Review Article
Assessment of coronary endothelial function using PET

https://doi.org/10.1007/s12350-011-9370-3Get rights and content

Abstract

Endothelial dysfunction is the earliest abnormality in the development of coronary atherosclerosis. Several coronary risk factors adversely affect endothelial function. Therefore, a finding of endothelial dysfunction may guide interventions for preventing the development of future cardiovascular events. The non-invasive aspects and coronary specificity of measurements of myocardial blood flow (MBF) using positron emission tomography (PET) with sympathetic stress make it widely applicable for the evaluation of endothelial function. PET MBF measurements with sympathetic stress have been applied to a variety of subjects with coronary risk factors and have been shown to have value for risk assessment in these subjects. Endothelial measurement using PET remains an ideal research tool for the study of the pathophysiology of several cardiac diseases. PET is also well suited for the acute and longitudinal evaluation of treatment. Thus, the continued development of this approach for the evaluation of new treatment effects should be expected.

Introduction

Endothelium is a single layer of blood cells. Coronary endothelial cells protect the coronary arteries by providing a mechanical barrier and releasing bioactive factors that control vasodilation, anti-inflammation, anti-hypertrophic, and anticoagulation functions.1 Endothelial dysfunction is the earliest abnormality in the development of coronary atherosclerosis and is also independently associated with future cardiovascular events.2 Therefore, it is important to detect endothelial dysfunction as doing so may guide early interventions toward reducing the risk of future cardiovascular events.

Coronary angiography, ultrasound, biomarkers, and positron emission tomography (PET) are established diagnostic tests for evaluating endothelial function.3 PET can noninvasively measure myocardial blood flow (MBF) and can evaluate coronary endothelial function. Thus, among these measurements, PET has great advantages when compared to other techniques.4,5

Myocardial perfusion PET has been considered the most accurate technique for measuring global and regional MBF.6, 7, 8 Tissue perfusion in milliliters per minute per gram of weight can be measured in vivo by relating myocardial tracer kinetics. 15O-labeled water and 13N-ammonia have most often been employed for MBF quantification to evaluate endothelial function. Recently, generator-produced rubidium-82 (82Rb) has also been employed for this measurement.9 Specific protocols such as pharmacological stress tests, mental stress tests, and cold pressor tests have been proposed for endothelial function measurement. Standard stress protocols should be established.

This review will describe the basic aspects of coronary endothelial function and practical measurements of coronary endothelial function using myocardial perfusion PET. This article will also review the clinical application of coronary endothelial function measurements in subjects with various coronary risk factors.

Section snippets

Endothelial Function: Basic Aspects

Endothelial dysfunction is the earliest abnormality in the development of coronary atherosclerosis. Coronary endothelial cells protect the coronary artery by providing a mechanical barrier and releasing bioactive factors (Figure 1>). Coronary endothelial dysfunction is also independently associated with future cardiac events. Several coronary risk factors adversely affect endothelial function.

Endothelial Function Measurements Using Imaging Techniques

Coronary angiography, ultrasound [flow-mediated vasodilatation (FMD)], biomarkers, and PET are established diagnostic tests (Figure 3; Table 1).12

Quantitative coronary angiography and Doppler flow guide wire measurements during intracoronary administration of acetylcholine are the standard approaches for measurement of coronary endothelial function. Acetylcholine induces endothelium-dependent NO-mediated vasodilation. In the case of endothelial dysfunction, normal vasodilator response is

Myocardial Perfusion Tracers

The commonly used PET blood flow tracers for endothelial function measurements can be divided into (a) inert freely diffusible tracers such as 15O-labeled water and (b) physiologically retained tracers such as 13N-ammonia and rubidium-82. The commonly used PET myocardial blood flow tracers are listed in Table 2.5,6,8,19

15O-labeled water diffuses freely across cell membranes resulting in a distribution of tracer between vascular and extravascular space related to the partition coefficient. This

Stress Test Protocols: Preparation and Practice

As a noninvasive diagnostic test, a stress protocol for PET studies has to be safe and simple. Stress protocols for endothelial function measurements aim to trigger NO synthase from endothelium. PET endothelial measurements do not directly measure NO release but evaluate the MBF increase induced by NO release during stress.

Coronary Artery Disease

The appearance of endothelial dysfunction precedes the development of coronary atherosclerosis, but because sympathetic tests are very stressful, they are not used for preliminary detection of CAD, which can be done more simply using other standard diagnostic tests.

In patients with CAD, MBF response during the mental stress test was lower even in segments without significant epicardial coronary stenosis.40

As was the case in previous studies observed by coronary angiography (CAG), a reduced MBF

New Approach

In most previous studies, PET MBF measurements during CPT have been performed using either 15O-labeled water or 13N-ammonia, which require immediate access to an on-site cyclotron. Thus, it is difficult to evaluate risk assessment or therapeutic interventions in larger populations for which an on-site cyclotron may not generally be available. On the other hand, rubidium-82 (82Rb) is a PET perfusion tracer produced from an 82Sr/ 82Rb generator and is widely used in PET centers without immediate

Summary and Conclusions

The noninvasive aspects and coronary specificity of MBF measurements using PET with sympathetic stress make it widely suitable for the evaluation of endothelial function. Although test protocols still need to be standardized, PET MBF measurements with CPT stress have been applied to a variety of subjects with coronary risk factors and have been shown to have value for risk assessment in these subjects. New approaches including the use of 82Rb PET have been developed. Endothelial measurement

References (70)

  • Pop-BusuiR et al.

    Sympathetic dysfunction in type 1 diabetes: Association with impaired myocardial blood flow reserve and diastolic dysfunction

    J Am Coll Cardiol

    (2004)
  • HilzMJ et al.

    Cold pressor test demonstrates residual sympathetic cardiovascular activation in familial dysautonomia

    J Neurol Sci

    (2002)
  • SchindlerTH et al.

    Positron emission tomography-measured abnormal responses of myocardial blood flow to sympathetic stimulation are associated with the risk of developing cardiovascular events

    J Am Coll Cardiol

    (2005)
  • NayaM et al.

    Olmesartan, but not amlodipine, improves endothelium-dependent coronary dilation in hypertensive patients

    J Am Coll Cardiol

    (2007)
  • CelermajerDS et al.

    Aging is associated with endothelial dysfunction in healthy men years before the age-related decline in women

    J Am Coll Cardiol

    (1994)
  • Di CarliMF et al.

    Role of chronic hyperglycemia in the pathogenesis of coronary microvascular dysfunction in diabetes

    J Am Coll Cardiol

    (2003)
  • SchelbertHR

    Coronary circulatory function abnormalities in insulin resistance: Insights from positron emission tomography

    J Am Coll Cardiol

    (2009)
  • YoshinagaK et al.

    What is the prognostic value of myocardial perfusion imaging using rubidium-82 positron emission tomography?

    J Am Coll Cardiol

    (2006)
  • SchindlerTH et al.

    Relationship between increasing body weight, insulin resistance, inflammation, adipocytokine leptin, and coronary circulatory function

    J Am Coll Cardiol

    (2006)
  • YoshinagaK et al.

    Generator-produced rubidium-82 positron emission tomography myocardial perfusion imaging-from basic aspects to clinical applications

    J Cardiol

    (2010)
  • VermaS et al.

    Fundamentals of endothelial function for the clinical cardiologist

    Circulation

    (2002)
  • LermanA et al.

    Endothelial function: Cardiac events

    Circulation

    (2005)
  • GanzP et al.

    Testing endothelial vasomotor function: Nitric oxide, a multipotent molecule

    Circulation

    (2003)
  • YoshinagaK et al.

    Application of cardiac molecular imaging using positron emission tomography in evaluation of drug and therapeutics for cardiovascular disorders

    Curr Pharm Des

    (2005)
  • CamiciPG et al.

    Coronary microvascular dysfunction

    N Engl J Med

    (2007)
  • Yoshinaga K, Tamaki N, Ruddy T, DeKemp RA, Beanlands R. Evaluation of myocardial perfusion. In: Wahl R, editors....
  • YoshinagaK et al.

    Quantitative analysis of coronary endothelial function with generator-produced 82rb pet: Comparison with 15o-labelled water pet

    Eur J Nucl Med Mol Imaging

    (2010)
  • MoncadaS

    Nitric oxide: Discovery and impact on clinical medicine

    J R Soc Med

    (1999)
  • KellyJJ et al.

    Endothelin-1 as a mediator in cardiovascular disease

    Clin Exp Pharmacol Physiol

    (1999)
  • DeanfieldJE et al.

    Endothelial function and dysfunction: Testing and clinical relevance

    Circulation

    (2007)
  • PijlsNH et al.

    Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses

    N Engl J Med

    (1996)
  • CelermajerDS

    Reliable endothelial function testing: At our fingertips?

    Circulation

    (2008)
  • GokceN et al.

    Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease

    Circulation

    (1999)
  • LanzaGA et al.

    Primary coronary microvascular dysfunction: Clinical presentation, pathophysiology, and management

    Circulation

    (2010)
  • VermaS et al.

    Endothelial function testing as a biomarker of vascular disease

    Circulation

    (2003)
  • Cited by (0)

    The authors’ work presented in this article was supported in part by a grant from the Adult Vascular Disease Foundation (#H-20) (Kyoto, Japan).

    View full text