JP, Wagner PR, West SG. Am J Clin Nutr. 2011 Feb; 93(2):243-52. Compared the effects of a nutritional dose of EPA+DHA (0.85 g/d) to a pharmaceutical dose (3.4 g/d) on serum triglycerides, inflammatory markers, and endothelial function in 26 healthy subjects with moderately elevated triglycerides. Results: The higher dose of EPA+DHA lowered triglycerides by 27% vs. placebo whereas no effect of the lower dose was observed. No effects on total LDL, and HDL, endothelial function, inflammatory markers, or expression of inflammatory cytokine genes were observed. Conclusions: The higher dose of EPA+DHA significantly lowered triglycerides, but neither dose improved endothelial function or inflammatory status over 8 wk in this population. http://www.ncbi.nlm.nih.gov/pubmed/21159789

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12) Omega-3 fatty acid supplementation improves vascular function and reduces inflammation in obese adolescents. Dangardt F, Osika W, Chen Y, Nilsson U, Gan LM, Gronowitz E, Strandvik B, Friberg P. Atherosclerosis. 2010 Oct; 212(2):580-5. Examined whether Omega-3 supplementation increases serum n-3 PUFA concentration, improves vascular function and morphology, and lowers inflammation in 25 obese adolescents randomized to receive treatment or placebo for 3 months in a double-blind, cross-over design with a 6-week washout period. Results: With active treatment, serum-3 PUFA concentration increased and inflammatory markers decreased. EndoPAT response to treatment improved vs. placebo (p < 0.01). Conclusion: Daily supplementation of Omega-3 acid increases the serum n-3 PUFA concentration, improves vascular function, and lowers the degree of inflammation in obese adolescents. http://www.ncbi.nlm.nih.gov/pubmed/20727522 13) Elevated augmentation index derived from peripheral arterial tonometry is associated with abnormal ventricular-vascular coupling. Heffernan KS, Patvardhan EA, Hession M, Ruan J, Karas RH, Kuvin JT. Clin Physiol Funct Imaging. 2010 Sep; 30(5):313-7. Examined the relation of EndoPAT derived-AIx with measures of ventricular-vascular coupling derived by 2D echocardiography, {arterial elastance index (EaI), and Left ventricular end-systolic elastance index E(LV)I}, in 47 patients. Three Groups of ventricular-vascular coupling ratios EaI/E(LV)I were defined: low (<0.6, n = 21), optimal (mean 0.6-1.2, n = 16) and high (>1.2, n = 10). Results: After adjustment for potential confounders, optimal EaI/E(LV)I had lower AIx (1 +/- 4%, P<0.05) compared to low (13 +/- 4%) and high (19 +/- 5%) groups. Conclusion: Abnormal ventricular-vascular is associated with increased AIx as measured by EndoPAT. http://www.ncbi.nlm.nih.gov/pubmed/20545714

P a g e | 57 14) Effects of therapeutic lifestyle changes on peripheral artery tonometry in patients with abdominal obesity. Ferr R, Plana N, Merino J, Aragons G, Girona J, Heras M, Coll B, Cos R, Masana L. Nutr Metab Cardiovasc Dis. 2010. Assessed effects of Therapeutic lifestyle changes (TLSC) on endothelial function (EF) measured by EndoPAT in 150 patients with abdominal obesity (AO) and moderate CV risk, randomized to either conventional medical care group (CG) or one-year TLSC group (IG). EF, IMT and lifestyle (LS) assessed before and after intervention. Results: EndoPAT index improved in IG and worsened in CG. Global CV risk reduced in IG (P = 0.017) due to decreased systolic blood pressure (P < 0.001), increased HDL and ApolipoproteinA1 (P = 0.013), quitting smoking (P = 0.001) and increased physical activity (P = 0.014). Improvement in two LS components was associated with EndoPAT index increase (P = 0.051). EndoPAT index increase determined less IMT progression (P = 0.053). Conclusions: Good adherence to TLSC reduces global CV risk and improves EndoPAT index. Improvement in EndoPAT index is the main determinant of lower IMT progression. http://www.ncbi.nlm.nih.gov/pubmed/20708393 15) Beneficial effects of recreational football on the cardiovascular risk profile in untrained premenopausal women. Krustrup P, Hansen PR, Randers MB, Nybo L, Martone D, Andersen LJ, Bune LT, Junge A, Bangsbo J. Scand J Med Sci Sports. 2010 Mar 4. Examines cardiovascular health effects in matched healthy untrained premenopausal women after 16 weeks of (A) recreational football training, (n=25), (B) continuous running training (n=25), and (C) no physical training (n=25). Results: Systolic pressure, heart rate and total fat mass were reduced in both training groups. In group A, diastolic blood pressure, LDL to HDL ratio and AI measured by EndoPAT were reduced. No change was measured in controls. Conclusion: Regular recreational football training has significant favorable effects on cardiovascular risk profile in untrained premenopausal women and is at least as effective as continuous running.

P a g e | 58 http://www.ncbi.nlm.nih.gov/pubmed/20210909 16) Altering dietary lysine:arginine ratio has little effect on cardiovascular risk factors and vascular reactivity in moderately hypercholesterolemic adults. Vega-Lpez S, Matthan NR, Ausman LM, Harding SV, Rideout TC, Ai M, Otokozawa S, Freed A, Kuvin JT, Jones PJ, Schaefer EJ, Lichtenstein AH. Atherosclerosis. 2009 Dec 5. Studied the effect of dietary amino acids Lys:Arg ratio on cardiovascular risk factors and vascular reactivity in 30 moderately hypercholesterolemic adults using two randomized 35-day diet phases, on measurements of EndoPAT, BAUS and numerous blood tests. Results: Diets differing in Lys:Arg ratios showed no differences in fasting and/or postprandial total, LDL, HDL and sdLDL cholesterol, RemLC, Lp(a) or apo B concentrations, LCAT and CETP activities, FSR, glycated albumin, immunoreactive insulin, FMD or EndoPAT. Conclusion: Diets differing in Lys:Arg ratios had no or small effects on cardiovascular risk factors and vascular reactivity. http://www.ncbi.nlm.nih.gov/pubmed/20042191 17) Detrimental effects of energy drink consumption on platelet and endothelial function. Worthley MI, Prabhu A, De Sciscio P, Schultz C, Sanders P, Willoughby SR. Am J Med. 2010 Feb; 123(2):184-7. Tested the hypothesis that energy drink consumption alters platelet aggregation and endothelial function in 50 healthy volunteers. Platelet aggregation, and EndoPAT score were tested before, and 1 hour after consuming 250 mL of a sugar-free energy drink. Results: RHI decreased significantly following the energy drink by 0.33+/-0.13 vs. 0.07+/0.12 (control), (P <.05), and there was a significant increase in platelet aggregation following the energy drink. Conclusion: Energy drink consumption acutely increases platelet aggregation and decreases endothelial function in healthy young adults. http://www.ncbi.nlm.nih.gov/pubmed/20103032

P a g e | 59 18) Endothelial function and stress response after simulated dives to 18 msw breathing air or oxygen. Madden LA, Chrismas BC, Mellor D, Vince RV, Midgley AW, Mc Naughton LR, Atkin SL, Laden G. Aviat Space Environ Med 2010; 81(1): 41 5. Deleterious effects of decompression on endothelium were assessed in five healthy males undergoing hyperbaric chamber simulated dives, (60 min at 283 kPa, followed by two decompression stages), breathing air, and 1 wk later breathing 100% oxygen. Results: RH-PAT but not changes in expression of CD105 on MP, nor in other blood markers, were significantly decreased post-decompression endothelial function after breathing air versus oxygen. Conclusion: Decompression breathing air probably caused greater endothelial damage, eluding to potential therapeutic value of hyperbaric oxygen for diseases characterized by endothelial dysfunction. http://www.ncbi.nlm.nih.gov/pubmed/20058736 19) Effect of nut consumption on oxidative stress and the endothelial function in metabolic syndrome. Lpez-Uriarte P, Nogus R, Saez G, Bull M, Romeu M, Masana L, Tormos C, CasasAgustench P, Salas-Salvad J. Clin Nutr. 2010 Jan 9. Examined effects of 30 g of mixed nuts daily for 12 weeks on markers of oxidation and endothelial function, in 50 adult metabolic syndrome patients randomly assigned to consume or not consume nuts. Oxidative blood markers and endothelial function using EndoPAT were assessed at the beginning and end of the trial. Results: No significant differences in changes between groups were observed in blood markers, or in endothelial function, however the reduction in DNA damage was significant in the Nut group. Conclusion: Nut consumption has no deleterious effect on lipid oxidation. http://www.ncbi.nlm.nih.gov/pubmed/20064680

P a g e | 60 20) Experience of appendicular thermal therapy applied to a patient with a left ventricular assist device awaiting heart transplantation. Higashi H, Komamura K, Oda N, Kato TS, Yanase M, Mano A, Hashimoto S, Wada K, Shishido T, Hashimura K, Kitakaze M, Kitamura S, Nakatani T. J Cardiol. 2009 Apr; 53(2):301-5. The authors describe their experience with appendicular thermal therapy applied to a patient fitted with an extracorporeal left ventricular assist device (LVAD), waitlisted for a heart transplant. They found elevations of serum nitrite and nitrate levels compared with the baseline values, and improved endothelial function determined by RH-PAT. Conclusion: Appendicular thermal therapy was safe for this patient with an extracorporeal LVAD. http://www.ncbi.nlm.nih.gov/pubmed/19304137 21) Potential Benefits on Impairment of Endothelial Function after a High-fat Meal of 4 weeks of Flavonoid Supplementation. Barringer TA, Hatcher L, Sasser HC. Evid Based Complement Alternat Med. 2008 Jul 3. Described the effect of 4 weeks of flavonoid supplementation on endothelial function in a high-fat meal dietary. This was a double-blind, cross-over design to 4 weeks of daily supplementation with OPC-3, or a matching placebo. The RHPAT index (RHI) was measured both before and 3h after a high-fat meal, in 23 healthy volunteers (mean age 43.410.4, 78% female), it was measured at the beginning (baseline) and after 4-week treatment. Results: The high-fat meal caused a similar decline in endothelial function at baseline in the placebo (-10.71%, P=0.006) and flavonoid (- 9.97%, P=0.077) groups. When measured after 4 weeks of treatment, the high fat meal produced a decline in the placebo group (-12.37%, P=0.005), but no in the flavonoid supplement group (-3.16%, P=0.663), and the difference between the responses to the high fat meal in the two groups was highly significant (P<0.0001). Conclusions: These results provided by the EndoPAT suggest that the flavonoid supplement used in this study mitigates the impairment of endothelial function caused by a high-fat meal. http://www.ncbi.nlm.nih.gov/pubmed/18955351

P a g e | 61 22) Enhanced external counterpulsation improves endothelial function in patients with symptomatic coronary artery disease. Bonetti PO, Barsness GW, Keelan PC, Schnell TI, Pumper GM, Kuvin JT, Schnall RP, Holmes DR, Higano ST, Lerman A. J Am CollCardiol. 2003 May 21; 41(10):1761-8. Assessed EndoPAT responses immediately before and after EECP sessions, and after one month, in 23 patients with refractory angina. RESULTS: EECP led to symptomatic improvement in 17 (74%) patients; EECP was associated with a significant immediate increase in average EndoPAT index after each treatment (p < 0.05), and average EndoPAT index at one-month follow-up was significantly higher than before EECP therapy (p < 0.05). When patients were divided by their clinical response, EndoPAT index at one-month follow-up increased only in those patients who experienced clinical benefit. CONCLUSIONS: EECP enhances peripheral endothelial function with beneficial effects persisting at one-month follow-up in patients with a positive clinical response. http://www.ncbi.nlm.nih.gov/pubmed/12767662

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Pediatric/adolescents
1) Endothelial Function as Measured by Peripheral Arterial Tonometry Increases during Pubertal Advancement. Bhangoo A, Sinha S, Rosenbaum M, Shelov S, Ten S. Horm Res Paediatr. 2011 Jul 22. Studied the relation of puberty and sex steroids with endothelial function using EndoPAT in 89 healthy boys and girls divided into 3 pubertal groups on the basis of their estrogen levels: group 1, Tanner stage I; group 2, Tanner stages II-III, and group 3, Tanner stages IV-V. Results: EndoPAT index was lowest at 1.42 0.44 in group 1 and significantly increased in group 2 at 1.71 0.35 (p = 0.02) and group 3 at 1.92 0.38 (p < 0.001). The Endo-PAT index correlated positively with E(2), DHEAS and age. Conclusions: Increase of the EndoPAT index was associated with an increment in Tanner stages. Changes in E(2) and DHEAS levels may contribute to increasing endothelial response to shear stress or arterial blood flow. http://www.ncbi.nlm.nih.gov/pubmed/21778688 2) Reduced brachial flow-mediated vasodilation in young adult ex extremely low birth weight preterm: a condition predictive of increased cardiovascular risk? Bassareo PP, Fanos V, Puddu M, Demuru P, Cadeddu F, Balzarini M, Mercuro G. J Matern Fetal Neonatal Med. 2010 Oct; 23 Suppl 3:121-4. Assessed potential alterations to endothelial function using EndoPAT in 32 young adults born preterm at extremely low birth weight (<1000 g; ex ELBW), versus 32 healthy age-matched subjects born at term. Results: Endothelial function was significantly reduced in ex-ELBW subjects compared to Controls (1.94 0.37 vs. 2.68 0.41, p< 0.0001). Moreover, it also correlated significantly with gestational age (r=0.56, p< 0.0009) and birth weight (r=0.63, p< 0.0001). Conclusions: Taken together, these results suggest that an ELBW may underline the onset of early circulatory dysfunction predictive of increased cardiovascular risk. http://www.ncbi.nlm.nih.gov/pubmed/20925458

P a g e | 63 3) High Levels of Soluble Intercellular Adhesion Molecule-1, Insulin Resistance and Saturated Fatty Acids are Associated with Endothelial Dysfunction in Healthy Adolescents. Chen Y, Osika W, Dangardt F, Gan LM, Strandvik B, Friberg P. Atherosclerosis. 2010 Aug; 211(2):638-42. Examined the influence of cardiovascular risk factors on endothelial function in 257 healthy adolescents. Endothelial function was measured using the EndoPAT2000. Blood samples were collected for analysis of lipids, insulin, glucose, fatty acid composition of plasma phospholipids, and markers of inflammation and endothelial function. Results: RHI was inversely associated with plasma ICAM-1, HOMA index for insulin resistance and saturated fatty acids of plasma phospholipids. The associations remained significant after adjusting for age, height, BMI-z-score, sex, blood pressure, HDL and smoking. Conclusions: In healthy adolescents, impaired endothelial function is significantly associated with high level of soluble ICAM-1, HOMAIR and SFA. http://www.ncbi.nlm.nih.gov/pubmed/20362293 4) Postprandial Endothelial Function, Inflammation, and Oxidative Stress in Obese Children and Adolescents. Metzig AM, Schwarzenberg, B.Schwarzenberg SJ, Fox CK,Deering MM, Nathan BM, Kelly AS. Obesity (Silver Spring). 2011 Examined whether acute glucose ingestion reduces endothelial function as measured by EndoPAT2000, and increases inflammation and oxidative stress; and if transient elevations in plasma glucose correlate with endothelial function, inflammation, and oxidative stress, in 34 obese children and adolescents (BMI = 37.9 6.7), in a fasting state and at 1-h - and 2-h following glucose ingestion. Results: Compared to baseline, there were no statistically significant differences in 1-h - and 2-h RHI, CRP, IL-6, and oxLDL. However at 1hr, glucose level was significantly inversely correlated with RHI (r = -0.40, P < 0.05). Conclusions: An acute oral glucose load did not reduce endothelial function or increased levels of inflammation or oxidative stress in obese youths. However, associations of postprandial hyperglycemia with endothelial function and oxidative stress may have implications in impaired glucose tolerance or frank type 2 diabetes. http://www.ncbi.nlm.nih.gov/pubmed/21233813

P a g e | 64 5) Peripheral arterial tonometry in assessing endothelial dysfunction in pediatric sickle cell disease. Sivamurthy KM, Dampier C, MacDermott M, Maureen M, Cahill M, Hsu LL. Pediatr Hematol Oncol. 2009 Nov; 26(8):589-96. The authors studied EndoPAT in 36 SCD children to determine the influence of hemoglobin genotype and treatment on endothelial function. Results: Blunted RHI was seen in the majority of children with SCD, especially with increased symptomatology (1.53 and 1.71; p value .032). RHI was not normal in children on chronic transfusion or hydroxyurea. RHI correlated with reticulocyte fraction (Spearman r = -0.47, p = 0.037). Conclusions: EndoPAT merits further exploration as a measure of endothelial function in SCD. http://www.ncbi.nlm.nih.gov/pubmed/19954369

6) Impaired vascular function in asymptomatic young adult survivors of Hodgkin Lymphoma following mediastinal radiation. Zelcer S, Chen B, Mangel J, Vujovic O, Thiessen-Philbrook HR, Reider M, Mahmud FH. J Cancer Surviv. 2010 Sep; 4(3):218-24. Evaluated endothelial function (EndoPAT2000), cardiovascular risk factors, and activity level in 26 Hodgkin lymphoma survivors (HLS) aged 12-30, (>2 years from therapy) vs. 26 matched controls, and also determined the influence of mediastinal radiation. Results: HLS were on average 6.74.6 yrs post treatment. No differences in endothelial function or cardiovascular risk factors were observed between HLS and control groups, but endothelial function was impaired in those HLS who received mediastinal radiation (n=13), vs. controls (1.670.39 vs. 2.030.37, p<0.01). Conclusions: Impaired endothelial function was preferentially observed in HLS who received mediastinal radiation, confirming that mediastinal radiation is an additional cardiovascular risk factor in this young patient cohort. http://www.ncbi.nlm.nih.gov/pubmed/20652436

P a g e | 65 7) Anger, depression and anxiety associated with endothelial function in childhood and adolescence. Osika W, Montgomery SM, Dangardt F, Wahrborg P, Gan LM, Tideman E, Friberg P. Arch Dis Child. 2009 Oct 11. Tested if endothelial function, assessed by EndoPAT, is inversely associated with increased psychological burden, in 248 children (age 14.0 1.0, 136 females). Results: Low self-assessed psychological health, (higher levels of anger, depression and anxiety), is related to lower PAT scores in girls aged 12-16. In boys there is an association between disruptive behavior and higher PAT scores. Conclusion: Psychological health is already associated with endothelial function in childhood, the association being more pronounced in girls. Measuring endothelial function in an operator independent manner is convenient for large-scale field studies. http://www.ncbi.nlm.nih.gov/pubmed/19822537