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- Henry Gewirtz, MD⁎ ()
The editorial by Strauss and Schoder (1) indicates that all useful myocardial perfusion tracers, regardless of chemical structure, mechanism of uptake, and retention, follow the Sapirstein principle, even when, save perhaps for 15O-water, they actually fail to conform to the essential requirement postulated by Sapirstein (2) for such a tracer; namely, first-pass extraction fraction of 1. The editorial goes on to state that such tracers “… still provide accurate measurements of regional and absolute [emphasis added] perfusion and perfusion reserve if imaging is performed before significant loss of indicator from the tissue” (1). We performed an additional analysis of the data pertinent to the relationship between 4-[18F]-Tetraphenylphosphonium (18F-TPP) measurement of absolute myocardial blood flow (MBF) and corresponding microsphere measurements of absolute MBF under conditions of adenosine stimulation with phenylephrine support (Fig. 1) to further address the issue raised by Strauss and Schoder (1) in their editorial.
In brief, we used all the ex vivo tissue samples (n = 112) from all the animals (n = 6) reported in our study (3). Each myocardial sample had a microsphere measurement of absolute MBF and a well counter determined measure of 18F-TPP concentration. We modified slightly the method of Di Rocco et al. (4) to compute absolute MBF by 18F-TPP and plotted the value (MBFapparent) versus microsphere MBF in the same tissue sample (see Fig. 1A, shown in more detail in Fig. 1B; data for MBF ≤2 ml/min/g). It is evident there is no correlation between absolute values of MBF determined by 18F-TPP and radiolabeled microspheres, notwithstanding the left ventricular blood and myocardial time activity curves shown in Figure 4 of Gurm et al. (3).
Further, once true MBF exceeds 1.5 to 2.0 ml/min/g, values of absolute MBF by 18F-TPP demonstrate an essentially flat line very far below the line of identity for true MBF (i.e., grossly and uniformly underestimate true MBF). Unsurprisingly, the line looks very much like that for sestamibi shown in Figure 1 of Di Rocco et al. (4), only lower in terms of absolute, and essentially constant, value along the ordinate. Thus, like sestamibi, 18F-TPP appears to be useful for determination of relative (Fig. 3A, Fig. 6 of Gurm et al. ) but not absolute MBF (Figure 3B of Gurm et al. ).
Finally, Figure 1C shows that extraction fraction (ExtFx) for 18F-TPP, computed per Di Rocco et al. (4), exhibits relatively rapid decline between MBF 0 to 2 ml/min/g (0.4 to ∼0.2) with slow progressive decline thereafter as MBF increases to as much as 17 ml/min/g (ExtFx ∼0.002). Accordingly, low and ever-declining (albeit slowly) ExtFx as MBF increases from 2 to 17 ml/min/g offers a very plausible explanation for the data shown in Figure 1A here and Figure 3B of Gurm et al. (3).
The reasons for low myocardial 18F-TPP extraction fraction, similar, although less than that of sestamibi, likely are multifactorial and, we agree, require additional study. However, flow dependence, common to all less-than-perfect Sapirstein flow tracers and physicochemical properties of the molecule, including its positive charge, likely play important roles. It should be recalled that the positive charge would be expected to cause 18F-TPP (and sestamibi) to be repelled by the myocyte cell membrane (lipophilic nature notwithstanding) during systole when the membrane is depolarized and the net charge across it is positive, an effect that will increase with increasing heart rate (more time in systole) and also with coronary stenosis severity, as phasic flow reversal occurs with increasing fraction of all flow occurring in systole as stenosis severity increases (5). Finally, both the cytoplasmic and mitochondrial membrane potentials, which may be dissociated from MBF by a variety of interventions, are very likely to play a role and, we agree, certainly merit further investigation.
Please note: Dr. Gewirtz has received a research grant from FluoroPharma, Inc., and Wild Family Foundation.
- American College of Cardiology Foundation
- Strauss H.W.,
- Schoder H.
- Sapirstein L.A.
- Di Rocco R.J.,
- Rumsey W.L.,
- Kuczynski B.L.,
- et al.