Special Feature
Endothelial Function
By Jonathan Abrams, MD
Vascular biology and studies of endothelial physiology and function have been an important development for scientific investigation over the past decade. Our ability to understand the diverse and complex roles of the endothelial monolayer in blood vessels has increased exponentially. It now appears that endothelial cells have an enormous capability to produce many diverse substances in response to various stimuli. The endothelium is an important modulator of atheriosclerosis (or resistance to vascular disease)-it controls vasomotor regulation of the coronary arterial bed and participates in aspects of thrombosis and fibrinolysis.
The major clinical research focus of endothelial function has capitalized on the ability to assess vascular vasodilator/constrictor activity through endothelial dependent probes, such as acetylcholine, with an emphasis on the many factors that impair normal endothelium vasomotor activity. Specifically, when an endothelium-dependent dilating substance, such as acetylcholine, bradykinin, or substance P, is exposed to an artery, the normal response is arterial vasodilatation of large and small vessels, usually with increased blood flow. In the presence of a variety of coronary artery disease (CAD) risk factors, it has been shown that normal physiologic endothelial dilator responses may be blunted, and there may be vasoconstriction induced by the normal dilating compound. In general, an increase in blood flow or a fall in vascular resistance implies small vessel dilatation, whereas direct changes in the caliber of the vessel being assessed by arteriography or ultrasound reflects conduit vessel caliber and vasomotion.
The cardiology literature is becoming increasingly fueled with research articles assessing endothelial functions with one of these techniques, usually implying a potential therapeutic intervention or delivering an endothelial probe that may enhance or block normal endothelial dilator responses.
It is important for physicians to understand that most experts believe that endothelial vasomotor function may act as a surrogate for the propensity toward atherosclerosis, smooth muscle proliferation, and adverse thrombotic-fibrinolytic activity; therefore, vasomotor activity is believed to predict other endothelial-related phenomenon. For instance, it is widely assumed that impaired endothelial dilator responses in individuals with CAD risk factors may suggest a worse prognosis than in those who have a normal response to a specific probe, such as acetylcholine.
Clinicians need to understand the basic physiology of the endothelium, as the literature is becoming replete with such investigations. Innovative research in this area may predict future therapies, or at the very least, such studies can provide motivation to mount clinical trials when a specific intervention appears to be beneficial.
The following is a brief summary of four recently published studies that use endothelial function assessment and appear to have important implications for our understanding of vascular disease.
A New Mechanism of Aspirin Efficacy
An interesting study from the NHLBI suggests that aspirin may have a direct effect on endothelial vasomotor function in the presence of coronary atherosclerosis.1 The investigators speculate as to whether a prostenoid vasoconstricting factor is released in the presence of endothelial dysfunction and might contribute to the abnormal response to acetylcholine that has been repeatedly documented in CAD patients. Using femoral artery resistance as an end point, these investigators demonstrate that an infusion of intravenous aspirin improved vascular flow and decreased arterial resistance in a group of individuals with documented coronary atherosclerosis but not in subjects with CAD risk factors and no documented vascular disease. The authors speculate that the acetylcholine-induced arterial dilatation might be abnormal in the presence of atherosclerosis, not only because of a decrease in nitric oxide availability but also through the induction of a cyclo-oxygenase-dependent vasoconstrictor. They raise the question as to whether aspirin may have an additional action over and above its antiplatelet efficacy and call for further studies. Clearly, this could be a remarkable new development with respect to our understanding of endothelial dysfunction as well as the efficacy of aspirin in patients with CAD.
Vitamin C in Diabetics
An interesting study from the Brigham and Women's Hospital, one of the leading groups studying vascular biology, suggests that the antioxidant vitamin C improves endothelium-dependent vasodilatation in insulin-dependent diabetics.2 Diabetes and controls were studied using forearm blood flow determined by venous occlusion plethysmography. Methacholine, an endothelium dependent vasodilator similar to acetylcholine, was infused intra-arterially. The diabetics were found to have abnormal endothelial-dependent dilator responses, which were augmented by a concomitant infusion of soluble vitamin C, whereas controls had no alteration in vasodilator responses with vitamin C. The authors conclude that the antioxidant effects of vitamin C were instrumental in restoring the forearm blood flow responses toward normal in the diabetics, none of whom had overt vascular disease, hypertension, or other abnormalities that have been associated with endothelial dysfunction. In other studies, oxidant stress induced by free radicals has been associated with abnormal vascular tone. It is well known that superoxide anions inactivate nitric oxide, and vascular endothelial cell production of superoxide anions appear to be related to impaired endothelium-dependent relaxation in a variety of conditions. Vitamin C may have acted as an oxygen-derived free radical scavenger, as well as possibly repleting decreased tissue levels of vitamin C that are known to occur in diabetics. A previous report from the same group demonstrated enhanced endothelial function in non-insulin diabetics as well. These results suggest a link between different types of diabetes, and possibly other conditions (such as hypercholesterolemia), that are associated with oxidant stress and impaired endothelial function. The authors call for clinical trial studies using oral vitamin C in diabetics.
Endothelial Dysfunction and Microvascular Angina in Syndrome X
A study from Athens, Greece, suggests that patients with microvascular angina have generalized impairment of vascular endothelial function.3 This investigation examined 11 middle-aged women with microvascular angina or syndrome X (angina, normal coronary arterial arteries, positive stress test) using brachial artery flow-mediated dilation as well as ultrasound measurements of intima-media thickness of the common carotid artery. The interesting finding was that flow-mediated dilation, an endothelium modulated phenomenon, was abnormal in patients with microvascular angina (as well as a group of individuals with CAD) and significantly lower than in healthy controls, in spite of the fact that carotid intima-medial thickness was comparable in the microvascular angina patients and controls, and less than those patients with CAD. The authors conclude that endothelial dysfunction in these subjects is a generalized process involving not only the coronary arteries, but also peripheral conduit arteries. While not directly related to a specific therapy, these data help us understand the problem of microvascular angina as a valid biologic phenomenon and offer the possibility of therapy by strategies that enhance vascular nitric oxide production or decrease its destruction by oxidant stress.
Impaired Fibrinolysis in Acute Coronary Syndromes
A study from Germany suggests that impaired fibrinolysis in patients with acute coronary syndromes is related to reduced endothelial fibrinolytic capacity, which could be partially responsible for a hypercoagulable state.4 Subjects with acute myocardial infarction or unstable angina were compared to 25 patients with stable angina. Venous levels of fibrinolytic system markers and hypercoagulability were assessed over a 10-day period. In addition, endothelial t-PA release was measured. Those individuals with an acute coronary syndrome had marked elevations of t-PA mass concentrations, as well as elevated plasminogen activator inhibitor (PAI-1) levels, when compared to patients with stable angina. In addition, there was evidence of hypercoagulability (elevated thrombin and D-dimer activity). Maximal endothelial t-PA release was reduced in acute coronary patients with late recovery. These studies suggest that endothelial modulation of fibrinolysis may be impaired during the acute phase of myocardial infarction and unstable angina with later normalization. This disordered function could be a component of enhanced thrombotic activity, and offers new clues as to the assessment of vascular risk in these coronary syndromes. Such studies involving endothelial fibrinolytic reserve are relatively new and represent a potentially important focus for the cardiovascular community. The interrelationships between t-PA and PAI-1 are clearly important with respect to the propensity toward thrombosis.
In summary, these four studies emphasize how widespread and important endothelial function research is. All of these reports further our knowledge of underlying pathophysiology of a variety of important syndromes, and most offer some potential for therapy. It is clear that endothelial dysfunction, however measured, is a potential marker for a variety of adverse sequelae, presumably both short- and long-term. It is wise for all of us to become more informed and knowledgeable about the methodology, technology, and biology of endothelial function testing.
References
1. Husain S, Circulation 1998;97:716-720.
2. Timimi FK, J Am Coll Cardiol 1998;31:552-557.
3. Lekakis JP, J Am Coll Cardiol 1998;31:541-546.
4. Hoffmeister HM, J Am Coll Cardiol 1998;31: 547-551.
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content