Number 22, 2004
Endothelial Dysfunction

Imaging of endothelial dysfunction

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Paul Knaapen, Willem G. van Dockum
Department of Cardiology, VU University Medical Center, Amsterdam, The Netherlands
Correspondence: Dr P. Knaapen, Department of Cardiology, 6D room 120, VU University Medical Center, De Boelelaan 1117, 1081 HVAmsterdam, The Netherlands
Tel: +31 204442244, fax: +31 204442446, e-mail p.knaapen@vumc.nl

Case report
A 56-year-old woman was referred to our clinic because of typical anginal symptoms and exertional dyspnea. Her general physician had previously diagnosed mild hypertension and hyperlipidemia, for which she was successfully treated with an angiotensin-converting enzyme (ACE) inhibitor and statins. No additional cardiovascular risk factors were present. Her symptoms had started 1 year before her referral and were slowly progressive. On physical examination the pulse was 76 beats/min, and the blood pressure was 145/85mm Hg. The patient was obese (body mass index 33kg/m²). Jugular venous pressure was 3cm H₂0, and heart sounds were normal, without murmurs. Pulmonary and abdominal examinations were normal, and there was no peripheral edema. The electrocardiogram (ECG) (Figure 1) revealed marked abnormalities. In addition to an incomplete right bundle branch block, there was ST-segment depression with concomitant T-wave inversion in leads II, III, aVF, and V_46. Criteria for left or right ventricular hypertrophy were not met. Echocardiography was virtually impossible because of a poor acoustic window. Magnetic resonance imaging (Figure 2), however, demonstrated a normal cardiac function and normal dimensions of the cardiac chambers; hypertrophy and valvular pathology were also ruled out. During exercise stress technetium-99m sestamibi single-photon emission computed tomography (SPECT), the patient had complaints of chest pain and her ECG revealed additional ST-segment depression of 1mm in several leads. Surprisingly, the SPECT images were completely normal, both at rest and during stress. Quantitative perfusion determined by positron emission tomography (PET) using oxygen-15-labeled water, however, showed a relatively high resting perfusion (1.3mL/min per mL) and an impaired hyperemic response to pharmacologically induced vasodilatation (2.4mL/min per mL). Perfusion reserve, therefore, was also impaired (1.8). Interestingly, the impairment in perfusion reserve was evenly distributed throughout the left ventricle, explaining the false negative results of the SPECT images (see Comment section).

Pharmacological treatment was extended with aspirin and a -blocker. Although the patient did respond to medical treatment, she remained symptomatic (New York Heart Association Class II), even after treatment had been further extended with nitrates and a calcium antagonist. Coronary angiography was therefore performed and showed no epicardial stenosis in any of the coronary arteries. Quantitative measurements of coronary flow velocity by intracoronary Doppler guidewire confirmed the PET perfusion data, demonstrating a relatively high basal flow (3035cm/s) and impaired flow reserve (1.82.0) in each of the coronary arteries. These findings are suggestive of increased microvascular resistance. To evaluate whether the impairment of flow reserve indeed caused ischemia in this patient, an exercise stress [¹⁸F]2-fluoro-2-deoxyglucose (FDG) PET scan was performed. Figure 3 shows the image obtained, clearly demonstrating an inhomogeneous distribution pattern of FDG. These results are indicative of myocardial ischemia in the areas of increased FDG uptake. Trimetazidine was added as antiischemic medical treatment. The patient is currently in a stable condition and her symptoms are no longer progressive.

Comment
Endothelial dysfunction is a prognostic factor for future cardiovascular events and is considered to be an early phase of coronary atherosclerosis [1]. Endothelial function has an important role in regulating thrombosis, thrombolysis, platelet, and leukocyte interactions, vascular tone, and coronary blood flow. Nitric oxide metabolism seems to be of particular importance in endothelial function, hence decreased production of nitric oxide characterizes endothelial dysfunction [2]. Early detection of endothelial dysfunction is important, because pharmacological, dietary, and lifestyle modifications can prevent cardiovascular events and revascularization procedures [35]. Several imaging techniques are available to detect endothelial dysfunction, such as coronary arteriography in combination with intracoronary ultrasonography and Doppler guidewire flow measurements, invasive venous occlusion plethysmography, functional magnetic resonance, SPECT, and PET [5]. Obviously, noninvasive imaging is preferred to invasive procedures.
SPECT with a perfusion tracer is noninvasive and widely available, but has an important limitation. As demonstrated in this particular case report, SPECT imaging represents the relative distribution of a tracer and therefore necessitates a normal reference area, leading to false negative results in the event of a diffuse reduction in perfusion. PET has the capability of quantifying perfusion in absolute terms, but is limited by its availability and high cost. Both techniques can also visualize metabolic processes such as glycolysis, using FDG. Endothelial dysfunction can eventually lead to ischemia, which is caused by limited blood supply in relation to demand; perfusion alone cannot truly identify ischemia. In ischemic myocardium, anaerobic glycolysis is increased, which leads to glycogen depletion. In the post-ischemic period, glucose uptake is enhanced in post-ischemic myocardium, in order to restore the glycogen pool [6]. This probably explains the regionally increased uptake of FDG tracer noted in this case report.
Intracoronary Doppler guidewire flow reserve measurements are invasive, but can be performed in the majority of cardiovascular clinical centers. In the absence of an epicardial stenosis, an impaired flow reserve suggests the presence of increased microvascular resistance, which is associated with endothelial dysfunction.
Once the diagnosis of endothelial dysfunction has been made likely, treatment can be initiated that allows restoration of endothelial function. Results of large trials provide evidence for a prognostic benefit from treatment with statins and ACE inhibitors [3,4]. The effects of these pharmacological agents seem to go beyond the reduction of cholesterol concentrations and decreasing blood pressure. Statins, among others, stimulate nitric oxide synthase, have anti-inflammatory effects, and reduce oxidative stress through their antioxidant properties [7]. In the Heart Outcomes Prevention Evaluation trial, the reduction in cardiovascular events with the ACE inhibitor, ramipril, was independent of the reduction in blood pressure [4]. Inhibition of the breakdown of bradykinin, together with antioxidative properties, are the proposed beneficial effects of ACE inhibitors on endothelial function [7]. More studies are needed to elucidate the exact effects of these agents on the endothelium.

Conclusion
Endothelial dysfunction is considered to be an early phase of atherosclerosis. Detection of this disorder is important, as pharmacological treatment can prevent cardiovascular events. A variety of invasive and noninvasive techniques are currently available for the detection of endothelial dysfunction.

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REFERENCES

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