Physiology of endothelin in producing myocardial perfusion heterogeneity: a mechanistic study using darusentan and positron emission tomography

Abstract

Background: Heterogeneity of resting perfusion may be due in part to up-regulation of coronary vasoconstriction via endothelin (ET) type A receptors, as homogeneity increases during subsequent vasodilatory hyperemia. Therefore, we conducted a mechanistic study using an ET receptor antagonist to determine if it could alter the homogeneity of myocardial perfusion.

Methods: Included subjects demonstrated a low myocardial perfusion homogeneity index (HI) compared to normal volunteers. Four serial cardiac positron emission tomography Rb-82 scans were performed 2 weeks apart. Before the middle two scans, subjects were randomized to receive either darusentan first then placebo or visa versa. Absolute flow and coronary flow reserve were quantified for each study. Rest flow was adjusted for the pressure-rate product (PRP).

Results: We screened 37 subjects and randomized 20 who satisfied entry criteria. Rest HI increased significantly while taking darusentan (0.39 ± 0.10 vs 0.33 ± 0.04 on placebo, P = .030, compared to a normal range of 0.52 ± 0.10) without an increase in the PRP (6,859 ± 1,503 vs 6,976 ± 1,092, P = .79), leading to a higher adjusted flow at rest (0.69 ± 0.18 cc/minute/g at 7,000 PRP vs 0.59 ± 0.07 with placebo).

Conclusions: Antagonism of the type A ET receptor increases homogeneity of resting myocardial perfusion. The mechanism appears to be increased absolute rest flow without an increase in either the PRP or myocardial perfusion during hyperemia. Our translational results are consistent with one mechanism for the observed heterogeneity of myocardial perfusion in humans.

Figures

Figure 1

Study design. If all entry criteria were met after the baseline PET scan, subjects were randomized to receive either placebo or darusentan first, before crossing over to receive the other treatment. Four sequential PET scans (#1 to #4) were performed after every 2-week interval. Each subject had a baseline, darusentan, and washout PET study. Based on the order determined by randomization, subjects had a PET study to assess either reproducibility or late washout but not both

Figure 2

Enrollment flow diagram. CONSORT flow diagram of study enrollment, allocation, follow-up, and analysis

Figure 3

Paired homogeneity index. Myocardial perfusion homogeneity under resting conditions significantly increased during darusentan treatment compared to baseline (P = .030). Typical values of resting homogeneity from 56 young, asymptomatic “true normal” volunteers come from our prior work. Paired homogeneity index values for all 20 study subjects are shown in addition to summary box plots

Figure 4

Example images. Relative uptake maps of the four LV quadrants are shown for a normal volunteer (top row) from our prior work as well as a notable patient at baseline (middle row) and while taking darusentan (bottom row). The left column shows the raw uptake images while the right column displays them as analyzed for homogeneity (range truncated to 50%-85%, basal four and apical two slices removed) along with the homogeneity index value. Whole LV average rest flow increased from 0.51 cc/minute/g at 7,000 bpm mm Hg at baseline to 0.74 with darusentan