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==Testing==
==Testing==
The gold standard for measuring endothelial function is angiography with acetylcholine injection<ref>Ludmer PL, Selwyn AP, Shook TL, Wayne RR, Mudge GH, Alexander RW, Ganz P. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med. 1986 Oct 23;315(17):1046-51</ref> , however due to the invasive and complex nature of the procedure it has never been used outside research<ref>Monnink SH, Tio RA, van Boven AJ, van Gilst WH, van Veldhuisen DJ. The role of coronary endothelial function testing in patients suspected for angina pectoris. Int J Cardiol. 2004 Aug;96(2):123-9.</ref>.
As more research is conducted to improve testing methodologies for endothelial dysfunction, however, several non-invasive tests have been created by various medical-research companies.
A noninvasive method to measure endothelial dysfunction is ultrasound Flow Mediated Vasodilation (FMD).
However, there is a serious flaw in measurements of endothelial function with FMD which involve the percentage change in diameter as the selected statistic. There is a negative correlation between percent flow mediated dilation and baseline artery size, but this has only recently been recognised as a fundamental scaling problem, showing that peak diameter does not change as a constant proportion of baseline diameter. This dependence of percent FMD on baseline diameter can lead to biased estimates of endothelial function. For reseaerch on flow-medaited dilation an ANCOVA approach to adjusting FMD for variation in baseline diameter is more appropriate.
There are serious flaws in measurements of endothelial function with FMD which involve the percentage change in diameter as the selected statistic. There is a negative correlation between percent flow mediated dilation and baseline artery size, but this has only recently been recognised as a fundamental scaling problem, showing that peak diameter does not change as a constant proportion of baseline diameter. This dependence of percent FMD on baseline diameter can lead to biased estimates of endothelial function. For research on FMD an ANCOVA approach to adjusting FMD for variation in baseline diameter is more appropriate. A major challenge of FMD is also the variability across centers and the requirement of highly qualified technicians to perform the procedure<ref>Thijssen DH, Black MA, Pyke KE, Padilla J, Atkinson G, Harris RA, Parker B, Widlansky ME, Tschakovsky ME, Green DJ. Assessment of flow-mediated dilation in
⚫
<br>An FDA approved device for measuring Endothelial function, EndoPAT, that works through the method of Peripheral Arterial Tonometry (PAT) has been tested in several clinical trials in multiple centers with good and reproducible outcomes for diagnosing endothelial dysfunction. Additionally results from clinical trials have shown that Endopat is useful for risk evaluation, stratification and prognosis of major cardiovascualar events (MACE).<ref>Kuvin JT, Patel AR, Sliney KA, Pandian NG, Sheffy J, Schnall RP, Karas RH, Udelson JE. Assessment of peripheral vascular endothelial function with finger arterial pulse wave amplitude. Am Heart J. 2003 Jul;146(1):168-74.</ref> <ref>Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr, Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol. 2004 Dec
humans: a methodological and physiological guideline. Am J Physiol Heart Circ Physiol. 2011 Jan;300(1):H2-12 </ref>.
<br>An FDA approved non-invasive device for measuring Endothelial function, EndoPAT,<ref> Kuvin JT, Mammen A, Mooney P, Alsheikh-Ali AA, Karas RH. Assessment of
peripheral vascular endothelial function in the ambulatory setting. Vasc Med.
2007 Feb;12(1):13-6. </ref><ref>Axtell AL, Gomari FA, Cooke JP. Assessing endothelial vasodilator function
⚫
with the Endo-PAT 2000. J Vis Exp. 2010 Oct 15;(44).</ref> has been tested in several clinical trials in multiple centers. It works through the method of Peripheral Arterial Tonometry (PAT). Results from clinical trials have shown that Endopat is useful for risk evaluation, stratification and prognosis of getting major cardiovascualar events (MACE).<ref>Kuvin JT, Patel AR, Sliney KA, Pandian NG, Sheffy J, Schnall RP, Karas RH, Udelson JE. Assessment of peripheral vascular endothelial function with finger arterial pulse wave amplitude. Am Heart J. 2003 Jul;146(1):168-74.</ref> <ref>Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr, Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol. 2004 Dec
7;44(11):2137-41.</ref> <ref>Hamburg NM, Keyes MJ, Larson MG, Vasan RS, Schnabel R, Pryde MM, Mitchell GF, Sheffy J, Vita JA, Benjamin EJ. Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Circulation. 2008 May 13;117(19):2467-74.</ref><ref>Rubinshtein R, Kuvin JT, Soffler M, Lennon RJ, Lavi S, Nelson RE, Pumper GM,Lerman LO, Lerman A. Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J. 2010 May;31(9):1142-8</ref> <ref>Matsuzawa Y, Sugiyama S, Sugamura K, Nozaki T, Ohba K, Konishi M, Matsubara J,
7;44(11):2137-41.</ref> <ref>Hamburg NM, Keyes MJ, Larson MG, Vasan RS, Schnabel R, Pryde MM, Mitchell GF, Sheffy J, Vita JA, Benjamin EJ. Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Circulation. 2008 May 13;117(19):2467-74.</ref><ref>Rubinshtein R, Kuvin JT, Soffler M, Lennon RJ, Lavi S, Nelson RE, Pumper GM,Lerman LO, Lerman A. Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J. 2010 May;31(9):1142-8</ref> <ref>Matsuzawa Y, Sugiyama S, Sugamura K, Nozaki T, Ohba K, Konishi M, Matsubara J,
Sumida H, Kaikita K, Kojima S, Nagayoshi Y, Yamamuro M, Izumiya Y, Iwashita S,
Sumida H, Kaikita K, Kojima S, Nagayoshi Y, Yamamuro M, Izumiya Y, Iwashita S,
Matsui K, Jinnouchi H, Kimura K, Umemura S, Ogawa H. Digital assessment of
Matsui K, Jinnouchi H, Kimura K, Umemura S, Ogawa H. Digital assessment of
endothelial function and ischemic heart disease in women. J Am Coll Cardiol. 2010
endothelial function and ischemic heart disease in women. J Am Coll Cardiol. 2010
Apr 20;55(16):1688-96. </ref><ref>Akiyama E, Sugiyama S, Matsuzawa Y, Konishi M, Suzuki H, Nozaki T, Ohba K, Matsubara J, Maeda H, Horibata Y, Sakamoto K, Sugamura K, Yamamuro M, Sumida H,
Apr 20;55(16):1688-96. </ref><ref>Heffernan KS, Karas RH, Patvardhan EA, Jafri H, Kuvin JT. Peripheral arterial
tonometry for risk stratification in men with coronary artery disease. Clin
Cardiol. 2010 Feb;33(2):94-8.</ref><ref>Akiyama E, Sugiyama S, Matsuzawa Y, Konishi M, Suzuki H, Nozaki T, Ohba K, Matsubara J, Maeda H, Horibata Y, Sakamoto K, Sugamura K, Yamamuro M, Sumida H,
Kaikita K, Iwashita S, Matsui K, Kimura K, Umemura S, Ogawa H. Incremental
Kaikita K, Iwashita S, Matsui K, Kimura K, Umemura S, Ogawa H. Incremental
prognostic significance of peripheral endothelial dysfunction in patients with
prognostic significance of peripheral endothelial dysfunction in patients with

Revision as of 20:39, 10 December 2012

In human vascular diseases, endothelial dysfunction is a systemic pathological state of the endothelium (the inner lining of blood vessels) and can be broadly defined as an imbalance between vasodilating and vasoconstricting substances produced by (or acting on) the endothelium.[1] Normal functions of endothelial cells include mediation of coagulation, platelet adhesion, immune function and control of volume and electrolyte content of the intravascular and extravascular spaces.

Endothelial dysfunction can result from and/or contribute to several disease processes, as occurs in septic shock, hypertension, hypercholesterolaemia, diabetes, Behcet's disease it can also result from environmental factors, such as from smoking tobacco products and exposure to air pollution.

Atherosclerosis

Endothelial dysfunction is thought to be a key event in the development of atherosclerosis and predates clinically obvious vascular pathology by many years. This is because endothelial dysfunction is associated with reduced anticoagulant properties as well as increased adhesion molecule expression, chemokine and other cytokine release, and reactive oxygen species production from the endothelium, all of which play important roles in the development of atherosclerosis.

In fact, endothelial dysfunction has been shown to be of prognostic significance in predicting vascular events including stroke and heart attacks. Because of this, endothelial function testing may have great potential prognostic value for the detection of cardiovascular disease, but currently the available tests are too difficult, expensive, and/or variable for routine clinical use.

NO bioavailability

A key and quantifiable feature of endothelial dysfunction is the inability of arteries and arterioles to dilate fully in response to an appropriate stimulus that stimulates release of vasodilators from the endothelium like nitric oxide (NO). Endothelial dysfunction is commonly associated with decreased NO bioavailability, which is due to impaired NO production by the endothelium and/or increased inactivation of NO by reactive oxygen species.

This can be tested by a variety of methods including iontophoresis of acetylcholine, direct administration of various vasoactive agents to segments of blood vessels, localised heating of the skin and temporary arterial occlusion by inflating a blood pressure cuff to high pressures. Testing can also take place in the coronary arteries themselves but this is invasive and not normally conducted unless there is a clinical reason for intracoronary catheterisation.

Of all the current tests employed in the research setting, flow-mediated dilation is the most widely used non-invasive test for assessing endothelial function. This technique measures endothelial function by inducing reactive hyperemia via temporary arterial occlusion and measuring the resultant relative increase in blood vessel diameter via ultrasound. As people with endothelial dysfunction have low NO bioavailability, their blood vessels have a decreased capacity to dilate in response to certain stimuli, compared to those with normal endothelial function.

Because NO has anti-inflammatory and anti-proliferative effects and therefore helps inhibit atherosclerosis, it is easy to see how endothelial dysfunction may contribute to future adverse cardiovascular events. Unfortunately the variability in such tests (e.g. due to time of day, food, menstrual cycle, temperature, etc.) means that no technique has yet been identified that would allow endothelial testing to attain routine clinical significance, although there are some tests under clinical evaluation such as measuring of arterial stiffness.

Testing

The gold standard for measuring endothelial function is angiography with acetylcholine injection[2] , however due to the invasive and complex nature of the procedure it has never been used outside research[3]. A noninvasive method to measure endothelial dysfunction is ultrasound Flow Mediated Vasodilation (FMD). There are serious flaws in measurements of endothelial function with FMD which involve the percentage change in diameter as the selected statistic. There is a negative correlation between percent flow mediated dilation and baseline artery size, but this has only recently been recognised as a fundamental scaling problem, showing that peak diameter does not change as a constant proportion of baseline diameter. This dependence of percent FMD on baseline diameter can lead to biased estimates of endothelial function. For research on FMD an ANCOVA approach to adjusting FMD for variation in baseline diameter is more appropriate. A major challenge of FMD is also the variability across centers and the requirement of highly qualified technicians to perform the procedure[4].
An FDA approved non-invasive device for measuring Endothelial function, EndoPAT,[5][6] has been tested in several clinical trials in multiple centers. It works through the method of Peripheral Arterial Tonometry (PAT). Results from clinical trials have shown that Endopat is useful for risk evaluation, stratification and prognosis of getting major cardiovascualar events (MACE).[7] [8] [9][10] [11][12][13][14]

Prevention and treatment

Endothelial function can be improved significantly by exercise and improved diet. A study published in 2005 has determined that a positive relationship exists between the consumption of trans fat (commonly found in hydrogenated products such as margarine) and the development of endothelial dysfunction.[15] Other factors have been identified as improving endothelial function and include cessation of smoking, loss of weight and treatment of hypertension and hypercholesterolemia amongst other things. Some studies have found antioxidants, potassium[16] and arginine supplementation to restore impaired endothelial function. New third-generation β-blockers and 5-phosphodiesterase inhibitors may affect endothelial function. However to date it remains not possible to assess which set of patients are improving their endothelial function. Furthermore, the HMGCoA-reductase inhibitors currently used to reduce cholesterol levels have major pleiotropic anti-inflammatory and anti-hypertensive effects. The preservation or recovery of endothelial function in hypertensive patients is crucial to inhibit the development of atherosclerosis and the onset of cardiovascular events. This review focuses on the ancillary effects of hypertensive drugs and HMGCoA-reductase inhibitors that go beyond lowering blood pressure and cholesterol levels.[17]

Epidemiology

Endothelial dysfunction has been observed in a 2001 study of women where it was found that this disorder is present in approximately half of women with chest pain, in the absence of overt blockages in large coronary arteries. This endothelial dysfunction cannot be predicted by typical risk factors for atherosclerosis (e.g., obesity, cholesterol, smoking) and hormones.[18]

See also

References

  1. ^ Deanfield J, Donald A, Ferri C, Giannattasio C, Halcox J, Halligan S, Lerman A, Mancia G, Oliver JJ, Pessina AC, Rizzoni D, Rossi GP, Salvetti A, Schiffrin EL, Taddei S, Webb DJ (2005). "Endothelial function and dysfunction. Part I: Methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension". J Hypertens. 23 (1): 7–17. doi:10.1097/00004872-200501000-00004. PMID 15643116. {{cite journal}}: Cite has empty unknown parameter: |month= (help)CS1 maint: multiple names: authors list (link)
  2. ^ Ludmer PL, Selwyn AP, Shook TL, Wayne RR, Mudge GH, Alexander RW, Ganz P. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med. 1986 Oct 23;315(17):1046-51
  3. ^ Monnink SH, Tio RA, van Boven AJ, van Gilst WH, van Veldhuisen DJ. The role of coronary endothelial function testing in patients suspected for angina pectoris. Int J Cardiol. 2004 Aug;96(2):123-9.
  4. ^ Thijssen DH, Black MA, Pyke KE, Padilla J, Atkinson G, Harris RA, Parker B, Widlansky ME, Tschakovsky ME, Green DJ. Assessment of flow-mediated dilation in humans: a methodological and physiological guideline. Am J Physiol Heart Circ Physiol. 2011 Jan;300(1):H2-12
  5. ^ Kuvin JT, Mammen A, Mooney P, Alsheikh-Ali AA, Karas RH. Assessment of peripheral vascular endothelial function in the ambulatory setting. Vasc Med. 2007 Feb;12(1):13-6.
  6. ^ Axtell AL, Gomari FA, Cooke JP. Assessing endothelial vasodilator function with the Endo-PAT 2000. J Vis Exp. 2010 Oct 15;(44).
  7. ^ Kuvin JT, Patel AR, Sliney KA, Pandian NG, Sheffy J, Schnall RP, Karas RH, Udelson JE. Assessment of peripheral vascular endothelial function with finger arterial pulse wave amplitude. Am Heart J. 2003 Jul;146(1):168-74.
  8. ^ Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr, Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol. 2004 Dec 7;44(11):2137-41.
  9. ^ Hamburg NM, Keyes MJ, Larson MG, Vasan RS, Schnabel R, Pryde MM, Mitchell GF, Sheffy J, Vita JA, Benjamin EJ. Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Circulation. 2008 May 13;117(19):2467-74.
  10. ^ Rubinshtein R, Kuvin JT, Soffler M, Lennon RJ, Lavi S, Nelson RE, Pumper GM,Lerman LO, Lerman A. Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J. 2010 May;31(9):1142-8
  11. ^ Matsuzawa Y, Sugiyama S, Sugamura K, Nozaki T, Ohba K, Konishi M, Matsubara J, Sumida H, Kaikita K, Kojima S, Nagayoshi Y, Yamamuro M, Izumiya Y, Iwashita S, Matsui K, Jinnouchi H, Kimura K, Umemura S, Ogawa H. Digital assessment of endothelial function and ischemic heart disease in women. J Am Coll Cardiol. 2010 Apr 20;55(16):1688-96.
  12. ^ Heffernan KS, Karas RH, Patvardhan EA, Jafri H, Kuvin JT. Peripheral arterial tonometry for risk stratification in men with coronary artery disease. Clin Cardiol. 2010 Feb;33(2):94-8.
  13. ^ Akiyama E, Sugiyama S, Matsuzawa Y, Konishi M, Suzuki H, Nozaki T, Ohba K, Matsubara J, Maeda H, Horibata Y, Sakamoto K, Sugamura K, Yamamuro M, Sumida H, Kaikita K, Iwashita S, Matsui K, Kimura K, Umemura S, Ogawa H. Incremental prognostic significance of peripheral endothelial dysfunction in patients with heart failure with normal left ventricular ejection fraction. J Am Coll Cardiol. 2012 Oct 30;60(18):1778-86.
  14. ^ Matsue Y, Suzuki M, Nagahori W, Ohno M, Matsumura A, Hashimoto Y, Yoshida K, Yoshida M. Endothelial dysfunction measured by peripheral arterial tonometry predicts prognosis in patients with heart failure with preserved ejection fraction. Int J Cardiol. 2012 Sep 26
  15. ^ Lopez-Garcia E, Schulze MB, Meigs JB, Manson JE, Rifai N, Stampfer MJ, Willett WC, Hu FB, "Consumption of trans fatty acids is related to plasma biomarkers of inflammation and endothelial dysfunction", Journal of Nutrition, Mar 2005;135(3):562-6.
  16. ^ Potassium softens vascular endothelium and increases nitric oxide release H. Oberleithnera,1,C. Calliesa,K. Kusche-Vihroga,H. Schillersa,V. Shahina,C. Riethmüllera,G. A. MacGregorb anH. E. de Wardenerb+ Author Affiliations aInstitute of Physiology II, University of Münster, D-48149 Münster, Germany; and bBlood Pressure Unit, Department of Cardiac and Vascular Medicine, St. George's University of London, London SW17 ORE, United Kingdom Communicated by Gerhard Giebisch, Yale University School of Medicine, New Haven, CT, December 21, 2008 (received for review August 20, 2008)
  17. ^ Tomasoni L, Sitia S, Borghi C, Cicero AF, Ceconi C, Cecaro F, Morganti A, De Gennaro Colonna V, Guazzi M, Morricone L, Malavazos AE, Marino P, Cavallino C, Shoenfeld Y, Turiel M., "Effects of treatment strategy on endothelial function", Autoimmunity Review, 2010 Oct;9(12):840-4
  18. ^ Reis SE, Holubkov R, Smith AJC, Kelsey SF, Sharaf BL, Reichek N, Rogers WJ, Merz NB, Sopko G, Pepine CJ, “Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: Results from the NHLBI WISE Study,” Am Heart J, V. 141, No. 5 (May 2001), pp. 735-741
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