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lntracorona Adenosine 5Wiphosphate as an Alternative to Papaverine 7 or Measuring Coronary Flow Reserve Hiroyuki Yamada, MD, Akihiro Azuma, MD, Satoshi Hirasaki, MD, Miyuki Kobara, MD, Atsushi Akagi, MD, Takatomo Shima, MD, Hiroshi Miyazaki, MD, Hiroki Sugihara, MD, Yoshio Kohno, MD, Jun Asayama, MD, and Masao Nakagawa, MD

M easurement of coronary flow reserve (Cl%) is the accepted method for assessing functional respons-

es to physiologic and pharmacologic stimuli in patients with and without coronary atherosclerotic disease. Intra- coronary papaverine is the agent most widely used for measuring Cl%,’ even though it sometimes produces serious ventricular arrhythmias and significant QT pro- longation.2 We evaluated the coronary vasodilator poten- cy of intracoronary adenosine 5’4riphosphate (ATP) and assessed its use as an alternative agent for determining coronary vasodilator reserve.

Patients who were undergoing elective coronary arte- riography for the diagnosis of chest pain were consid- ered for admission to this study if angiography revealed a nonoccluded left anterior descending coronary artery. Patients with severe valvular disease, lef ventricular hypertrophy, or old myocardial infarction were excluded. Twenty-Jive patients (22 men and 3 women, mean age 57.8 ?I 8.4 years, body weight 57.3 f 5.3 kg) were select- ed. Nine patients with no stenosis in the left anterior descending artery were categorized as group I. The 16 remaining patients had 25% to 75% stenosis as seen on quantitative angiography, and they formed group 2. Each patient gave written informed consent before cardiac catheterization for participation in the study. After intra- venous injection of heparin (5,000 U) and intracoronary injection of isosorbide dinitrate (3 mg), a Doppler guidewire (Flowire, Cardiometrics, Inc., Mountain View, California) was advanced through a 6Fr diagnostic coronary catheter (Judkins type) into the proximal third of the left anterior descending artery.3 A temporary pac- ing catheter was placed in the right ventricular apex. Coronary blood flow velocity, arterial pressure, and a 12-lead electrocardiogram were recorded continuously. After obtaining baseline measurements, 50 pg of ATP (10 E.Lglml) was injected through the catheter into the left coronary ostium within 10 seconds. When the coro- nary blood flow velocity and systemic hemodynamics had returned to baseline values, 10 mg of papaverine (2 mglml) was injected. Coronary vasodilator potency was assessed by calculating the quotient of the peak mean bloodflow velocity during each hyperemic stimulus and the rest mean flow velocity. All data are expressed as mean + SD.

The value for CFR determined with ATP resembled that determined with papaverine in each patient in both groups (Figure 1). The mean values of CFR with ATP were 3.4 It 0.9 in group 1 and 2.5 f 0.8 in group 2. The mean CFR values with papaverine were 3.4 f 1 .l and 2.5 + 0.9 in groups I and 2, respectively. The CFR in group 2 was lower than that in group 1 with both ATP and papaverine. Coronary blood flow velocity achieved a maximum more quickly after administration of ATP (19.4 f 5.9 seconds) than after papaverine (34.2 + 9.5 seconds). Coronary bloodflow velocity returned to base- line values more rapidly after ATP administration (62.3 + 14.6 seconds) than after administration of papaver- ine (114.0 + 28.4 seconds). Mean heart rate at the time of peak coronary dilator effect obtained with both ATP and papaverine showed no difference from baseline val- ue. The mean arterial pressure was slightly decreased by ATP and papaverine. Intracoronary administration of papaverine signtjicantly increased the QTc interval ji-om 447.2 IL 12.7 to 566.2 + 62.4 ms in precordial leads. In contrast, ATP had no sign$cant effect on QTc inter- val during the study (Table I). There was no atrioven- tricular block after administration of ATP in the left coronary artery. No patient complained of chest pain,

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Differences in mean values were tested by the paired or unpaired t test. Statistical signtjicance was defined as a p value of 10.05.

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lntracoronary ATP

From the Second Department of Medicine, Kyoto Prefectural Universi- ty of Medicine, Kawaramachi-Hirokoji 465, Kamigyo-ku, Kyoto, Japan. Manuscript received April 6, 1994; revised manuscript received and accepted May 25, 1994.

FlGUREl.Comparlsonbetwwnthe ooronaly flow re serve (CFR) determined wRh adenosine 8’4riphospbte (ATP) and with papaverlne. A strong linear correlation (c = 0.93) was ohserved between CFR measured with intracorunary ATP (50 pg) and CFR measured with intro coronmy papaverine (10 mg). Its regredon line (y = -0.38 + Lizx) was nearly equal to the line of identity (Y = xl.

940 THE AMERICAN JOURNAL OF CARDIOLOGY@ VOLUME 74 NOVEMBER 1, 1994

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Group 2

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headache, jlushing, or dyspnea after receiving either ATP or papaverine.

We compared the coronary and systemic hemody- namic responses to intracoronary administration of 50 kg of ATP with those produced by intracoronary papaverine, an agent that had been thought to produce maximal coronary dilatation. The coronary vasodilator effect of ATP, assessed as peak/resting coronary flow velocity ratio, was equivalent to that of papaverine both in patients with normal coronary arteriograms and in those with moderate stenoses. Intracorona.ry papaverine is known to produce a marked QT prolongation.’ This phenomenon may be related to the serious ventricular arrhythmias that have occurred in some cases immedi- ately after the intracoronary injection of papaverine.4 Intracoronary ATP did not affect the QTc in this study. Therefore, ATP may be safer (i.e., less arrhythmogenic) than papaverine for assessing CFR. ATP did not produce serious bradycardia or atrioventricular block when the intracoronary dose of ATP was ~50 kg. Although we were prepared to institute right ventricular pacing in all cases, emergency pacing was not required. However, ATP was injected only into the left coronary artery in this study; the chronotropic effect of injecting ATP into the right coronary artery should be assessed in the future.

Whereas papaverine has been known to produce marked vasodilatation through direct relaxation of arte- riolar smooth muscle, the pharmacologic mechanism of action of ATP as a coronary vasodilator is still unclear. Burnstock and Kennedy5 reported that the vasodilator effect of ATP is dependent on the endotbelium. Brown et al6 reported that an antagonist to the synthesis of nitric oxide, recognized as an endothelium-dependent relaxing factor, failed to block the vasodilatory effect of ATP We cannot exclude the possibility that some of our patients had an impaired endothelial function, because we did

TABLE I Hemodynamic Responses to Adenosine S-Triphos- phate (ATP) and Papaverine (PAP)

Baseline ATP PAP

HR (beats/min) 62.7 + 11.1 61.9 f 9.1 64.5 f 9.4 Mean BP (mm Hg) 94.1 + 15.6 84.9 +_ 16.1* 86.0 + 11.7’ Tmax (set) - 19.4 + 5.9 34.2 -+ 9.5+ TBL (set) - 62.3 + 14.6 114.5 k 28.4* QTc (ms) 447.2 2~ 12.7 463.5 t 26.3 566.2 + 62.4’+

‘p ~0.01 versus baseline; *p ~0.05 versus adenosine 5’Wiphosphate: *p ~0.01 versus adenosine 5’Wphosphate.

BP = blood pressure; HR = heart rate; TEL = time from injection until flow velocity returned lo baseline: Tmax = time from injection to maximal velocity.

not evaluate such function in this study. Additional basic and clinical studies are required to clarify the mecha- nism of the vasodilatory action of ATP.

In conclusion, 50 pg of intracoronary ATP exhib- ited a vasodilator potency similar to that of papaver- ine without producing any marked changes in hemo- dynamics or a prolongation of the QTc. Intracoronary ATP may therefore be safer than papaverine for mea- suring CFR; more conclusive evidence about the safe- ty of intracoronary ATP will have to await the con- clusion of larger trials.

1. Wilson RF, White CW. 1ntmcoronary papawine: an ideal vasodilator for stud- ies of the coronary circulation in conscious humans. Circulation 1986;73:44&452. 2. Wilson RF, White CW. Serious ventricular dysrhythmias after intracoronary papaverine. Am .I Car&d 1988;62:1301-1302. 3. Segal 3, Kern MJ, Scott NA, King SB III, Doucette JW, Heuser RR, Otili E, Siegel R. Alteration of phasic coronary artery flow velocity in humans during per- cutaneous coronary angioplasty. .I Am Cdl Cardid 1992;20:27&286. 4. Vrolix M, Piessens J, Geest HD. Torsades de pointes after intracoronary papaver- inc. Eur Heart J 1991;12:273-276. 5. Bumstock G, Kennedy C. A dual function for adenosine 5’-hiphosphate in the regulation of vascular tone. Circ Res 1986;58:31%330. 6. Brown IF’, Thompson CI, Belloni FL. Mechanisms of coronary vasodilatation produced by ATP in guinea-pig isolated perfused heart. Br .I Pharnmcol 1992; 105:211-215.

Uttrafast Computed Tomographic Scanning for Detection of Coronary Disease in Cardmc Transplant Recipients Mahmoud Barbir, MD, Tim Bowker, MD, Peter F. Ludman, MD, Andrew G. Mitchell, BA, BM, MRCP, David Wood, MB, MSc, FRCP, and Sir Magdi Yacoub, FRCS

C oronary disease is the leading long-term cause of mortality and morbidity in cardiac transplant recip-

ients, occurring in up to 40% of recipients within 3 years. l Angina is not present in the majority of these patients, who therefore have to undergo routine annual coronary angiography. Reports of noninvasive techniques (exercise stress testing and thallium scanning) as screening tests for coronary disease of 250% luminal stenosis in cardiac transplant recipients have been varied.2

Although transplant-related coronary disease has sev- eral distinctive pathologic and clinical features, it shares many characteristics with coronary atheroma in patients

From the Harefield Hospital, Royal Brompton & National Heart Hospi- tal, and the Department of Clinical Epidemiology, National Heart &Lung Institute, London SW3 6LY, United Kingdom. Professor Sir Magdi Yacoub’s address is: Harefield Hospital, Middlesex UB9 6JH, Harefield, United Kingdom. Manuscript received February 17,1994; revised manu- script received and accepted June 1, 1994.

who have not had transplants. 1 In the non-transplant popu- lation, coronary calcification is associated with athero- ma.3 Ultrafast computed tomography is the most sensitive noninvasive method available to detect coronary calci- um, which can be quantiiied by use of a scoring system.3

In asymptomatic persons, the prevalence of coronary calcification assessed by ultrafast computer tomograph- ic (CT) scanning is high, increasing in men and women, from 21% and ll%, respectively, in their fourth decade, to 94% and 89%, respectively, in their eighth decade. Calcification is related both to the overall extent of angio- graphic coronary disease and to age? A relation between degree of luminal narrowing (determined histopatho- logically) and amount of calcification (determined by ultrafast CT scanning) in postmortem hearts from non- transplant patients has been demonstrated.4

There has been no investigation of calcification in the coronary atheroma of transplanted hearts. The present

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