Number 22, 2004
Endothelial Dysfunction

Imaging of coronary endothelial dysfunction by use of positron emission tomography

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Frank M. Bengel
Nuklearmedizinische Klinik und Poliklinik der Technischen Universitt Mnchen, Germany
Correspondence: Dr Frank M. Bengel, Nuklearmedizinische Klinik und Poliklinik, Technische Universitt Mnchen, Klinikum rechts der Isar, Ismaninger Str. 22, 81675 Mnchen, Germany.
Tel +49 8941402971, fax +49 8941404950; e-mail: frank.bengel@lrz.tu-muenchen.de

Introduction
Nowadays the importance of endothelial integrity for the regulation and maintenance of normal vascular function is fully recognized. Clinically, a paradigm change in coronary artery disease has occurred. In past trials of lifestyle modification and lipid lowering, significant reductions in cardiac event rates were noted, despite there being little or no effect on the degree of coronary stenoses. The emphasis in the prevention of disease progression has thus shifted from modification of structural changes towards modification of functional alterations [1]. In addition, advances in basic science have contributed substantially to an increase and refinement of understanding of the role of endothelial dysfunction in early development and progression of atherosclerosis [2]. It has been demonstrated that individuals with impaired endothelial function are at increased risk for future development of overt coronary heart disease and for occurrence of cardiac events [3,4]. Reliable biologic imaging techniques that allow for testing of endothelial integrity are therefore sought, and could be of considerable clinical value.

Comparison of techniques for identification of endothelial dysfunction
Endothelial function can be tested at several vascular sites (Table I). Increases in forearm blood flow or brachial artery diameter in response to endothelium-specific stimuli such as transient occlusion are assessed by ultrasound and used as an indicator of the integrity of the endothelium. These measurements in peripheral vessels are then extrapolated to the coronary circulation. Questions remain, however, as to whether functional alterations in peripheral vessels always reflect alterations in the coronary circulation. Recently, for example, it was reported that there was no correlation between peripheral perfusion responses to transient forearm ischemia and dipyridamole-induced myocardial hyperemia, in groups of healthy normal individuals, patients with coronary artery disease, and patients with syndrome X, suggesting that extrapolation of findings between the two vascular beds is not feasible [5].
Invasive measurements of Doppler flow velocity or angiographic vessel diameters allow for testing of endothelial function of epicardial conduit vessels. Intracoronary injection of adenosine or papaverine normally results in a flow mediated (or shear stress mediated) increase in the release of nitric oxide and an increase in vessel diameter. A similar effect is provoked by intracoronary acetylcholine, which stimulates the release of nitric oxide directly via muscarinic endothelial receptors. The invasiveness of these approaches, however, precludes their largescale and repetitive clinical use.

Table I. Methods for detection of endothelial dysfunction.

By providing qualitative and, in particular, quantitative information about myocardial blood flow at baseline and in response to various stimuli, positron emission tomography (PET) is at present the only imaging modality that makes possible the noninvasive assessment of endothelial function at the level of the coronary microvasculature.

Quantification of myocardial blood flow by positron emission tomography
Regional myocardial blood flow is generally measured using two approaches, one based on the freely perfusible tracer, [¹⁵O]-water, and the other based on the metabolically trapped perfusion tracer, [¹³N]ammonia. Dynamic imaging, creation of timeactivity curves for blood and myocardium, and curve fitting to compartmental models are necessary steps for quantification. Both approaches have been extensively validated against independent microsphere blood flow measurements in animals and their reproducibility has been demonstrated, so that they are readily available for investigational and routine clinical use [6]. Current methodology allows for three-dimensional volumetric assessment of global and regional myocardial flow at rest and in response to stress stimuli (Figure 1). These parameters reflect tissue perfusion and thus the integrated function of the coronary circulation of the heart at the resistance level.

Endothelium-specific stress testing for positron emission tomography imaging
Typically, vasodilators such as adenosine or dipyridamole have been used in stress imaging in PET studies [6]. Those agents act directly on vascular smooth muscle cells via specific adenosine receptors, causing relaxation and thus increased vasodilatation and flow. Hyperemic flow in response to these agents normally increases 2.5- to 5-fold from baseline, and is believed to reflect an integrated response of the coronary circulatory system, partially mediated by direct smooth muscle effects and partially mediated by additional endothelial activation related to shear stress (Figure 2a) [7].

More recently, stress tests that are specific for endothelial function have been applied in positron emission tomography imaging. These are based on sympathetic stimulation, either by cold pressor test [8,9] or by mental stress [10]. Release of norepinephrine from stimulated sympathetic neurons activates -adrenoceptors on the endothelium that mediate the release of nitric oxide (Figure 2b). This vasodilatory signal results in a 3050% increase in baseline flow in the presence of an intact endothelium. -Adrenergic stimulation of vascular smooth muscle cells, which causes vasoconstriction, is normally counteracted, but may outweigh the endothelium-derived vasodilatation in the presence of impaired endothelial integrity. The resulting decrease in flow then indicates endothelial dysfunction. PET flow measurements during sympathetic stimulation are therefore believed to provide specific information about coronary endothelial function.

Characterization of the effects of traditional risk factors
Several early studies using PET at rest and during pharmacologic hyperemia demonstrated impairments in flow reserve in groups of patients with risk factors but no clinical evidence of coronary disease. A relationship with age was observed, characterized by a reduction in flow reserve in older individuals as a result of an increase in resting flow and a less pronounced decrease in hyperemic flow [11,12]. Further studies established positive correlations between impairment of lipid profile and microvascular reactivity [13,14]. Decreased flow reserve in association with increasing total and low-density lipoprotein cholesterol concentrations has been demonstrated in dyslipidemic individuals, whereas high-density lipoprotein cholesterol seems to be associated with greater vascular reactivity in healthy individuals [15].
Initial studies indicated an impaired flow response to dipyridamole during acute smoking in new smokers, but no impairments in chronic smokers [16]. More recent studies in this group of individuals at risk have involved the application of endothelial-dependent cold pressor testing to gain further insight into vascular reacitivity. Again, chronic smokers exhibited no impairment of hyperemic flow in response to pharmacologic vasodilatation, but their response to sympathetic stimulation by cold pressor testing was significantly impaired compared with that of normal individuals [8]. Furthermore, this impaired response to cold was alleviated by application of L-arginine, a precursor of nitric oxide and substrate of nitric oxide synthase [17].
Diabetes mellitus is another cardiovascular risk factor that has been evaluated extensively. Impairments of flow reserve in response to pharmacologic vasodilatation have been demonstrated in insulin-dependent and non-insulin-dependent diabetic individuals early in the course of their disease [1820]. More recently, an impaired response to cold has been identified in one third of a group of asymptomatic patients with mild diabetes controlled by diet [21]. Effects of impaired glucose tolerance, insulin, and the metabolic syndrome on microvascular reactivity are the subject of continuing and recently published studies [22].

Assessment of preventive and therapeutic interventions
On the basis of observations in groups of patients with specific risk factors, several strategies for prevention, risk factor modification, and medical treatment have been evaluated in coronary artery disease, with regard to their effects on myocardial blood flow and vascular reactivity. Using PET, improvements in perfusion have been observed as a consequence of short-term cardiovascular conditioning, low-fat diet, and long-term modification in risk factors [2325]. Beneficial effects of antioxidant vitamins have been observed, especially in smokers [26].
In addition, the effects of specific drugs have been evaluated. Antihypertensive agents and lipid-lowering drugs were shown to improve flow reserve in individuals with mild coronary disease, substantiating their potential in secondary prevention [27,28]. More recently, effects of estrogens have been evaluated, yielding no improvement in vascular response to hyperemia or to cold in women with risk factors, and only mild improvement in endothelium-dependent response to cold in otherwise healthy women [29,30]. The potential of PET to serve as a surrogate marker of drug effectiveness has been increasingly emphasized, and the number and size of clinical trials using PET flow measurements for the evaluation of the effects of drugs is increasing. The greater demand for this imaging procedure will not only increase its recognition, but may also stimulate its evaluation as a feasible diagnostic and prognostic tool in a clinical setting in the future.

Summary and conclusion
Positron emission tomography makes possible noninvasive, quantitative assessment of coronary microvascular reactivity and endothelial function. Studies in individuals with cardiovascular risk factors have demonstrated that abnormalities are present before the development of structural vascular changes. Further studies have also demonstrated that such abnormalities can be reversed by specific therapeutic interventions. Determination of whether such improvements in vasomotion translate into long-term benefits and improved outcome will be important. Nevertheless, imaging of endothelial function will have an increasing role as a surrogate marker of efficacy in clinical trials of preventive and novel pharmacotherapeutic strategies for cardiovascular disease. By targeting the earliest functional alterations that precede morphologic atherosclerotic changes, PET also has the potential to emerge as a future clinical tool for use in individuals at high cardiovascular risk.

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REFERENCES

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