Nitrates and viability: a durable affair.

The relationship between nitrate administration and viability detection dates back many years. Already in the 1970s, various groups had demonstrated that an improvement in regional left ventricular function produced by the acute administration of nitrates was related to a subsequent favorable response after coronary bypass surgery (1,2). In particular, Helfant et al. (1) showed that 15 of 18 asynergic segments with improvement after sublingual nitroglycerin had a similar improvement after bypass grafting, whereas the 2 segments with persistent dysfunction after nitroglycerin were unchanged even after bypass surgery. Similarly, Chesebro et al. (2) observed a good correlation between the changes in wall thickening produced by sublingual nitroglycerin and those registered several months after bypass surgery. Giving a histologic substrate to these clinical observations, Bodenheimer et al. (3) detected a lower degree of fibrosis in the nitrate-responsive segments than in the other asynergic segments. To explain these data, various mechanisms of action were suggested. Certainly, nitrates positively affect the relationship between myocardial oxygen supply and demand, mainly through the reduction in preload and afterload of the ventricles (4). However, it was also suggested that at least part of this effect was caused by a direct action on coronary circulation, either by vasodilatation of stenoses or by redistribution of flow to the ischemic areas, particularly through collateral vessels (5,6). The role of collateral circulation was confirmed in animal experiments by Hisano et al., who demonstrated that the improvement in regional function under isosorbide dinitrate was related to the degree of development of collaterals (7). In humans, Fujita et al. (8) observed that in patients in whom the territory of a completely occluded left ventricular descending artery was supplied by a good collateral circulation, both global and regional function improved significantly after sublingual nitroglycerin, whereas no change was registered in the remaining patients with occlusion but without collaterals. In all the above studies, attention was given mainly to the functional changes induced by nitrate administration. However, in good agreement with the hypothesis of a direct action on coronary collateral circulation, Aoki et al. demonstrated that in collateral-dependent noninfarcted myocardium the acute administration of nitroglycerin reduced the extent and severity of the 201Tl myocardial perfusion defect induced by exercise (9). In the second half of the 1980s, the concept of hibernating myocardium, that is, chronic regional asynergia of ischemic origin with reversible dysfunction after successful revascularization, was introduced and deeply modified the diagnostic approach to heart failure in patients with coronary artery disease (10). Perfusion/metabolism imaging with PET emerged as the most accurate test to detect viable hibernating myocardium and was found to be more reliable than stress-redistribution 201Tl myocardial perfusion scintigraphy (11). To overcome the limitations of stress-redistribution scans and because of the need to evaluate large numbers of patients, modifications of the standard 201Tl imaging protocol were proposed. Delayed redistribution (12), rest-reinjection (13), and rest-redistribution (14) were tested and had good results for viability detection. The possibility of using the acute effects of nitrate on coronary blood flow to improve the detection of viable hibernating myocardium was examined for the first time by He et al., who demonstrated the increase in 201Tl defect reversibility if the tracer was reinjected after isosorbide dinitrate administration (15). However, because all of the various protocols proposed for viability detection were effective, nitrate-enhanced imaging was not considered essential if 201Tl was chosen as the perfusion agent. In the case of 99mTc-labeled perfusion tracers, several early reports suggested an underestimation of myocardial viability in the standard resting images obtained using these agents (16,17). The imaging protocol modifications used for 201Tl imaging were hardly feasible with the 99mTc-labeled perfusion tracers, although resting 99mTc-sestamibi quantitative SPECT (18) and redistribution images (19) were reported to achieve quite good results. In contrast, the experimental data clearly showed that all 99mTc-labeled agents available for clinical use (99mTc-sestamibi, 99mTc-teboroxime, and 99mTc-tetrofosmin) were not just pure flow tracers but also required myocyte viability to be retained within the myocardium (20–22). Therefore, the use of nitrate enhancement appeared an attractive approach to improve their ability to recognize viable myocardium. Bisi et al. observed that stress defect reversibility in resting 99mTc-teboroxime images was greater after nitrate enhancement, with a closer agreement to 201Tl reinjection data (23). In patients with previous myocardial infarction, Galli et al. found a sizable decrease in resting 99mTc-sestamibi uptake defects after nitroglycerin administration in 20 of 36 subjects and correlated it with indexes of likely preserved viability (24). Finally, Bisi et al., using 99mTcsestamibi SPECT, demonstrated for the first time a direct relationship beReceived Jan. 7, 2003; revision accepted Jan. 20, 2003. For correspondence or reprints contact: Roberto Sciagrà, MD, Nuclear Medicine Unit, Department of Clinical Physiopathology, University of Florence, Viale Morgagni 85, 50134 Florence, Italy. E-mail: r.sciagra@dfc.unifi. it