Coronary vasodilator reserve. Comparison of the effects of papaverine and adenosine on coronary flow, ventricular function, and myocardial metabolism

To evaluate coronary flow reserve during cardiac catheterization, intracoronary adenosine and papaverine have been used in the clinical setting. Although papaverine maximizes coronary blood flow, it induces several toxic side effects that reduce its desirability as a coronary dilator. This investigation was designed to compare the subselective intracoronary administration of papaverine with that of adenosine in an animal model. In dogs (n = 34), we studied the effects of each agent on hemodynamics, regional myocardial blood flow, contractility (sonomicrometric and echocardiographic), metabolism (coronary arterial and venous lactate and tissue high-energy phosphates), and electrocardiographic (ST and QT intervals) parameters. Barbiturate and morphine anesthesia/analgesia was induced, and a left thoracotomy was performed. An arterial shunt was created from the left carotid artery to the left anterior descending coronary artery. Two separate groups were studied: group 1 (n = 16) for regional myocardial blood flow and mechanical function and group 2 (n = 18) for biochemical measurements. Adenosine (67 +/- 2 micrograms/min) or papaverine (6 +/- 1 mg/min) was infused into the coronary shunt at a rate of 0.5 + 0.1 ml/min for a maximum duration of 3.5 minutes. Regional myocardial blood flows were determined at control (predrug) and maximal coronary flow using radiolabeled microspheres. All hemodynamic, wall motion, biochemical, and electrocardiographic parameters were also measured at these times. Both drugs produced comparable increases in total and regional coronary blood flows (adenosine, 1.21 +/- 0.15 to 4.83 +/- 0.36 ml/min/g; papaverine, 1.21 +/- 0.05 to 4.89 +/- 0.28 ml/min/g) upon infusion into the left anterior descending coronary artery. Papaverine produced significant (p less than 0.05) changes in subendocardial ST segment electrocardiogram (-2.5 mm), QT prolongation (8 +/- 2%), myocardial creatine phosphate (47% decrease), and coronary sinus serum lactate (277% increase) compared with control. In addition, intracoronary papaverine induced an abnormal contractile pattern. No significant changes in any of these parameters (i.e., ST segment, QT prolongation, myocardial creatine phosphate level, or lactate level) were observed with intracoronary adenosine infusions. We conclude that intracoronary adenosine is comparable to papaverine for maximizing coronary blood flow without the deleterious properties observed with intracoronary papaverine.     

Intravenous adenosine: continuous infusion and low dose bolus administration for determination of coronary vasodilator reserve in patients with and without coronary artery disease

To assess the use of adenosine as an alternative agent for determination of coronary vasodilator reserve, hemodynamics and coronary blood flow velocity were measured at rest and during peak hyperemic responses to continuous intravenous adenosine infusion (50, 100 and 150 micrograms/kg per min for 3 min) and intracoronary papaverine (10 mg) in 34 patients (17 without [group 1] and 17 with [group 2] significant left coronary artery disease), and in 17 patients (11 without and 6 with left coronary artery disease) after low dose (2.5 mg) intravenous bolus injection of adenosine. The maximal adenosine dose did not change mean arterial pressure (-10 +/- 14% and -6 +/- 12% for groups 1 and 2, respectively) but increased the heart rate (15 +/- 18% and 13 +/- 16, respectively). For continuous adenosine infusions, mean coronary flow velocity increased 64 +/- 104%, 122 +/- 94% and 198 +/- 59% and 15 +/- 51%, 110 +/- 95% and 109 +/- 86% in groups 1 and 2, respectively for each of the three doses. Mean coronary flow velocity increased significantly after 100 and 150 micrograms/kg of adenosine and 10 mg of intracoronary papaverine (48 +/- 25, 52 +/- 19 and 54 +/- 21 cm/s, respectively; all p less than 0.05 vs. baseline) and was significantly higher than in group 2 (37 +/- 24, 32 +/- 16, 41 +/- 23 cm/s; all p less than 0.05 vs. group 1). The coronary vasodilator reserve ratio (calculated as the ratio of hyperemic to basal mean flow velocity) for adenosine and papaverine was 2.94 +/- 1.50 and 2.94 +/- 1.00, respectively, in group 1 and was significantly and similarly reduced in group 2 (2.16 +/- 0.81 and 2.38 +/- 0.78, respectively; both p less than 0.05 vs. group 1). Low dose bolus injection of adenosine increased mean velocity equivalently to that after continuous infusion of 100 micrograms/kg, but less than after papaverine. There was a strong correlation between adenosine infusion and papaverine for both mean coronary flow velocity and coronary vasodilator reserve ratio (r2 = 0.871 and 0.325; SEE = 0.068 and 0.189, respectively; both p less than 0.0005). No patient had significant arrhythmias or prolongation of the corrected QT (QTc) interval with adenosine, but papaverine increased the QT (QTc) interval from 445 +/- 44 to 501 +/- 43 ms (p less than 0.001 vs. both maximal adenosine and baseline) and produced nonsustained ventricular tachycardia in one patient.(ABSTRACT TRUNCATED AT 400 WORDS)     

Comparison of coronary vasodilation with intravenous dipyridamole and adenosine.

Although both intravenous dipyridamole and adenosine have been used to produce coronary vasodilation during cardiac imaging, the relative potency of the commonly administered doses of these agents has not been evaluated. Accordingly, the coronary and systemic hemodynamic effects of intravenous adenosine (140 micrograms/kg per min) and intravenous dipyridamole (0.56 mg/kg over 4 min) were compared with a maximally dilating dose of intracoronary papaverine in 15 patients. Coronary blood flow responses were assessed using a Doppler catheter in a nonstenotic coronary artery. The protocol was discontinued in two patients because of transient asymptomatic atrioventricular (AV) block during adenosine infusion. The mean heart rate increased more with adenosine (11 +/- 9 beats/min) and dipyridamole (11 +/- 7 beats/min) than with papaverine (4 +/- 3 beats/min, p less than 0.05 vs. adenosine and papaverine). The mean arterial pressure decreased less with dipyridamole (-10 +/- 3 mm Hg) and papaverine (-9 +/- 4 mm Hg) than with adenosine (-16 +/- 5 mm Hg, p less than 0.01 vs. dipyridamole and papaverine). The peak/rest coronary blood flow velocity ratio was greater with papaverine (3.9 +/- 1.1) than with adenosine (3.4 +/- 1.2, p less than or equal to 0.05 vs. papaverine) or dipyridamole (3.1 +/- 1.2, p less than 0.01 vs. papaverine). A larger decrease in coronary resistance as measured by the coronary vascular resistance index occurred with papaverine (0.25 +/- 0.06) and adenosine (0.26 +/- 0.09) than with dipyridamole (0.31 +/- 0.10, p less than 0.01 vs. papaverine, p less than 0.05 vs. adenosine).(ABSTRACT TRUNCATED AT 250 WORDS)     

Value and limitations of intracoronary adenosine for the assessment of coronary flow reserve

An ideal coronary vasodilator for studying coronary flow reserve should rapidly produce a maximal hyperemic response, be short acting to permit repeated measurements, and not alter systemic hemodynamics. We measured with a Doppler tip balloon catheter, in 12 patients before and/or after percutaneous transluminal coronary angioplasty the hyperemic response following 12.5 mg intracoronary papaverine and following gradually incremental bolus injections of intracoronary adenosine, starting from 0.05 mg until a maximal hyperemic response or side effects. The mean dose (+/- SD) of adenosine needed to produce maximal hyperemia was 0.23 (+/- 0.20 mg). Coronary blood flow velocity after adenosine increased to 1.6 +/- 0.3 times resting coronary blood flow velocity, comparable in magnitude to the hyperemia following intracoronary papaverine. The time from injection to peak effect after adenosine was 7.4 (SD +/- 2.2) sec and after papaverine 26 (SD +/- 7) sec. Adenosine resulted in a bradyarrhythmia in three patients. Intracoronary adenosine is a potent and very short acting vasodilator for studying coronary flow reserve, but the side effects and unpredictability of the dosage needed to produce maximal hyperemia may limit its applicability.     

Inverse relationship between coronary flow velocity and myocardial oxygen extraction during intracoronary infusion of papaverine]

The relationship between coronary blood flow velocity (CBFV) and myocardial oxygen extraction (O2-Ext) was investigated during rapid changes of CBFV after intracoronary papaverine infusion. In 6 patients without stenosis of the left anterior descending artery (LAD), one with hypertrophic cardiomyopathy, 2 with syndrome X and 3 with effort angina pectoris, simultaneous measurements of CBFV using the Doppler catheter system and coronary venous oxygen saturation using the fiberoptic catheter system were continuously performed before and during intracoronary infusion of papaverine. When O2-Ext was related to CBFV in every cardiac cycle, there was a good, inverse linear relationship, both in the increase (r = 0.81 +/- 0.24) and decrease (r = 0.93 +/- 0.04) phases of CBFV. The increase in cross-sectional area of segment 6 in the LAD as observed on orthogonal coronary angiograms was 6.0 +/- 2.0%. These results imply that the increase in CBFV during intracoronary papaverine infusion seems parallel to that of coronary blood flow, and that papaverine induces no significant change in myocardial oxygen consumption. Myocardial oxygen extraction in response to changes in coronary flow is regulated readily to meet the myocardial oxygen demand.     

Role of adenosine in coronary blood flow regulation after reductions in perfusion pressure

We employed intracoronary infusion of adenosine deaminase to test the hypothesis that endogenous adenosine contributes to regulation of coronary blood flow following acute reductions in coronary artery pressure. In 16 closed-chest anesthetized dogs, we perfused the left circumflex coronary artery from a pressurized arterial reservoir and measured coronary blood flow following changes in perfusion pressure before and 10 minutes after the start of intracoronary adenosine deaminase, 5 U/min per kg body weight. Parallel studies showed that this dose of enzyme resulted in cardiac lymph adenosine deaminase concentrations of 3.2 +/- 0.4 U/ml. Adenosine deaminase abolished the vasodilator response to intracoronary adenosine, 4 and 8 micrograms, but had no effect on the vasodilator response to intracoronary papaverine, 200 and 300 micrograms, demonstrating enzyme efficacy and specificity. Additional experiments demonstrated that adenosine deaminase reversibly attenuated myocardial reactive hyperemia following 5- and 10-second coronary occlusions by 30% (P less than 0.05), evidence that the infused enzyme effectively degraded endogenous adenosine. However, adenosine deaminase did not alter the time course for coronary autoregulation or the steady state autoregulatory flow response over the pressure range between 125 and 75 mm Hg. Further, adenosine deaminase did not alter steady state coronary flow when perfusion pressure was reduced below the range for effective autoregulation (60-40 mm Hg). Such results show that adenosine is not essential for either coronary autoregulation or for the maintenance of coronary vasodilation when autoregulatory vasodilator reserve is expended.     

Intracoronary papaverine: an ideal coronary vasodilator for studies of the coronary circulation in conscious humans

An ideal coronary vasodilator for studying coronary flow reserve in humans would rapidly produce maximal coronary vasodilation, be short acting to permit repeated measurements, and not alter systemic hemodynamics. The two commonly used vasodilators (dipyridamole and meglumine diatrizoate) do not satisfy these criteria; meglumine diatrizoate does not produce maximal hyperemia and dipyridamole has a long duration of effect (greater than 30 min). In this study we used a subselective coronary Doppler catheter to measure the dose-response kinetics of a shorter acting vasodilator, intracoronary papaverine. In 10 patients with normal coronary vessels, the maximal vasodilator response to papaverine was compared with that to intravenous dipyridamole (0.56 mg/kg infused over 4 min) and intracoronary meglumine diatrizoate. The increase in coronary blood flow velocity after the maximal dose of papaverine (4.8 +/- 0.4 peak/resting velocity ratio, mean +/- SEM) was nearly identical to that seen after infusion of dipyridamole (4.8 +/- 0.6) and was significantly greater than that after meglumine diatrizoate (3.1 +/- 0.2, p less than .01). At maximal hyperemia, mean arterial blood pressure fell 9 +/- 2% (mean +/- SEM) after intracoronary papaverine, 8 +/- 4% after dipyridamole, and 3 +/- 3% after meglumine diatrizoate. The dose-response kinetics of intracoronary papaverine were studied in 13 patients with normal coronary arteries. In the left coronary artery, maximal vasodilation (5.4 +/- 0.6) was achieved with 8 mg in six of eight patients and with 12 mg in all patients. In the right coronary artery, maximal vasodilation (4.8 +/- 0.7) was achieved with 6 mg in four or five patients and with 8 mg in all patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of ATP-sensitive potassium channel inhibition on resting coronary vascular responses in humans

Experimental data suggest that vascular ATP-sensitive potassium (K(ATP)) channels regulate coronary blood flow (CBF), but their role in regulating human CBF is unclear. We sought to determine the contribution of K(ATP) channels to resting conduit vessel and microvascular function in the human coronary circulation. Twenty-five patients (19 male/6 female, aged 56 +/- 12 years) were recruited. Systemic and coronary hemodynamics were assessed in 20 patients before and after K(ATP) channel inhibition with graded intracoronary glibenclamide infusions (4, 16, and 40 microg/min), in an angiographically smooth or mildly stenosed coronary artery following successful elective percutaneous coronary intervention to another vessel. Coronary blood velocity was measured with a Doppler guidewire and CBF calculated. Adenosine-induced hyperemia was determined following bolus intracoronary adenosine injection (24 microg). Time control studies were undertaken in 5 patients. Compared with vehicle infusion (0.9% saline), glibenclamide reduced resting conduit vessel diameter from 2.5 +/- 0.1 to 2.3 +/- 0.1 mm (P<0.01), resting CBF by 17% (P=0.05), and resting CBF corrected for rate pressure-product by 18% (P=0.01) in a dose-dependent manner. A corresponding 24% increase in coronary vascular resistance was noted at the highest dose (P<0.01). No alteration to resting CBF was noted in the time control studies. Glibenclamide reduced peak adenosine-induced hyperemia (P=0.01) but did not alter coronary flow reserve. Plasma insulin increased from 5.6 +/- 1.2 to 7.6 +/- 1.3 mU/L (P=0.02); however, plasma glucose was unchanged. Vascular K(ATP) channels are involved in the maintenance of basal coronary tone but may not be essential to adenosine-induced coronary hyperemia in humans.     

Intracoronary continuous adenosine infusion.

BACKGROUND: Various methods are used to induce maximal hyperemia for physiologic studies, but the feasibility and efficacy of continuous intracoronary (IC) infusion of adenosine for measurement of fractional flow reserve (FFR) has not been well-defined. METHODS AND RESULTS: Patients with intermediate coronary artery stenosis were consecutively enrolled. In the phase I study, FFR was measured after 3 dosages of IC adenosine infusion (180, 240 and 300 microg/min) in 30 patients. The phase II study was performed to compare the hyperemic efficacy of IC infusion (240 microg/min) with IC bolus injection (40, 80 microg) and intravenous (IV) infusion (140 microg x kg (-1) x min(-1)) of adenosine in 20 patients. In the phase I study, no significant differences in FFR were observed with the 3 different doses of IC infusion (p = 0.06). In the phase II study, FFR after an IC bolus injection (0.83+/-0.06) was significantly higher than with IV (0.79+/-0.07) or IC (0.78+/-0.09) infusion (p < 0.01). However, no difference in FFR was observed for IC and IV infusions. CONCLUSION: IC infusion of adenosine seems to be a safe and effective method of inducing maximal hyperemia for FFR measurement.     

Role of adenosine in coronary vasodilation during exercise

This study examined the hypothesis that increases in myocardial blood flow during exercise are mediated by adenosine-induced coronary vasodilation. Active hyperemia associated with graded treadmill exercise and coronary reactive hyperemia were examined in chronically instrumented awake dogs during control conditions, after intracoronary infusion of adenosine deaminase (5 units/kg/min for 10 minutes), and after adenosine receptor blockade with 8-phenyltheophylline. Both adenosine deaminase and 8-phenyltheophylline caused a rightward shift of the dose-response curve to intracoronary adenosine; 8-phenyltheophylline was significantly more potent than adenosine deaminase. Adenosine deaminase caused a 33 +/- 7 to 39 +/- 3% decrease in reactive hyperemia blood flow following coronary occlusions of 5-20 seconds duration, respectively, while 8-phenyltheophylline produced a 40 +/- 6 to 62 +/- 8% decrease in reactive hyperemia. Increasing myocardial oxygen consumption during treadmill exercise was associated with progressive increase of coronary blood flow. Neither adenosine deaminase nor 8-phenyltheophylline attenuated the increase in coronary blood flow or the decrease of coronary vascular resistance during exercise. Neither agent altered the relation between myocardial oxygen consumption and coronary blood flow. Thus, although both adenosine deaminase and 8-phenyltheophylline antagonized coronary vasodilation in response to exogenous adenosine and blunted coronary reactive hyperemia, neither agent impaired coronary vasodilation associated with increased myocardial oxygen requirements produced by exercise. These findings fail to support a substantial role for adenosine in mediating coronary vasodilation during exercise.     

Does intracoronary papaverine dilate epicardial coronary arteries? Implications for the assessment of coronary flow reserve

Intracoronary papaverine is used as a means to induce a strong and short-lasting hyperemia in several recently developed methods to measure coronary flow reserve. Changes in stenosis geometry from papaverine would influence the measured coronary flow reserve. Therefore, we investigated the influence of intracoronary papaverine on stenosis geometry with quantitative analysis of the coronary angiogram and assessed the influence of papaverine on pressure-flow characteristics of the stenosis and coronary flow reserve. The cross-sectional areas (mean +/- SD) of the stenosis increased 18% +/- 7% after papaverine. The normal proximal and distal parts of the coronary artery dilated 5% +/- 2% after papaverine. This results in a decrease of the calculated pressure drop over the stenosis varying from 20% to 30%. Coronary flow reserve of a flow-limiting epicardial stenosis is overestimated by 16% when papaverine is used to induce hyperemia. These papaverine-induced changes can nevertheless be circumvented by maximal vasodilation of the major epicardial coronary artery with 3 mg intracoronary isosorbidedinitrate prior to the investigation of the coronary flow reserve with papaverine.     

Intracoronary adenosine and papaverine do not increase myocardial systolic thickening.

STUDY OBJECTIVE--The aim was to determine if myocardial systolic thickening increases when coronary flow is augmented by infusing intracoronary vasodilators (adenosine and papaverine). DESIGN--Systolic thickening fraction was measured with pulsed Doppler crystals and sonomicrometer crystals before and during the intracoronary infusion of adenosine and papaverine. SUBJECTS--Sixteen anaesthetized mongrel dogs were studied. MEASUREMENTS AND MAIN RESULTS--Intracoronary adenosine did not alter systemic haemodynamics, but did induce a three- to fourfold increase in myocardial blood flow. Intracoronary papaverine caused a slight decrease in systemic arterial pressure and rise in heart rate. Neither intracoronary adenosine nor intracoronary papaverine increased systolic thickening: control thickening fraction (TF%) = 20 (SEM 1)%, adenosine TF% = 18(1)%; control TF% = 22(2)%, papaverine TF% = 20(2)%. CONCLUSIONS--These experiments do not support the hypothesis that an increase in myocardial blood flow induced by intracoronary vasodilators causes an increase in myocardial systolic function.     

Effects of calcitonin gene-related peptide on normal and atheromatous vessels and on resistance vessels in the coronary circulation in humans

BACKGROUND. Calcitonin gene-related peptide (CGRP) is a potent dilator of normal epicardial coronary vessels in humans, but its effects on myocardial blood flow and atheromatous coronary vessel diameter are unknown. METHODS AND RESULTS. Seven patients were entered for study of the effects of CGRP on coronary blood flow and 13 for the comparison of its effects on normal and atheromatous coronary arteries. In the first seven patients, left anterior descending artery (LAD) diameter at an angiographically normal site, coronary sinus oxygen saturation (CSO2S), systemic blood pressure, and heart rate were measured during intracoronary infusion of increasing concentrations of CGRP (up to 200 ng/ml at 2 ml/min) followed by intracoronary adenosine (0.267 micrograms/ml at 2 ml/min) and finally intracoronary glyceryl trinitrate (GTN) (5 micrograms/ml at 2 ml/min). CGRP dilated the normal segment of the LAD by 22.6 +/- 8% (mean +/- 95% confidence interval), p less than 0.001, with only a small increase in CSO2S from 40.1 +/- 2.7% to 47.3 +/- 2.7%, p less than 0.001. Adenosine, a potent dilator of myocardial resistance vessels, caused no further increase in LAD diameter but caused a rise in CSO2S from 47.3 +/- 2.7% to 76.0 +/- 2.7%, p less than 0.001. GTN caused no further increase in LAD diameter. As heart rate-blood pressure product remained unchanged throughout the study, the increase of CSO2S indicated only a small increase in myocardial blood flow after CGRP infusion. In 13 patients with atheromatous coronary artery disease, the effects of intracoronary CGRP at angiographically normal sites, stenoses, angiographically normal sites immediately adjacent to stenoses, and sites of coronary artery wall irregularity were compared after intracoronary infusion of a single dose of CGRP (200 ng/ml at 2 ml/min) followed by intracoronary GTN (5 micrograms/ml at 2 ml/min). At these four sites, CGRP resulted in dilatation by 17.0 +/- 5.6%, 15.3 +/- 12.1% (NS), 7.6 +/- 5.4% (NS), and 15.9 +/- 7.8%, respectively. There was no significant further dilatation after GTN at any of the four sites. CONCLUSIONS. These data indicate that CGRP has little effect in humans at rest on coronary resistance vessels in nonischemic myocardium but causes marked dilatation of normal arteries and variable dilatation of atheromatous epicardial arteries.     

Coronary pressure-flow relations in hypertensive left ventricular hypertrophy. Comparison of intact autoregulation with physiological and pharmacological vasodilation in the dog

Coronary pressure-flow relations during autoregulated and vasodilated flow states were compared between eight dogs with renovascular hypertension and left ventricular hypertrophy and 12 normal dogs. Each relation was constructed from serial steady-state measurements of end-diastolic coronary pressure and flow during perfusion of the circumflex artery by an extracorporeal circuit at controlled diastolic pressures of 20-200 mm Hg. Autoregulated pressure-flow relations were compared at three levels of myocardial oxygen demand: resting, high (dobutamine 10 micrograms/kg/min), and low (propranolol 2.5 micrograms/kg/min). Autoregulatory capacity was assessed by calculation of closed-loop flow gain. At each level of myocardial oxygen demand, the lower limit of autoregulation occurred at higher perfusion pressures in the hypertrophy group (rest 65 +/- 3, high 92 +/- 4, low 66 +/- 4 mm Hg) than in the normal group (rest 53 +/- 2, p less than 0.05; high 75 +/- 5, p less than 0.05; low 51 +/- 3 mm Hg) (p less than 0.05). Maximum autoregulatory gain was similar in the normal and hypertrophy groups during resting and low myocardial oxygen demand but was reduced in the hypertrophy group during dobutamine studies. When coronary flow decreased below the lower limit of autoregulation, systolic shortening was reduced in both normal and hypertrophy groups. However, as the autoregulatory limits were at higher pressures in the hypertrophy group, shortening in this group deteriorated at perfusion pressures that did not affect the normal heart. Coronary pressure-flow relations during physiological (peak hyperemia after 15-second flow occlusion) and pharmacologica (intracoronary adenosine 400 micrograms/min) vasodilation was curvilinear and fitted by quadratic regression. During hyperemic vasodilation, maximal conductance per unit mass of myocardium was less in the hypertrophy group over a wide range of perfusion pressures. At a diastolic perfusion pressure of 80 mm Hg, maximum conductance was 4.6 +/- 0.5 ml/min/100 g/mm Hg in the normal group and 3.4 +/- 0.4 ml/min/100 g/mm Hg (p less than 0.05) in the hypertrophy group. Intracoronary adenosine elicited further vasodilation in both groups, but maximum conductance remained less in the hypertrophy group (8.5 +/- 1.7 ml/min/100 g/mm Hg at a perfusion pressure of 80 mm Hg) than in the normal group (13.5 +/- 2.0 ml/min/100 g/mm Hg) (p less than 0.05). Maximal coronary flow reserve is reduced in left ventricular hypertrophy, with a consequent shift of the lower limit of autoregulation to higher perfusion pressures. Thus, as coronary perfusion pressure is decreased, coronary flow and myocardial shortening become impaired at higher     

A simplified method to measure coronary blood flow velocity in patients: validation and application of a Judkins-style Doppler-tipped angiographic catheter

To facilitate more rapid and safe measurement of coronary flow velocity reserve in patients, we developed a Judkins-style angiographic catheter tipped with a 20 MHz Doppler crystal. In 19 patients without coronary artery disease, resting and hyperemic (10 mg intracoronary papaverine) mean and phasic coronary flow velocity signals were measured with the Judkins-style and 2.5F intracoronary Doppler catheters at identical coronary loci. Mean coronary flow velocity at rest was similar (14 +/- 8, 10 +/- 7 cm/sec, p = ns), but was higher during hyperemia for the Judkins-Doppler (41 +/- 8 versus 32 +/- 14 cm/sec, p less than 0.05). Coronary flow velocity reserve, calculated as the ratio of mean velocity at rest to mean velocity following papaverine, was 3.3 +/- 1.4 and 3.7 +/- 1.2 units (p = ns) for the Judkins and intracoronary Doppler techniques, respectively (r = 0.801, p less than 0.001). The Judkins-style Doppler catheter technique permits flow velocity and coronary flow velocity reserve measurements that correlate strongly with those of the intracoronary catheter technique, facilitating safe, quick, and accurate assessment of coronary physiology.     

Coronary circulation responses to binodenoson, a selective adenosine A2A receptor agonist

The purpose of this study was to define binodenoson dosing regimens that produce coronary hyperemia comparable to those of adenosine and that are tolerated well by patients. An open-label, randomized, parallel-group, multicenter study enrolled adult patients who had completed diagnostic cardiac catheterization. Coronary blood flow velocity (CBFV) was measured with a Doppler flow wire, and CBFV reserve was determined before binodenoson administration. Patients (n = 133) received a 3-minute infusion of 0.3, 0.5, or 1 microg/kg/min or a bolus intravenous injection of 1.5 or 3 microg/kg. Coronary hyperemic responses were evident within seconds of administering binodenoson, and the magnitudes and durations of coronary hyperemic responses were dose related. The 1.5- and 3-microg/kg doses, by infusion or bolus, produced maximal coronary hyperemia equivalent to CBFV reserve. All doses transiently decrease blood pressure and increased heart rate and rate-pressure product. In conclusion, the 1.5-microg/kg binodenoson bolus dose produced nearly maximal coronary hyperemia by 4.5 +/- 3.7 minutes that was sustained for 7.4 +/- 6.86 minutes, was accompanied by modest changes in blood pressure, heart rate, and rate-pressure product, and produced no adverse changes on electrocardiogram, including no second- or third-degree atrioventricular block.     

Effect of elevations of coronary artery partial pressure of carbon dioxide (PCO2) on coronary blood flow

This study was designed to examine the effect of increases in the partial pressure of carbon dioxide (PCO2) in coronary artery blood on coronary blood flow, coronary reactive hyperemia and the coronary response to intracoronary adenosine administration. The left anterior descending coronary artery was cannulated and perfused over a wide range of perfusion pressure (P) and flow (F) with blood equilibrated with 0 to 40% carbon dioxide in 16 open chest dogs. Increases in coronary artery PCO2 from 20 +/- 2 to 93 +/- 8 to 211 +/- 22 mm Hg (mean +/- SEM) increased the coronary flow from 28 +/- 3 to 68 +/- 16 to 87 +/- 22 ml/min, respectively, at a perfusion pressure of 60 mm Hg and from 49 +/- 6 to 139 +/- 30 to 206 +/- 48 ml/min, respectively, at a perfusion pressure of 100 mm Hg. Coronary reactive hyperemia following a 30 second coronary perfusion line occlusion and the response to an intracoronary bolus of adenosine (60 micrograms) were prominent at a low PCO2 but absent at a high PCO2. Beta-adrenergic blockade did not abolish the increase in coronary flow that occurred at increased PCO2. Thus, progressive elevations of regional coronary PCO2 produced substantial increases in coronary blood flow and maximal or near maximal coronary vasodilation.     

Can adenosine triphosphate induce maximal hyperemic response in patients with impaired coronary microcirculation?: comparison of hyperemic response to adenosine triphosphate administered by intravenous and by intracoronary injection using Doppler guide wire

OBJECTIVES: This study compared the hyperemic responses to adenosine triphosphate (ATP) administered by intravenous and by intracoronary injection in patients with impaired coronary microcirculation. METHODS: The hyperemic responses to intravenous and intracoronary administration of ATP in 107 patients (mean age 63 +/- 10 years, 77 males, 30 females) with impaired coronary circulation [including myocardial infarction (n = 68), cardiomyopath (n = 20) and diabetes mellitus (n = 11)] were compared by measurement of coronary flow reserve (CFR) using the Doppler guide wire. Patients with chest pain syndrome were used as the normal controls. The coronary blood flow velocity was measured at rest and during peak hyperemic responses to intravenous infusion (150 micrograms/kg/min) and intracoronary infusion of ATP (50 micrograms in the left coronary artery, 25 micrograms in the right coronary artery). The CFR was calculated as the ratio of averaged peak velocity during hyperemia to baseline averaged peak velocity. RESULTS: The CFR after intravenous administration of ATP (CFRi.v.) was well correlated with CFR by intracoronary administration of ATP(CFRic) (r = 0.77, p < 0.001). However, the CFRi.v. was also inversely correlated with the ratio of CFRic to CFRiv (CFRic/i.v.) (r = -0.36, p < 0.001). There were no relationships between the changes of hemodynamic parameters(blood pressure and heart rate) induced by ATP and CFRic/i.v. A lower CFRi.v. of less than 2.0 provided significantly greater CFRic/i.v. than that of CFRiv greater than 2.0. CONCLUSIONS: The maximal hyperemic response of coronary artery was not always induced by conventional intravenous administration of ATP, especially in patients with lower CFR than 2.0. High dose of intravenous ATP and/or intracoronary ATP should be administered in patients with lower CFR to attain maximum hyperemia in the impaired coronary circulation.     

Are high doses of intracoronary adenosine an alternative to standard intravenous adenosine for the assessment of fractional flow reserve?

Background

Achievement of maximal hyperemia of the coronary microcirculation is a prerequisite for the measurement of fractional flow reserve (FFR). Intravenous adenosine is considered the standard method, but its use in the catheterization laboratory is time consuming and expensive compared with intracoronary adenosine. Therefore, this study compared different high, intracoronary doses of adenosine for the potential to achieve a maximal hyperemia equivalent to the standard intravenous route.

Methods

FFR was assessed in 50 patients with 50 intermediate lesions during cardiac catheterization. FFR was calculated as the ratio of the distal coronary pressure to the aortic pressure at hyperemia. Different incremental doses of intracoronary adenosine (60, 90, 120, and 150 μg as boli) and a standard intravenous infusion of 140 μg/kg/min were administered in a randomized fashion.

Results

Different incremental doses of intracoronary adenosine were well tolerated, with fewer systemic adverse effects than intravenous adenosine. At baseline, there were no significant differences for mean aortic and distal coronary pressure or heart rate in the different adenosine doses and routes. FFR decreased with increasing adenosine doses, with the lowest values observed with the 150-μg intracoronary bolus and 140-μg/kg/min dose of intravenous adenosine. All intracoronary doses, except the 150-μg bolus, resulted in mean FFR values that were significantly (P <.05) higher than FFR after the administration intravenous adenosine. Furthermore, 5 patients (10%) with a FFR value >0.75 and 3 subjects (6%) with a FFR value >0.80 who received a 60-μg intracoronary bolus reached a value below the cutoff point of 0.75 with the intravenous administration.

Conclusions

This study suggests a dose-response relationship on hyperemia for intracoronary adenosine doses >60 μg. The administration of very high intracoronary adenosine boli is safe and associated with fewer systemic adverse effects than standard intravenous adenosine. However, intravenous adenosine administration with 140 μg/kg/min produced a more pronounced hyperemia than intracoronary adenosine in most patients and should be the preferred mode of application for the assessment of FFR.     

Adenosine metabolism in canine myocardial reactive hyperemia

In pentobrabital-anesthetized open chest dogs, myocardial adenosine content is elevated by 5 or 15 seconds of left coronary artery occlusion and falls exponentially to control levels during reactive hyperemia. The rate constants for adenosine dissipation are (mean +/- SEM): -0.08 +/- 0.01 and -0.034 +/- 0.007 sec-1 after 5- and 15-second occlusion, respectively. Kinetic analysis of the reactive hyperemia flow curves (Circ Res 14/15 (suppl I): 81-85, 1963) predicts rates of -0.069 +/- 0.009 sec-1 and -0.04 +/- 0.009 sec-1, indicating that changes in adenosine levels can account for the way coronary flow changes during this response. The log (dose-) response curve relating reactive hyperemia flow to tissue adenosine concentration has a steeper slope and is half-maximal at a lower adenosine concentration than the dose-response curve obtained by intracoronary infusions of adenosine in oxygenated hearts, indicating that the coronary vasoactivity of adenosine is enhanced during reactive hyperemia. This could explain why theophylline antagonizes the coronary vasocilatory effect of adenosine in oxygenated hearts but has relatively little effect on reactive hyperemia.