Journal of the American College of Cardiology
2008 by the American College of Cardiology Foundation
Interaction of Caffeine WithRegadenoson-Induced Hyperemic Myocardial BloodFlow as Measured by Positron Emission TomographyA Randomized, Double-Blind, Placebo-Controlled Crossover Trial
To the Editor: Regadenoson is a selective A2A adenosine receptor
was comparable with and without caffeine (2.75 Ϯ 0.16 vs. 2.97 Ϯ
agonist under investigation as a pharmacologic vasodilator in
0.16, p ϭ NS) The data show with 1-sided 95%
nuclear stress myocardial perfusion imaging (MPI) It has a
confidence that any CFR reduction associated with caffeine intake
higher affinity for A2A receptors than adenosine and is a more
potent coronary vasodilator. It selectively dilates coronary relative
Heart rate (HR) Ϯ SD during resting MBF was higher after
to peripheral vascular beds, potentially due to the high density of
caffeine as compared with placebo (65 Ϯ 11 beats/min vs. 61 Ϯ 9
coronary A2A receptors, and activation of a small percentage of
beats/min, p Ͻ 0.05). Similarly, systolic (118 Ϯ 11 mm Hg vs. 112 Ϯ
these receptors evokes maximal dilation The use of caffeine, a
10 mm Hg, p Ͻ 0.001) and diastolic (73 Ϯ 6 mm Hg vs. 70 Ϯ 7
nonselective competitive A2A receptor antagonist, has been con-
mm Hg, p Ͻ 0.001) blood pressure were higher after caffeine
traindicated before vasodilator MPI because it attenuates the
versus placebo. The HR increase induced by regadenoson was
coronary hyperemia caused by the nonselective adenosine receptor
blunted by 20 beats/min (p Ͻ 0.001) after caffeine, whereas blood
agonists adenosine and dipyridamole in a dose-dependent manner
pressure was not significantly affected by prior caffeine ingestion.
The objective of this study was to determine the effects of
No serious adverse event was reported. The most frequent
caffeine on regadenoson-induced hyperemic myocardial blood flow
adverse events were dyspnea (56%), palpitations (49%), flushing
(30%), headache (28%), sensation of heaviness (28%), and pares-
In this phase II, double-blind, randomized, placebo-controlled
thesia (19%). Caffeine pretreatment did not change the incidence
crossover study, 41 healthy volunteers (15 female) who were age 18
of adverse events but was associated with improved tolerability (as
years or older, nonsmokers, and regular coffee drinkers received in
assessed by a questionnaire) and attenuation of adverse event
a blinded fashion either a 200-mg caffeine capsule—a dose
corresponding to 2 cups of coffee on Day 1 and placebo on
Previous studies found a dose-dependent attenuation of
Day 2 or the inverse after refraining from methylxanthine-
adenosine-induced and dipyridamole-induced CFR by caffeine
containing products for at least 24 h.
The present study is the first to report the effect of caffeine on
The MBF was measured 2 h after capsule ingestion by positron
coronary hyperemia induced by a selective adenosine agonist in
emission tomography (PET) with 15O-labeled water at rest and
humans. It suggests that regadenoson-induced CFR was not
immediately after intravenous administration of regadenoson
significantly affected by prior caffeine ingestion (200 mg) and
(400 g over 10 s). Quantitative values of global MBF in
remained above 2.0 for the majority of subjects. Therefore, it seems
milliliters per minute per gram were obtained as reported Coronary flow reserve (CFR) was calculated as the ratio of
that caffeine blunts the vasodilatory effect of adenosine but has a
limited effect on regadenoson. This may be explained by the fact
Continuous variables summarized as mean and SD or SE were
that regadenoson has a higher A2A receptor affinity and
compared using analysis of variance. A value of p Ͻ 0.05 was
higher receptor reserve compared with adenosine, and is
administered as a bolus (as opposed to a 6-min infusion for
Twenty-one volunteers in the placebo/caffeine sequence and 20
adenosine). Therefore, regadenoson may lead to a higher A2A
in the caffeine/placebo sequence completed the study. All subjects
receptor occupancy and vasodilator effect compared with adenosine.
(mean age Ϯ SD 27 Ϯ 6 years) returned for the second study day
Regadenoson increases MBF by acting on coronary A2A recep-
after a washout period (2 to 14 days). Baseline caffeine levels Ϯ SE
tors, and it increases HR by acting on both chemosensory neurons
were comparable on the 2 study days (0.36 Ϯ 0.09 mg/l vs. 0.23 Ϯ
and peripheral vascular A2A receptors. There is a higher receptor
0.09 mg/l) and increased significantly after caffeine, but not after
reserve for coronary A2A agonist-mediated coronary vasodilation,
placebo (4.26 Ϯ 0.18 mg/l vs. 0.33 Ϯ 0.18 mg/l).
and 25% occupancy by regadenoson translates into 90% maximal
All resting and hyperemic MBF as well as CFR values were
vasodilation. The receptor reserve for regadenoson on peripheral
comparable irrespective of the sequence (caffeine/placebo or pla-
A2A receptors and chemosensory neurons, however, is unknown
cebo/caffeine) or period (Day 1 or 2). Thus, all data were pooled
and may be lower. If the effects of caffeine are inversely propor-
for comparison. The MBF Ϯ SE was not significantly different
tional to the receptor reserve, then the higher receptor reserve
between caffeine and placebo at rest (1.13 Ϯ 0.04 ml/min/g vs.
required to dilate coronary vessels than to increase HR may explain
1.06 Ϯ 0.05 ml/min/g) and stress (2.98 Ϯ 0.14 ml/min/g vs. 3.05 Ϯ
that caffeine significantly blunted the increase in HR but had a
0.14 ml/min/g). Consequently, the regadenoson-induced CFR
limited effect on MBF caused by regadenoson.
MBF Increased Significantly After Regadenoson
(A) Myocardial blood flow (MBF) at rest and after regadenoson; (B) regadenoson-induced coronary flow
reserve (CFR). Caffeine had no influence on resting or hyperemic MBF. Coronary flow reserve was not affected by caffeine.
Overall, regadenoson was well tolerated; side effects were generally
mild or moderate in severity and all self-limiting. Caffeine attenuated
1. Hendel RC, Bateman TM, Cerqueira MD, et al. Initial clinical
the severity of side effects and improved tolerability of regadenoson.
experience with regadenoson, a novel selective A2A agonist for phar-
The interaction of caffeine with adenosine-induced, dipyridamole-
macologic stress single-photon emission computed tomography myo-
induced, and even exercise-induced MBF changes may limit the
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correct detection of coronary artery disease and subsequently the proper
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withhold caffeine for 24 h before vasodilator stress testing Because the
for the clinical use of cardiac radionuclide imaging— executive sum-
hyperemic MBF response to regadenoson after caffeine administration
mary: a report of the American College of Cardiology/American Heart
lies well within the range of reported response to nonselective adenosine
Association Task Force on Practice Guidelines (ACC/AHA/ASNC
receptor agonists and bicycle stress the present study suggests that
Committee to Revise the 1995 Guidelines for the Clinical Use of
regadenoson causes coronary hyperemia with and without prior caffeine
Cardiac Radionuclide Imaging). J Am Coll Cardiol 2003;42:1318 –33.
ingestion in healthy volunteers and moderate caffeine consumption may
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caffeine on vasodilator stress perfusion studies. J Nucl Cardiol 2004;11:
not interfere with regadenoson stress MPI. Further study in patients with
coronary artery disease and possibly at higher caffeine doses would be
5. Bangalore S, Parkar S, Messerli FH. “One” cup of coffee and nuclear
required before definitive conclusions could be drawn
SPECT to go. J Am Coll Cardiol 2007;49:528 –9.
6. Namdar M, Koepfli P, Grathwohl R, et al. Caffeine decreases exercise-
induced myocardial flow reserve. J Am Coll Cardiol 2006;47:405–10. Oliver Gaemperli, MD
7. Eggbrecht H, Gossl M. Regadenoson (CV Therapeutics/Astellas). Tiziano Schepis, MD
Curr Opin Investig Drugs 2006;7:264 –71. Pascal Koepfli, MD
8. Zoghbi GJ, Htay T, Aqel R, Blackmon L, Heo J, Iskandrian AE. Effect
of caffeine on ischemia detection by adenosine single-photon emission
Patrick T. Siegrist, MD
computed tomography perfusion imaging. J Am Coll Cardiol
Samuel Fleischman, MD Patricia Nguyen, MD Ann Olmsted, PhD Whedy Wang, PhD Hsiao Lieu, MD *Philipp A. Kaufmann, MD
*Cardiovascular CenterNuclear CardiologyUniversity Hospital NUK C 32
Zurich Center for Integrative Human PhysiologyRamistrasse 100
In a clinical trial aiming to evaluate the safety and effectiveness
of drug-eluting stents in comparison with bare-metal stents
(BMS) in acute myocardial infarction (AMI), the description of
the end points should be clear and identical. As an importantcomposite clinical end point, major adverse cardiac events
(MACE) was given 3 possible full names without any definition
Please note: this study was supported by CV Therapeutics (Palo Alto, California) and
by Menichelli et al. in the SESAMI (Sirolimus-Eluting
Astellas Pharma US (Deerfield, Illinois) and by a grant from the Swiss NationalScience Foundation (SNSF Professorship Grant No. PP00A-68835 and PP00A-
Stent Versus Bare-Metal Stent in Acute Myocardial Infarction)
trial, which could cause confusion. In the Methods section,
Informative Article Lactic Acidosis In Critically Ill Patients Shafali Nandwani, *Mahip Saluja, **Mayank Vats ,**Yatin Mehta Department of Medicine, * Department of Pulmonary Medicine, Subharti Medical College, Meerut-250002, **Department of Pulmonary and Critical Care, Indraprastha Apollo Hospital, New Delhi-110044 Abstract: Lactic acidosis is defined as increase in blood lactate level
Terminating F100K ECL Inputs Introduction cuit. The designer should be aware that although Figure2A, Figure 2B, and Figure 2C supply ECL compatible sig- ing F100K ECL Many F100K designs require that certain inputs be pre-nals levels, they differ in power consumption and suscepti-sented with a HIGH or LOW level. Because of the con-bility to changes in temperature and VEE. structio