Radionuclide myocardial perfusion imaging plays an important role in detecting coronary artery disease and an even more important one in its management. By depicting the relative distribution of myocardial blood flow at rest and during stress, noninvasive myocardial perfusion imaging characterizes the extent and severity of CAD.
This imaging method has limitations, however. On perfusion images, regional reductions in tracer uptake are compared with other myocardial territories to reflect fluid dynamic consequences of anatomical stenoses. Inherent in these comparisons is the assumption that myocardial regions with the highest tracer uptake are subtended by normal coronary arteries, yet these may themselves be diseased, although less severely than other vessels.
A second limitation of standard myocardial perfusion imaging is that it provides little if any information on abnormal coronary vasomotor function. Since functional abnormalities may affect the coronary circulation homogeneously, they are likely to escape detection by standard myocardial perfusion imaging. Identification of abnormal coronary vasomotion may be important because functional derangements are likely to represent early or preclinical stages of coronary atherosclerosis, as invasive studies have demonstrated.
Functional abnormalities may cause clinical symptoms in some patients, however. Such functional abnormalities can be demonstrated noninvasively by quantitative estimates of myocardial blood flow and by responses of blood flow to specific interventions. Accurate and reproducible measurements of regional myocardial blood flow are available with PET and oxygen-15 water or nitrogen-13 ammonia.1 These measurement approaches have matured to where they can be used in the clinical setting, and have potential value in clarifying clinical symptoms.
CASE REPORT
A 46-year-old white female marathon runner noticed gradually worsening chest tightness progressing to angina-like chest pain while running. The symptoms' severity ultimately kept her from pursuing her athletic activities and began to limit routine daily activities. Her past medical and family history was unremarkable, with no record of premature coronary heart disease or diabetes in the family.
The patient's physical exam proved to be normal. Her heart rate at rest was 45 beats per minute, and the arterial blood pressure was 125/75 mmHg. Serum electrolytes, plasma lipids, and estrogen levels were within normal limits, although plasma norepinephrine levels were mildly elevated. A rest and treadmill exercise ECG was normal, as was a dipyridamole stress and rest single-photon emission computed tomographic (SPECT) myocardial perfusion study performed with thallium-201 (Figure 1). On angiography, the left ventricular (LV) ejection fraction was 67%, and the three major coronary arteries were free of disease and exhibited smooth and regular luminal surfaces. Echocardiography revealed a normally functioning left ventricle with normal wall motion, no evidence of mitral or aortic valvular disease, and normal LV and septal wall thickness.
The patient was then studied with PET using N-13 ammonia to reevaluate the relative distribution of myocardial blood flow and, more important, the responses of myocardial blood flow to cold pressor testing and to standard- dose dipyridamole. Similar to the earlier SPECT perfusion study findings, the relative distribution of myocardial blood flow at rest was normal (Figure 2). Global myocardial blood flow averaged 0.62 mL/min/g, which was consistent with the rate-pressure product of 6425 beats/min/mmHg.1 Following the dipyridamole infusion, myocardial blood flow increased to 2.61 mL/min/g. The myocardial perfusion reserve was thus 4.21 and within normal limits.
For the cold pressor test, the patient immersed her left hand in a slush of ice-cold water. The rate-pressure product increased by 62% to 10,408 beats/min/mmHg1 within 30 seconds, at which time myocardial blood flow was determined again with PET using N-13 ammonia. The rate-pressure product remained elevated for the next 90 seconds and returned to baseline after completion of the cold pressor test. Myocardial blood flow rose to 0.65 mL/min/g, only a 5% increase.
This flow response was abnormal because myocardial blood flow during cold pressor testing normally increases in proportion to cardiac work. The abnormal flow response was attributed to endothelial dysfunction. The patient was subsequently treated with l-arginine orally (3 g three times daily with meals), and she reported gradual relief of the angina-like symptoms and was able to resume long-distance running.
INTERPRETATION
This example poses a number of important pathophysiological questions, and it underscores the importance of coronary vasomotor function and its assessment with quantitative measurements of myocardial blood flow to explain clinical symptoms.
Endothelial dysfunction and, more generally, coronary vasomotor abnormalities are usually associated with well-established coronary risk factors: abnormal plasma lipids, diabetes, smoking, obesity, hypertension, estrogen withdrawal, and age.2-5 None of these risk factors were identified in this particular patient. The cause of the abnormal flow response to cold pressor testing remained uncertain, although the beneficial effect of l-arginine implicated endothelial dysfunction as a possible explanation of the clinical symptoms.
This case highlights the importance of identifying functional abnormalities of the coronary circulation. That endothelial dysfunction can produce marked perfusion abnormalities, especially during exercise stress, has been demonstrated by invasive techniques. Instead of the normal flow-dependent dilation of the epicardial coronary conduit vessels, their diameter may not change or may even lessen.
An increasing body of evidence, based on a series of investigations using noninvasive measurements of myocardial blood flow with PET, in addition to observations made by invasive approaches, emphasizes the importance of severe coronary vasomotor abnormalities in the presence of coronary risk factors.2-14 In most instances, myocardial blood flow will be normal at rest, but hyperemic blood flow in response to dipyridamole or adenosine is consistently attenuated.
Some of these observations have been made in patients with coronary artery disease, in myocardial territories subtended by arteriographically normal or minimally diseased vessels. Other studies report comparable reductions in maximum hyperemic blood flow in young patients with only mild risk factors or in patients with angiographically normal coronary arteries. Most likely, these reductions in hyperemic flow reflect abnormalities in the total integrated coronary vasomotor function, including the function of the vascular smooth muscles and of the endothelium of the large epicardial coronary conduit and the pre-arteriolar resistance vessels.
Along with assessments of the total integrated coronary vasomotor function with direct vascular smooth muscle relaxants, other approaches that target endothelial function are the cold pressor test used in the patient discussed and, to some extent, mental stress.15-17 Young long-term smokers or healthy postmenopausal women, for example, revealed normal hyperemic blood flow in response to direct vascular smooth muscle dilators such as adenosine or dipyridamole, but they showed absent or minimal, and statistically insignificant, flow responses to cold pressor testing.15,18 Intravenous administration of l-arginine as the substrate for nitric oxide synthase in the long-term smokers restored the flow response to normal.16
Similarly, postmenopausal women on long-term hormone replacement therapy demonstrated normal flow response to cold pressor testing, in contrast to similar women not on hormone replacement therapy.18 Besides targeting more specifically endothelial function, pharmacologic treatment (such as HMG-CoA reductase inhibitors)6,19 or cardiovascular conditioning20 markedly improved the total integrated coronary vasomotor function, as shown again with PET-based measurements of myocardial blood flow.
These observations support the potential value of quantitative measurements of myocardial blood flow, now available with PET, for identifying not only anatomic but especially functional disturbances of the coronary circulation. Such functional disturbances may in many patients with coronary risk factors represent an early preclinical stage of coronary atherosclerosis. It thus may become possible to identify the atherosclerotic process at a stage when it is still reversible and amenable to pharmacologic intervention.
Thus, measurements of myocardial blood flow might prove useful for identifying those patients who are at the highest risk for cardiac events and at the same time are likely to benefit most from lifestyle changes and pharmacologic intervention. Such noninvasive measurements of myocardial blood flow also offer an opportunity for monitoring the efficacy of therapeutic interventions. This could be particularly important because endothelial dysfunction may predict future cardiac events. Beyond patient-specific indications, estimates of myocardial blood flow may also prove useful as surrogate endpoints for assessing the efficacy of newly developed pharmacologic agents.6,19
DR. SCHELBERT is a professor of pharmacology and radiological sciences at the University of California, Los Angeles and the Laboratory of Structural Biology and Molecular Medicine.*
*Operated for the U.S. Department of Energy by the University of California under contract #DE-AC03-76-SF00012. This work was supported in part by the Director of the Office of Energy Research, Office of Health and Environmental Research, Washington DC, by research grants HL 33177, National Institutes of Health, Bethesda, MD.
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References
1. Schelbert HR. Principles of positron emission tomography. In: Skorten DJ, Schelbert HR, Wolf GL, Brundage BH, eds. Marcus cardiac imaging. 2nd ed. Philadelphia: W.B. Saunders, 1996:1063-1092.
2. Egashira K, Inou T, Hirooka Y, et al. Evidence of impaired endothelium-dependent coronary vasodilatation in patients with angina pectoris and normal coronary angiograms [see comments]. NEJM 1993;328:1659-1664.
3. Zeiher AM, Drexler H, Wollschlager H, Just H. Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation 1991;83:391-401.
4. Zeiher AM, Drexler H, Wollschlager H, Just H. Endothelial dysfunction of the coronary microvasculature is associated with coronary blood flow regulation in patients with early atherosclerosis. Circulation 1991;84:1984-1992.
5. Zeiher AM, Drexler H, Saurbier B, Just H. Endothelium-mediated coronary blood flow modulation in humans. Effects of age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Invest 1993;92:652-662.
6. Baller D, Notohamiprodjo G, Gleichmann U, et al. Improvement in coronary flow reserve determined by positron emission tomography after 6 months of cholesterol-lowering therapy in patients with early stages of coronary atherosclerosis. Circulation 1999;99:2871-2875.
7. Dayanikli F, Grambow D, Muzik O, et al. Early detection of abnormal coronary flow reserve in asymptomatic men at high risk for coronary artery disease using positron emission tomography. Circulation 1994;90:808-817.
8. Huggins GS, Pasternak RC, Alpert NM, et al. Effects of short-term treatment of hyperlipidemia on coronary vasodilator function and myocardial perfusion in regions having substantial impairment of baseline dilator reserve. Circulation 1998;98:1291-1296.
9. Pitkanen O-P, Nuutila P, Raitakari OT, et al. Coronary reactivity in young men with familial combined hyperlipidaemia. Eur Heart J 1998;19:547 (abstr).
10. Pitkanen O-P, Nuutila P, Raitakari OT, et al. Coronary flow reserve is reduced in young men with IDDM. Diabetes 1998;47:248-254.
11. Pitkanen O-P, Nuutila P, Raitakari OT, et al. Coronary flow reserve in young men with familial combined hyperlipidemia. Circulation 1999;99:1678-1684.
12. Yokoyama I, Murakami T, Ohtake T, et al. Reduced coronary flow reserve in familial hypercholesterolemia. J Nucl Med 1996;37:1937-1942.
13. Yokoyama I, Momomura S, Ohtake T, et al. Reduced myocardial flow reserve in non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 1997;30:1472-1477.
14. Yokoyama I, Ohtake T, Momomura S, et al. Altered myocardial vasodilatation in patients with hypertriglyceridemia in anatomically normal coronary arteries. Arterioscler Thromb Vasc Biol 1998;18:294-299.
15. Campisi R, Czernin J, Schoder H, et al. Effects of long-term smoking on myocardial blood flow, coronary vasomotion, and vasodilator capacity. Circulation 1998;98:119-125.
16. Campisi R, Czernin J, Schoder H, et al. L-Arginine normalizes coronary vasomotion in long-term smokers. Circulation 1999;99:491-497.
17. Di Carli MF, Bianco-Batlles D, Landa ME, Kazmers A, et al. Effects of autonomic neuropathy on coronary blood flow in patients with diabetes mellitus. Circulation 1999;100:813-819.
18. Campisi R, Nathan L, Hernandez PM. Effect of chronic hormone replacement therapy on coronary vasomotion in postmenopausal women. Circulation 1999;110:I 221(abstr).
19. Guethlin M, Kasel AM, Coppenrath K, et al. Delayed response of myocardial flow reserve to lipid-lowering therapy with fluvastatin. Circulation 1998;99:475-481.
20. Czernin J, Barnard RJ, Sun KT, et al. Effect of short-term cardiovascular conditioning and low-fat diet on myocardial blood flow and flow reserve. Circulation 1995;92:197-204.
