Dipyridamole-induced Vasodilation Research Articles

Women with coronary microvascular dysfunction and no obstructive coronary artery disease have reduced exercise capacity

BackgroundBoth coronary microvascular dysfunction (CMD) and reduced exercise capacity are associated with adverse cardiovascular prognosis. The association between CMD and cardiopulmonary exercise testing (CPET) derived exercise capacity in symptomatic individuals without obstructive coronary artery disease (CAD) is not clear. We investigated whether exercise capacity was reduced in women with angina, CMD and no obstructive CAD compared with sex-matched controls. Furthermore, we assessed the association between CMD and other CPET-derived variables. MethodsAll participants underwent transthoracic Doppler echocardiography of the left anterior descending artery with dipyridamole-induced vasodilation and CPET using ergometer cycle with an incremental test protocol. ResultsWe included 99 women with angina and no obstructive CAD (patients) and 27 asymptomatic women (controls), age (mean ± standard deviation) 61 ± 10 and 58 ± 10 years, respectively. Patients had a higher burden of risk factors compared with controls, while the weekly physical activity level was comparable between the groups (p = 0.72). CMD was present in 27 (27%) patients and 5 (19%) controls. Peak VO2 was significantly reduced in patients with CMD compared with controls with normal coronary microvascular function ((median (IQR) 17.3 (15.5–21.3) vs. 27.3 (21.6–30.8) ml/kg/min; age-adjusted p = 0.001), independent of cardiovascular risk factors (p = 0.041). Presence of CMD in symptomatic women was also associated with diminished heart rate reserve (p < 0.001) and blunted heart rate recovery. ConclusionsWomen with angina, CMD and no obstructive CAD have markedly reduced exercise capacity compared with sex-matched controls. Moreover, combination of angina and CMD is associated with impaired heart rate response and heart rate recovery.

The effect of eplerenone on adenosine formation in humans in vivo: a double-blinded randomised controlled study.

BackgroundIt has been suggested that mineralocorticoid receptor antagonists have direct cardioprotective properties, because these drugs reduce mortality in patients with heart failure. In murine models of myocardial infarction, mineralocorticoid receptor antagonists reduce infarct size. Using gene deletion and pharmacological approaches, it has been shown that extracellular formation of the endogenous nucleoside adenosine is crucial for this protective effect. We now aim to translate this finding to humans, by investigating the effects of the selective mineralocorticoid receptor antagonist eplerenone on the vasodilator effect of the adenosine uptake inhibitor dipyridamole, which is a well-validated surrogate marker for extracellular adenosine formation.Methods and ResultsIn a randomised, double-blinded, placebo-controlled, cross-over study we measured the forearm blood flow response to the intrabrachial administration of dipyridamole in 14 healthy male subjects before and after treatment with placebo or eplerenone (50 mg bid for 8 days). The forearm blood flow during administration of dipyridamole (10, 30 and 100 µg·min−1·dl−1) was 1.63 (0.60), 2.13 (1.51) and 2.71 (1.32) ml·dl−1·min−1 during placebo use, versus 2.00 (1.45), 2.68 (1.87) and 3.22 (1.94) ml·dl−1·min−1 during eplerenone treatment (median (interquartile range); P = 0.51). Concomitant administration of the adenosine receptor antagonist caffeine attenuated dipyridamole-induced vasodilation to a similar extent in both groups. The forearm blood flow response to forearm ischemia, as a stimulus for increased formation of adenosine, was similar during both conditions.ConclusionIn a dosage of 50 mg bid, eplerenone does not augment extracellular adenosine formation in healthy human subjects. Therefore, it is unlikely that an increased extracellular adenosine formation contributes to the cardioprotective effect of mineralocorticoid receptor antagonists.Trial RegistrationClinicalTrials.gov, NCT01837108

Roles of myocardial blood volume and flow in coronary artery disease: an experimental MRI study at rest and during hyperemia

To validate fast perfusion mapping techniques in a setting of coronary artery stenosis, and to further assess the relationship of absolute myocardial blood volume (MBV) and blood flow (MBF) to global myocardial oxygen demand. A group of 27 mongrel dogs were divided into 10 controls and 17 with acute coronary stenosis. On 1.5-T MRI, first-pass perfusion imaging with a bolus injection of a blood-pool contrast agent was performed to determine myocardial perfusion both at rest and during either dipyridamole-induced vasodilation or dobutamine-induced stress. Regional values of MBF and MBV were quantified by using a fast mapping technique. Color microspheres and (99m)Tc-labeled red blood cells were injected to obtain respective gold standards. Microsphere-measured MBF and (99m)Tc-measured MBV reference values correlated well with the MR results. Given the same changes in MBF, changes in MBV are twofold greater with dobutamine than with dipyridamole. Under dobutamine stress, MBV shows better association with total myocardial oxygen demand than MBF. Coronary stenosis progressively reduced this association in the presence of increased stenosis severity. MR first-pass perfusion can rapidly estimate regional MBF and MBV. Absolute quantification of MBV may add additional information on stenosis severity and myocardial viability compared with standard qualitative clinical evaluations of myocardial perfusion.

Rosuvastatin Increases Extracellular Adenosine Formation in Humans In Vivo

Statins may increase extracellular adenosine formation from adenosine monophosphate by enhancing ecto-5'-nucleotidase activity. This theory was tested in humans using dipyridamole-induced vasodilation as a read-out for local adenosine formation. Dipyridamole inhibits the transport of extracellular adenosine into the cytosol resulting in increased extracellular adenosine and subsequent vasodilation. In addition, we studied the effect of statin therapy in a forearm model of ischemia-reperfusion injury. Volunteers randomly received rosuvastatin or placebo in a double-blind parallel design (n=21). The forearm vasodilator response to intraarterial dipyridamole was determined in the absence and presence of the adenosine antagonist caffeine. During a separate visit the vasodilator response to nitroprusside and adenosine was established. In addition, healthy men were randomly divided in 3 groups to receive either placebo (n=10), rosuvastatin (n=22), or rosuvastatin combined with intravenous caffeine (n=12). Subsequently, volunteers performed forearm ischemic exercise. At reperfusion, Tc-99m-labeled annexin A5 was infused intravenously and scintigraphic images were acquired, providing an early marker of cell injury. Rosuvastatin treatment significantly increased the vasodilator response to dipyridamole, which was prevented by caffeine. Rosuvastatin did not influence the response to either sodium nitroprusside or adenosine indicating a specific interaction between rosuvastatin and dipyridamole, which does not result from an effect of rosuvastatin on adenosine clearance nor adenosine-receptor affinity or efficacy. Rosuvastatin increased tolerance to ischemia-reperfusion injury, which was attenuated by caffeine. Rosuvastatin increases extracellular adenosine formation, which provides protection against ischemia-reperfusion injury in humans in vivo. Therefore, statins and dipyridamole may interact synergistically.

Rosuvastatin increases extracellular adenosine in humans in vivo: A New perspective on cardiovascular protection

Objective—Statins may increase extracellular adenosine formation from adenosine monophosphate by enhancing ecto-5 -nucleotidase activity. This theory was tested in humans using dipyridamole-induced vasodilation as a read-out for local adenosine formation. Dipyridamole inhibits the transport of extracellular adenosine into the cytosol resulting in increased extracellular adenosine and subsequent vasodilation. In addition, we studied the effect of statin therapy in a forearm model of ischemia-reperfusion injury. Methods and Results—Volunteers randomly received rosuvastatin or placebo in a double-blind parallel design (n 21). The forearm vasodilator response to intraarterial dipyridamole was determined in the absence and presence of the adenosine antagonist caffeine. During a separate visit the vasodilator response to nitroprusside and adenosine was established. In addition, healthy men were randomly divided in 3 groups to receive either placebo (n 10), rosuvastatin (n 22), or rosuvastatin combined with intravenous caffeine (n 12). Subsequently, volunteers performed forearm ischemic exercise. At reperfusion, Tc-99m–labeled annexin A5 was infused intravenously and scintigraphic images were acquired, providing an early marker of cell injury. Rosuvastatin treatment significantly increased the vasodilator response to dipyridamole, which was prevented by caffeine. Rosuvastatin did not influence the response to either sodium nitroprusside or adenosine indicating a specific interaction between rosuvastatin and dipyridamole, which does not result from an effect of rosuvastatin on adenosine clearance nor adenosine-receptor affinity or efficacy. Rosuvastatin increased tolerance to ischemia-reperfusion injury, which was attenuated by caffeine. Conclusions—Rosuvastatin increases extracellular adenosine formation, which provides protection against ischemiareperfusion injury in humans in vivo. Therefore, statins and dipyridamole may interact synergistically. (Arterioscler Thromb Vasc Biol. 2009;29:963-968.)

Fast mapping of myocardial blood flow with MR first‐pass perfusion imaging

Accurate and fast quantification of myocardial blood flow (MBF) with MR first-pass perfusion imaging techniques on a pixel-by-pixel basis remains difficult due to relatively long calculation times and noise-sensitive algorithms. In this study, Zierler's central volume principle was used to develop an algorithm for the calculation of MBF with few assumptions on the shapes of residue curves. Simulation was performed to evaluate the accuracy of this algorithm in the determination of MBF. To examine our algorithm in vivo, studies were performed in nine normal dogs. Two first-pass perfusion imaging sessions were performed with the administration of the intravascular contrast agent Gadomer at rest and during dipyridamole-induced vasodilation. Radiolabeled microspheres were injected to measure MBF at the same time. MBF measurements in dogs using MR methods correlated well with the microsphere measurements (R2=0.96, slope=0.9), demonstrating a fair accuracy in the perfusion measurements at rest and during the vasodilation stress. In addition to its accuracy, this method can also be optimized to run relatively fast, providing potential for fast and accurate myocardial perfusion mapping in a clinical setting.

Improvement of quantification of myocardial first‐pass perfusion mapping: A temporal and spatial wavelet denoising method

Mapping of myocardial blood flow (MBF) with first-pass perfusion imaging is becoming an important tool in the study of coronary artery disease. In this study a wavelet-based denoising method was developed to improve the accuracy of pixel-by-pixel MBF maps. We performed an in vivo study in five stenotic dogs with 70% stenosis in the left coronary arteries. First-pass perfusion imaging sessions were performed by administering the intravascular contrast agent Gadomer at rest and during dipyridamole-induced vasodilation. Color microspheres (MS) were injected into the dogs to measure MBF at the same time. After denoising was performed, the signal-to-noise ratio (SNR) of the first-pass perfusion image improved by approximately 180%, whereas spatial variation of MBF maps decreased 38%. It was also found that the correlation of MBFs measured by MRI with the MS method indicates a significant improvement with the denoising method (R2 increased from 0.24 to 0.78, P < .001). This suggests that the wavelet denoising method may be an effective way to increase the accuracy of pixel-by-pixel MBF quantification and reduce spatial variation, and may be applicable to other forms of noise-sensitive image analysis.

Dynamic estimation of the myocardial oxygen extraction ratio during dipyridamole stress by MRI: a preliminary study in canines.

The myocardial oxygen extraction fraction (OEF) reflects the balance between myocardial oxygen supply and demand. The feasibility of quantifying myocardial OEF was demonstrated with MRI during pharmacologic vasodilation in dogs. Dipyridamole was infused intravenously to increase blood flow and change in myocardial oxygen content. Arterial and coronary sinus blood sampling was performed during dipyridamole-induced vasodilation to measure the myocardial blood oxygen content. Myocardial T(2) was measured dynamically during the vasodilation, and quantified with a simplified diffusion model as a function of myocardial OEF and blood volume. The results showed a strong correlation (R(2) = 0.89) between myocardial OEF values measured by MRI and those measured by blood sampling. Regional differences in the OEF were demonstrated by direct infusion of dipyridamole into coronary arteries in dogs. Combined with vasodilator stress, dynamic assessments of the OEF may provide a putative measurement of myocardial flow reserve and allow consecutive monitoring of myocardial dose and response.

Doppler monitoring of the vascular resistance in the lower limbs during dipyridamole test in preparation for myocardial tomoscintigraphy

Objective: the aim of this work was to quantify the intensity of the vasodilation induced by dipyridamole used to simulate a stress test during a myocardial tomoscintigraphy. Methods: Doppler measurements of the femoral artery and the thoracic aorta were made on 26 patients (11 men, 15 women), using transducers attached to the skin, measurements being performed every 2 min during the 10 min of the stress test. The following parameters were measured: (a) the vascular resistance index of the lower limbs defined as R fa= D/ S with S and D, respectively, the maximum amplitude of the systolic wave and the maximum amplitude of the diastolic reflux measured on the Doppler femoral spectrogram; (b) the aortic and femoral blood flows obtained from the mean velocity on the Doppler spectrogram. Results: 14 of the 26 patients (54%) showed a significant vasodilation (i.e. a decrease of R fa of more than 10%). Eighty-seven percent of the patients with a positive myocardial scintigraphy showed a vasodilation. Sixty-six percent of patients who had prior vasodilator treatment showed no vasodilation. A slight decrease in blood pressure was observed for vasodilated patients but also for non-vasodilated patients. The aortic flow increased slightly for all patients. Conclusions: Doppler monitoring of femoral vascular resistance is a useful method for quantifying the dipyridamole-induced vasodilation, and hence the stress level upon which the diagnostic efficiency of myocardial scintigraphy is depending. Our study demonstrates that testing with dipyridamole was inconclusive in 66% of patients who had already vasodilator treatment.

Noninvasive Functional Assessment of Left Internal Mammary Artery Grafts by Transcutaneous Doppler Echocardiography

A noninvasive method to assess left internal mammary artery (LIMA) patency and function would be useful because this vessel is frequently used for revascularization of the left anterior descending coronary artery. The purpose of this study was to assess the feasibility of measuring changes in LIMA velocities by transcutaneous Doppler during dipyridamole-induced vasodilation. Twenty-five patients with a LIMA graft anastomosed to the left anterior descending coronary artery were studied at least 1 month after surgery by the use of a 5 MHz transducer placed in the left supraclavicular fossa. Doppler velocity parameters were measured at baseline and after intravenous administration of dipyridamole. Dipyridamole increased mean velocity by 127% ± 54% ( p < 0.001), systolodiastolic velocity time integral by 89% ± 31% ( p < 0.001), and diastolic-to-systolic peak velocity ratio from 0.7 ± 0.3 to 1.2 ± 0.4 ( p < 0.001). The dipyridamole-to-baseline mean velocity ratio was 2.3 ± 0.5. We conclude that it is possible to measure dipyridamole-induced changes in LIMA flow velocities and thus obtain an index of LIMA blood velocity reserve by transcutaneous Doppler echocardiography. (J Am Soc Echocardiogr 1998;11:403-8.)

Dipyridamole Potentiates Pulmonary Vasodilation Induced by Acetylcholine and Nitric Oxide in the Ovine Fetus

Nitric oxide (NO) modulates pulmonary vascular resistance (PVR) in the normal fetus by increasing the cyclic guanosine 3',5'-monophosphate (cGMP) content of pulmonary vascular smooth muscle cells. Although several vasodilator stimuli, including acetylcholine, decrease fetal PVR through the release of endogenous NO, fetal pulmonary vasodilation is often transient despite prolonged treatment. Because cGMP is hydrolyzed and inactivated by cGMP-specific (type 5) phosphodiesterases (PDE5), we hypothesized that PDE5 activity contributes to high fetal PVR and limits the capability of the fetal pulmonary circulation to dilate or sustain vasodilation in response to cGMP-dependent stimuli. To test this hypothesis, we studied the hemodynamic effects of dipyridamole in 19 late-gestation fetal lambs. To determine whether dipyridamole-induced vasodilation is dependent upon basal NO release, we measured the response to dipyridamole before and after pretreatment with the NO synthase antagonist nitro-L-arginine (L-NA) in five fetal lambs. L-NA completely blocked dipyridamole-induced pulmonary vasodilation. To evaluate the effect of dipyridamole on pulmonary vasodilation due to the stimulated release of NO, we studied effects of prolonged intrapulmonary acetylcholine infusions, with and without concomitant administration of low-dose dipyridamole, in six fetal lambs. During prolonged (2-h) infusions, acetylcholine and dipyridamole individually caused transient pulmonary vasodilation. When administered together, pulmonary vasodilation was of greater magnitude and was sustained for the entire study period. To determine the effects of dipyridamole on endothelium-independent pulmonary vasodilation, we investigated the hemodynamic effects of inhaled NO (5 and 20 ppm) alone and in combination with dipyridamole during mechanical ventilation with low FlO2. The combination of dipyridamole with inhaled NO resulted in a greater degree of pulmonary vasodilation than that achieved with inhaled NO alone. We conclude that dipyridamole-induced pulmonary vasodilation is dependent on endogenous (basal) NO production and that dipyridamole potentiates vasodilator responses to endothelium-dependent and -independent dilators in the ovine fetal pulmonary circulation. We speculate that PDES activity opposes vasodilation and maintains high PVR in the normal fetal lung.

Interstitial adenosine with dipyridamole: effect of adenosine receptor blockade and adenosine deaminase.

Dipyridamole is proposed to increase coronary blood flow (CBF) by inhibition of adenosine uptake into cells, resulting in an increase in interstitial fluid (ISF) adenosine and an adenosine-mediated vasodilation. The purpose of this study was to determine the changes in CBF and ISF adenosine, inosine, and hypoxanthine during dipyridamole infusion in the absence or presence of adenosine receptor blockade or adenosine deaminase. To sample cardiac ISF, cardiac microdialysis probes were implanted in the left ventricular myocardium of chloralose-urethan-anesthetized dogs and perfused with Krebs-Henseleit buffer. The metabolite concentration in the effluent dialysate was used as an index of intramyocardial ISF metabolite concentration. In response to dipyridamole, CBF and dialysate adenosine concentration increased 4.4-fold and 2.2-fold, respectively, whereas dialysate inosine was unchanged and dialysate hypoxanthine decreased 50%. Adenosine receptor blockade, achieved by intracoronary 8-(p-sulfophenyl)theophylline infusion, attenuated the increase in CBF induced by dipyridamole without changing dialysate adenosine concentration. Adenosine deaminase fully attenuated the dipyridamole-induced increases in CBF and dialysate adenosine. These results demonstrate that dipyridamole increases ISF adenosine in the dog and suggest that adenosine is the sole mediator of dipyridamole-induced coronary vasodilation.

Sympathectomy stimulates capillary but not precapillary growth in hypertrophic hearts

Sympathetic nerves are known to influence vascular growth, but their role in coronary vascular adaptations to pressure-overload left ventricular (LV) hypertrophy is unknown. Accordingly, regional sympathectomy (SYMX) was produced by painting a ring of phenol on the posterior third of the LV in seven renal hypertensive (Page: 1 kidney, 1 wrap) and seven normotensive (sham: 1 kidney, no wrap) rabbits. Two months later, maximal myocardial blood flow (MBF) following dipyridamole-induced coronary vasodilation was determined with microspheres in the intact anterior and the sympathectomized posterior regions of conscious rabbits. Histomorphometric methods were then utilized to evaluate capillary density (CD), intercapillary distance (ICD), and volume density (VD) of subepicardial and endocardial samples of each region of perfused-fixed hearts. The Page procedure significantly increased systolic blood pressure (+29%) and LV wt/body wt (+20%) above sham rabbits. In both sham and Page groups, MBF was not significantly different between intact and sympathectomized regions within either group. SYMX did not significantly alter CD, ICD, or VD between regions in the sham animals. In contrast, SYMX significantly increased CD (+30%) and VD (+26%) and decreased ICD (-21%) in the subendocardial region of Page animals. Regional SYMX did not alter myocyte cross-sectional area in Page animals. We conclude that SYMX neither 1) significantly increases resistance vessel cross-sectional lumen area in either normal or hypertrophic hearts, nor 2) significantly influences capillary growth in normal hearts, but SYMX does 3) promote capillary growth in hearts undergoing hypertrophy in response to hypertension.

Evaluation and clinical use of early washout ratio of thallium-201 in normal and ischemic myocardium after dipyridamole-induced vasodilation using ring-type emission computed tomography.

Using newly developed ring-type emission computed tomography (SPECT), we investigated the washout ratio (WR) of T1-201 in the myocardium quantitatively with fast dynamic scanning after infusion of dipyridamole (0.57 mg/kg), and assessed the feasibility of early WR as a marker to detect coronary artery disease. Twenty-three patients with and 8 patients without coronary artery disease had serial SPECT images obtained every 5 min for 45 min and at 180 min after dipyridamole and subsequent T1-201 injection. The best appropriate transaxial slice was selected for WR analysis. Most appropriate diagnostic time was 25 min after infusion of T1-201 (WR-25). Normal WR-25 was 7.1 +/- 4.0%, 5.9 +/- 3.1% and 7.1 +/- 2.3% at the septum, anterior and lateral wall, respectively. Sensitivity, specificity and accuracy to identify coronary stenosis greater than 50% with a usage of abnormal WR-25, defined as WR-25 less than (mean of normals--1SD) in each region of inferest of the left ventricle (LV), were 96%, 100% and 97%, respectively. These results were better than those achieved by visual analysis (sensitivity 78%, specificity 100%, accuracy 84%). In patients with single as well as multivessel disease, the regional accuracy in assessing stenosis of more than 50% in the left anterior descending artery (LAD) and left circumflex artery (LCX) by WR-25 was 94% and 83%, respectively, which was significantly better than using visual methods (LAD 72% and LCX 50%; p less than 0.05). Thus, evaluation of early washout ratios (WR-25) after dipyridamole injection is a valuable method to increase sensitivity in assessing regional myocardial perfusion abnormality and is helpful in detection of ischemic heart disease, even with multivessel disease.

Effects of dipyridamole and aminophylline on hemodynamics, regional myocardial blood flow and thallium-201 washout in the setting of a critical coronary stenosis

Experiments were performed to characterize the interaction of intravenous dipyridamole and aminophylline on thailium-201 transport kinetics, regional myocardial blood flow and systemic hemodynamics in the presence of a critical coronary artery stenosis. In 12 dogs with a critical left anterior descending coronary artery stenosis, arterial pressure decreased from a mean value (±SEM) of 107 ± 6 to 94 ± 3 mm Hg (p < 0.05) and distal left anterior descending artery pressure decreased from 70 ± 7 to 55 ± 4 mm Hg (p < 0.05) after intravenous administration of dipyridamole (0.25 mg/kg body weight). In the left anterior descending perfusion zone, the endocardial/epicardial flow ratio decreased from 0.70 to 0.36 and the intrinsic thallium washout rate was significantly prolonged. Intravenous aminophylline (5 mg/kg) reversed the dipyridamole-induced systemic hypotension and transmural coronary steal and restored the thallium washout rate to baseline values. In six other dogs, aminophylline alone resulted in no alterations in systemic and coronary hemodynamics or regional myocardial blood flow. As expected, dipyridamole-induced vasodilation and coronary steal were prevented by aminophylline pretreatment.These data show that in a canine model of partial coronary stenosis, systemic hypotension, adverse regional flow effects (coronary steal) and prolonged thallium-201 washout consequent to intravenously administered dipyridamole are promptly reversed by intravenous aminophylline administration. Aminophylline alone had no significant hemodynaniic and coronary flow effects. This study provides further insight into the altered thallium kinetics occurring as a consequence of dipyridamole-induced vasodilation and suggests that the prompt reversal of symptoms and signs of ischemia with aminophylline in patients receiving intravenous dipyridamole for clinical imaging studies probably reflects the reversal of transmural coronary steal.

Redistribution of coronary microvascular resistance produced by dipyridamole

This study assessed the redistribution of coronary microvascular resistance during vasodilation produced by dipyridamole. Measurements of microvascular diameter and pressure in the beating left ventricle of anesthetized cats were accomplished by means of a computer-controlled system that enabled measurements in the beating heart. Resistances of coronary arteries, microvessels, and veins were calculated from the quotients of the pressure gradient across each vascular compartment and myocardial perfusion (radioactive microspheres). Administration of dipyridamole increased coronary blood flow from 1.80 +/- 0.09 to 6.42 +/- 0.31 ml.min-1. g-1 (P less than 0.05). During control conditions, 25 +/- 8% of total resistance occurred in coronary arteries (proximal to 170 microns), 68 +/- 8% of total resistance was in coronary microvessels (between arterioles less than 170 microns in diameter and venules less than 150 microns in diameter), and 7 +/- 7% of resistance resided in veins (distal to 150 microns). There was a significant redistribution (P less than 0.05) of resistance in all vessel classes after dipyridamole: coronary arteries constituted 42 +/- 6%, microvessels contained 27 +/- 5%, and veins had 31 +/- 8% of total coronary resistance. During control conditions, vascular resistance in coronary arteries and microvessels was 17 +/- 4 and 45 +/- 6 mmHg.min.g.ml-1, respectively. During vasodilation, resistance was significantly reduced (P less than 0.05) in both the arterial and microvessel segments to 6 +/- 2 and 4 +/- 2 mmHg.min.g.ml-1, respectively. Venous resistance was not significantly affected during dipyridamole-induced vasodilation. In conclusion, there was a marked reduction of coronary vascular resistance in response to dipyridamole, with the major component accounted for by dilation of microvessels.(ABSTRACT TRUNCATED AT 250 WORDS)

Aminophylline termination of dipyridamole stress as a trigger of coronary vasospasm in variant angina

Dipyridamole testing represents an alternative to exercise stress testing for documentation of ischemia related to coronary artery disease (CAD). In such a case, ischemia is attributed to maldistribution of coronary flow during dipyridamole-induced vasodilation. The present study evaluated the potential role of dipyridamole testing in producing ischemia through a vasospastic mechanism, following rapid withdrawal of vasodilation induced by aminophylline. The possibility was tested in 36 inhospital patients with variant angina pectoris who underwent dipyridamole infusion (up to 0.84 mg/kg over 10 minutes) with continuous 12-lead electrocardiographic and 2-dimensional echo monitoring. Medications were withdrawn from all patients. The test was pharmacologically stopped with the dipyridamole antidote (aminophylline, 80 to 240 mg intravenously over 1 to 3 minutes) in all patients. Two to 6 minutes after starting aminophylline infusion, 10 patients (28%) developed (>0.10 mV) ST-segment elevation (2.9 ± 0.8 mm from baseline), always accompanied by obvious asynergy detected by echocardiography, in the same electrocardiographic leads showing spontaneous or ergonovine-induced ST-segment elevation. Nitrates promptly resolved ischemia in all patients. At coronary angiography, 5 of these 10 patients showed significant CAD (>70% lumen diameter reduction of at least 1 major coronary artery), whereas 5 had nonsignificant CAD. The rate pressure product at the onset of ST-segment elevation (after dipyridamole plus aminophylline) was considerably less than that recorded at peak exercise stress test in these patients (9,600 ± 2,200 vs 18,400 ± 4,900, p < 0.01). In all patients the infusion of aminophylline alone (at the same dosages and rate as in the dipyridamole test) was unable to provoke any significant echo and electrocardiographic alterations or chest pain. In conclusion, abrupt withdrawal by aminophylline of arteriolar coronary dilation induced by dipyridamole may unmask the vasospastic tendency in a substantial number of patients with variant angina.

Sensitivity, specificity, and prognostic significance of noninvasive testing for occult or known coronary disease

T HE DEVELOPMENT of radionuclide techniques performed in conjunction with exercise stress testing for the assessment of myocardial perfusion and global and regional cardiac dynamics in the past decade has provided the clinical cardiologist with noninvasive approaches for detecting occult coronary artery disease (CAD) and determining both the extent and severity of functionally significant coronary narrowings. Information derived from cardiac radionuclide imaging is different from anatomic information obtained from coronary arteriography. Coronary angiography is presently the gold standard for establishing the diagnosis of CAD in patients with chest pain and documenting its extent by the delineation of focal coronary obstructions that are considered significant (eg >_50% stenosis). However, the angiographic evaluation of the epicardial segments of the three major coronary arteries cannot provide data relevant to the amount of myocardium that is rendered ischemic under such stress conditions as exercise, dipyridamole-induced vasodilation, and cold pressor stimulation. Some studies have shown interobserver variability in the interpretation of coronary arteriograms, with disagreement concerning the number of major vesels and a 70% stenosis occurring approximately 30% of the time) The disagreement in grading regional wall motion abnormalities is even higher. 2 When compared with autopsy measurements of the degree of narrowing, stenotic lesions ranging between 50% and 70% are usually underestimated by angiographers using visual or caliper gradings.3This most likely relates to the observation that the atherosclerotic process tends to be diffuse, and employing the measurement of percent narrowing may not indicate the true severity of the coronary obstruction. 4 The new computer-assisted quantitative techniques using edge detection 5 or videodensitrometric 6 measurements of coronary stenoses with digital subtraction angiography may enhance the accuracy of grading the severity of these lesions. Even if the degree of coronary artery stenoses could be precisely measured by quantitative angiography, the functional or physiologic severity of CAD from a prognostic sense may still not be forthcoming unless coronary reserve capacity can be simultaneously addressed] Investigative efforts are underway to develop techniques for assessing regional myocardial perfusion and coronary flow reserve during angiography using computer-assisted techniques for quantitative myocardial contrast uptake, washout, or both) The functional importance of visualized coronary collaterals must also be taken into account. Although collaterals are demonstrated angiographically, this does not necessarily indicate protection against exercise-induced ischemia, or infarction if the proximal stenosis should become totally occluded. 9 Finally, the extent of myocardium in the risk region distal to a given stenotic vessel cannot easily be ascertained by coronary arteriography alone. Risk areas distal to given locations of coronary stenoses may vary considerably from patient to patient. Some patients with single-vessel disease; particularly involving the proximal portion of the left anterior descending coronary artery, may be at high risk for an adverse outcome, because a large area of the anterior wall and septum is rendered ischemic, particularly at low levels of exercise. Certain patients with multivessel CAD may have an excellent prognosis because of lack of extensive ischemia in the myocardial risk regions of the diseased vessel during stress. This certainly was true for the majority of patients with three-vessel CAD and mild symptoms in the randomized arm of the Coronary Artery Surgery Study (CASS) in which the medically treated group had a surprisingly low 5-year cardiac event rate. 1° In this review, emphasis is placed on the

Dipyridamole-induced coronary vasodilation in human transplanted heart: preliminary report.

Coronary sinus blood flow and resistance were studied before and after intravenous dipyridamole in 4 patients with transplanted heart and normal coronary arteriogram treated by cyclosporine-prednisolone. Results were compared to those of a normal group of 7 subjects. Left ventricular endomyocardial biopsies were performed in the heart transplanted group. Mean right atrial pressure, cardiac index and left ventricular function were normal in the transplanted heart group. Mean aortic pressure and systemic vascular resistances were significantly higher in the transplanted group than in normals (p less than 0.01), but coronary resistance were similar. Dipyridamole-induced vasodilation resulted in an increased coronary sinus blood flow and a decreased coronary resistance in both groups, but these effects were reduced in 1 patient with a transplanted heart that evidenced an important perivascular fibrosis after a subacute rejection. In conclusion, this preliminary report of coronary blood flow in patients with transplanted heart indicates that the ability of coronary sinus blood flow to increase after dipyridamole is normal in the transplanted heart without allograft rejection. A major limitation in coronary vasodilation was observed in 1 patient with rejection antecedents and perivascular fibrosis, which could play a role in left ventricular function deterioration in some patients after heart transplantation.

Intrinsic washout rates of thallium-201 in normal and ischemic myocardium after dipyridamole-induced vasodilation.

Infusion of dipyridamole has been suggested as an alternative to exercise stress for myocardial perfusion imaging for detection of ischemia, but the mechanism and significance of thallium-201 (201Tl) redistribution after administration of dipyridamole are uncertain. If disparate intrinsic cellular efflux rates of 201Tl from normal and relatively underperfused myocardium in response to dipyridamole-induced vasodilation were observed, this could explain delayed 201Tl redistribution. We investigated eht effect of an intravenous infusion of 0.15 mg/kg dipyridamole on the intrinsic myocardial washout rate of 201Tl as measured with a gamma-detector probe after intracoronary injection (50 muCi) of the radionuclide in open-chested anesthetized dogs. In six normal dogs the t 1/2 for intrinsic 201Tl washout from the myocardium was 89 +/- 11 min (SE) at control conditions and became more rapid at 59 +/- 10 min (p = .0001) after dipyridamole. This corresponded to a significant increase in microsphere-determined epicardial (0.95 +/- 0.11 to 2.23 +/- 0.46 ml/min/g; p = .01) and endocardial (0.86 +/- 0.10 to 1.53 +/- 0.27; p = .029) flows. In 12 dogs with a critical coronary stenosis, the 201Tl intrinsic washout rate slowed from 70 +/- 5 to 104 +/- 6 min (p = .0001) after production of the stenosis and slowed even further to 169 +/- 21 min (p = .003) after dipyridamole.(ABSTRACT TRUNCATED AT 250 WORDS)