- Email: [email protected]
Coronary vasomotor function in a normotensive, nondiabetic referral population with normal coronary arteriograms
I. Nixdorff U, Erbel R, Pop T, Rupprecht H-J, Henrichs K-J, Mdrchen S, Meyer J. Long-term follow-up of global and regional left ventricular function by twodimensional echocardiography after thrombolytic therapy in acute myocardial infarction. Int .I Cardiol 1993;41:31-47. 2. Erbel R, Pop T, Henrichs K-J, van Olshausen K, Schuster CJ, Rupprecht H-J, Steuemagel C, Meyer J. Percutaneous transluminal coronary angioplasty after thrombolytic therapy: a prospective controlled randomized trial. JAm Coil Cardiol 1986;8:485-495. 3. Gruppo ltaliano per lo Studio della Sopravvivenra nell’infarto Miocardio. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancer 1994;343:1115- 1122. 4. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: a randomized factorial trial assessing early oral captopril. oral mononitrate, and intravenous magnesium sulphate in 58050 patients with suspected acute myocardial infarction. Lancer 1995;345:669-685. 5. Konstan MA, Kronenberg MW, Rousseau MF, for the SOLVD Investigators. Effects of the angiotensin converting enzyme inhibitor enalapril on the longterm progression of left ventricular dilatation in patients with asymptomatic systolic dysfunction. Circulation 1993;88:2277-2283. 6. Pfeffer MA, Braunwald E, Moye LA, Basta L, Brown W, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker CC, Klein M, Lamas GA, Packer M, Rouleau J, Rouleau JL, Rutherford J, Wertheimer JH, Hawkins CM, on behalf of the SAVE-Investigators. Effects of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial. N Engl J Med 1992;327:669-677. 7. Pardee HEB. An electrocardiographic sign of coronary zutery obstruction. Arch Intern Med 1920:26:244-253. 8. Christian TF, Clements IP, Behrenbeck T, Huber KC, Chesebro JH, Gersh BJ, Gibbons RJ. Limitations of the electrocardiogram in estimating infarction size after acute reperfusion therapy for myocardial infarction. Ann Inrem Med 1991; 114:264-270. 9. Yusuf S, Lopez R, Maddison A, Maw P, Ray N, McMillan S, Sleight P. Value of electrocardiogram in predicting and estimating infarct size in man. Br Heart J 1979;42:286-293. 10. Ross AM, for the TIM1 Investigators. Electrocardiographic and angiographic correlations in myocardial infarction patients treated with thrombolytic
agents: a report from the NHLBl Thrombolysis in Myocardial infarction (TIMI ) trial. JAm Coil Cardiol 1985;2:495-502. 11. “on Ersen R. Schmidt W, Uebis R, Edelman B, Effert S, Sinly J, Rau G. Myocardial infarction and thrombolysis: electrocardiographtc short term and long term results using precordial mapping. Br Hecrrt J 1985;54: 6-10. 12. Savage RM. Wagner GS, Ideker RE. Podolsky SA, Hackel DB. Correlation of postmortem anatomic findings with electrocardiographic changes in patients with typical anterior and posterior infarct\. Ciwu/atr,,rr 1917;55:279-285. 13. Palmeri ST, Harrison DG, Cobb FR. Morris KG, Harrell FE, ldeker R. Selvester RH, Wagner GS. A QRS scormg system for assessmg left ventricular function after myocardial infarction. N Efzg/ .I Med 1982; 306:4-9. 14. Schaper J. Ultrastructural arpects of ixhemia and reperfwion in canine and human heart. In: Effen S, van Essen R. eds. Thrombolysis: Fact\ and Hope\. Darmstadt, Germany: Steinkopff, 1986: l-53. 15. Vermeer F, Simoons ML, Bbr FW, Tijssen JGP. van Domburg RT. Serruys PW, Verheugt FWA, Res JCJ, de Zwaan C. van der Laarw A, Krauss XH, Lubsen J, Hugenholtz PG. Which patients benefit mobt from early thrombolytic therapy with intracoronary streptokinase? Cir-culution 1986; 74: 1379- 1389. 16. Hindman N, Grande P, Harrell FE, Anderson C, Harrison D, ldcker RE, Selvester RH. Wagner GS. Relation between electrocardiographic and entymatic method? of estimatmg acute myocardial Infarct \ire. Arrr .I c‘w&/ 1986;58:31-35. 17. Swedberg K. Held P, KJekskes J. Rasmussen K, Rydm L. Wedel H. on behalf of the CONSENSUS II Study Group. Effect\ of the early administration of enalapril on mortality in patient5 with acme myocardial infarction. N &~1 .I Med 1992;327:678-684. 18. Nabel EC, Top01 EJ, Galeana A, Ellis SG, Bates ER, Werns SW. Walton JA, Muller DW, Schwaiger M, Pitt B. A randomized placebo-controlled trial of combined early intravenous captopril and recombinant tissue-type plasmmogen activator therapy in acute myocardial infarction. J Am Co// Colz/k~/ 1991;11:467-473. 19. Kingma JH. van Gilst WH, Peels CH. Dambrink JH, Verheugt FW. Wielenga RP. Acute intervention with captopril during thrombolysis in patients with first anterior myocardial infarction: results from the Captopril and Thromholyqis Study (CATS). Eur Heart J 1994: 15:898-907.
Coronary Vasomotor Function in a Normotensive, Nondiabetic Referral Population With Normal Coronary Arteriograms Jan L. Houghton,
MD, Vivienne
David
E. Smith, MD, Warren M. Breisblatt, MD, Nancy S. Strogatz, PhD, and Albert A. Carr, MD
oronary vasomotor function, defined as potential for vasorelaxation and augmentation of coronary C blood flow, is adversely affected by multiple factors, including increased age, systemic hypertension, left ventricular hypertrophy, hyperlipidemia, atherosclerosis, estrogen deficiency, diabetes mellitus, and longterm use of tobacco.‘-7 Pathophysiology of acute coronary syndromes, vasospastic angina, and progression of atherosclerosis all appear to be linked to coronary endothelial dysfunction and depressedcapacity for coronary relaxation.8-10The purpose of this study was to define the reference range for pharmacologically induced coronary vasodilation in a healthy referral cardiac population composed of normotensive, nondiabetic subjects with normal coronary arteriograms that From the Division of Cardiology, Albany Medical College, Albany, New York. This study was supported by Grant HE0262 from the National Heart, lung, and Blood Institute, Bethesda, Maryland. Dr. Houghton’s address is: Division of Cardiology, A-44, Albany Medical College, New Scotland Avenue, Albany, New York 12208 Manuscript received September 13, 1995; revised manuscript received and accepted January 1 1, 1996.
0 1996 by Excerpta Medica, All rights reserved.
Inc.
L. Henches,
BSN,
showed no angiographic evidence of atherosclerosis. This population is hereafter referred to as referral normal. Intracoronary Doppler measurementsof coronary blood flow velocity and quantitative coronary angiography were used to study 3 indicators of coronary vasomotor function: endothelium-dependent vasodilator response to intracoronary acetylcholine, endothehum-independent vasodilator response to intracoronary adenosine, and endothelium-independent vasodilator response to intracoronary nitroglycerin. ... Patients were recruited for the study after clinical referral for cardiac catheterization to evaluate chest pain. This investigation is part of a larger study whose purpose is to examine the influence of hypertension, left ventricular hypertrophy, hemodynamitally insignificant atherosclerosis, gender, and ethnicity on coronary vascular relaxation. Patients were excluded from the study because of a prior history of myocardial infarction, balloon angioplasty, bypass surgery, significant valvular heart disease, or other serious medical disorder. Vasoactive cardiac 0002.9 149/96/$15.00 PII SOOO2-9 149(96)00173-7
1241
lowed by baseline recording of coronary flow velocity. Adenosine was administered in 8, 16, and finally I 20 yg bolus infusions through the guiding catheter. Number Characteristics After return to baseline values, an infusion monorail catheter was advanced over the Doppler wire and 15 (48%) Tobacco use 9 (29%) Hyperlipidemio placed near the tip of the guiding catheter. Baseline 135 + 34 LDLcholesterol (mg/dl) recordings of coronary flow velocity were obtained 44t 10 HDL cholesterol (mg/dl) and followed by 2-minute graded infusions of ace34 + 24 WI (w/4 tylcholine (lo-*, 10p7, low6 mol/L) through an in27 2 6 Body mass index (kg/m’) fusion catheter via a syringe pump (Medfusion, Du62 2 10% Ejection fraction 101 2 17 LVMI (g/m’) luth, Georgia). This corresponded to 0.15,, 1.5, and 0.4 k 0.08 Relative wall thickness 15 pglmin of acetylcholine. Thirteen subjects (42%) 95 k 9 Mean arterial pressure (mm Hg) received twice the usual peak dose (30 pg/min or 95% 15 Serum glucose (mg/dl) 2.0 X lop6 mol/L) to evaluate an aggressive dosing Values are expressedes mecln2 SDor number(%I. protocol in normal patients. Coronary angiography HDL = highdensity lipoprotein; LDL = low-density lipoprotein; Lp(a) = lipswas repeated at the end of each graded infusion of protein(a); LVMI = left ventricular ~BII index. acetylcholine. Finally, 100 to 300 pg of nitroglycerin was administered by bolus infusion through the medications were withheld for 2 12 hours before car- guiding catheter and followed by coronary angiogdiac catheterization. Current tobacco smokers ab- raphy. Coronary artery diameter was measured with stained from smoking for ~8 hours. electronic digital calipers at the site of velocity mea... surements in response to each vasoactive drug inCoronary vascular function was tested in the fol- fusion. Peak coronary blood flow in response to the lowing manner: a 0.018-inch Doppler-tipped guide- endothelium-dependent and endothelium-indepenwire (Cardiometrics Flo-Wire [Mounain View, Cal- dent agents was calculated as the product of peak ifornia]) was placed in the proximal to midportion coronary flow velocity and cross-sectional area at the of the left anterior descending or circumflex arteries. site of velocity measurements. Percent increase Baseline coronary angiography was performed, fol- above baseline was calculated for each drug infusion. TABLE I Characteristics of 3 1 Normotensive Nondiabetic Subjects With Normal Coronary Angiograms
TABLE II Individual Clinical and Coronary Vasorelaxation
Properties of 3 1 Patients
Patient Number
Age (yd & Sex
Race
MAP
Total Chol.
LDL Chol.
HDL Chol.
LP(a)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
45F 46M 53F 45M 31M 44F 46F 47M 37M 60M 37M 33M 31M 43M 56F 54F 37M 56M 67M 67M 43M 42F 6OF 37M 33F 42F 43F 43F 35M 63M 5OF
w W w W W w W W W w W W W W W W W W W W W B B B B B B B B B B
103 86 86 89 108 93 89 92 86 112 112 102 101 84 91 85 92 96 100 86 102 100 86 89 112 75 100 99 92 103 93
212 181 225 205 164 220 210 184 232 175 156 135 188 194 280 249 202 201 259 256 205 207 221 179 158 167 184 156 231 164 201
126 120 150 156 109 149 152 121 175 87 112 81 109 133 200 193 150 145 184 182 148 121 143 117 81 96 111 88 190 121 130
48 38 40 39 45 63 43 43 41 36 35 43 65 36 32 36 43 41 48 52 41 36 51 52 69 49 42 54 26 34 58
20 44 4 34 9 35 18 18 6 25 1 34 49 32 4 44 5 16 75 50 39 73 61 61 42 29 44 90
moss index
(kg/m’);
CBF = coronaty
BMI = body
blood
fl ow; ETT = exercise
: 0 0 0 + 0 0 + + + + 0 i 0 i 0 0 : A + A 0 : + treadmill
low-densitylipoprotein cholesterol(mg/dl); Lp(a)= lipoprotein(a) (mg/dl); MAP =
1242
THE AMERICAN JOURNAL OF CARDIOLOGY@’
Tob.
VOL. 77
BMI
Positive Thallium or ETT
45 29 30 26 28 25 29 29 27 32 30 30 26 21 31 24 24 24 22 23 25 26 25 33 21 24 31 42 24 26 16
Adenosine
NTG
260 85 174 138 21 258 212 86 409 182 241 306 15 105 500 104 272 437 386 38 233 112 98 143 293 265 277 204 338 127 247
246 122 301 345 217 211 229 263 157 167 201 245 268 186 348 184 277 269 253 185 192 225 350 322 310 186 184 217 258 201 228
166 183 193 362 156 152 143 494 214 199 302 70 188 466 209 254 238 474 273 313 245 390 192 441 234 155 539 399 266 285
0 0 0 0 + 0 0 + 0 + 0 0 0 + + ; 0 0 0 0 0 0 0 0 + 0 0 0
test; HDL Chol.
meon arterial
Percent increase in CBF Acetylcholine
pressure
= high-density
lipoprotein
(mm Hg); NTG
= nitroglycerin;
JUNE 1, 1996
cholesterol
(mg/dlJ;
Tob. = tobacco
LDL Chol. use.
=
Thirty-one normotensive nondiabetic SWsubjects with normal coronary arteries were studied over a period of 2 years. The 0 h wosubjects included 10 black and 21 white s patients, of whom 13 were women and 18 f! awere men. Mean age -+ SD was 46 years d + 10. Important clinical variables are 9 a; 300listed in Table I as summary data for the S study group. Table II presents clinical and e test results for individual patients. Figure u zoos 0 1 demonstrates peak percent increase in B coronary blood flow in response to graded i? ‘O”0 or bolus infusion of acetylcholine, adenI osine, and nitroglycerin. e o! 8 0 s Peak response to acetylcholine infusion in this cohort resulted in a 212 t 22 _--1w; . , . , . , . , . , . , SE% increase in coronary blood flow ACb2 AChl At33 ACLP Adem NT72 above baseline (see Figure 1) , primarily through vasodilation of the microcirculaFIGURE 1. Percent increase in coronary blood flow (mean ? SD) in the left antion. This corresponds to a greater than k rror * descending or circumflex artery in response to raded infusion of the enthreefold increase above the baseline cor- dothelium-dependent agent acetylcholine (ACh) and # e endothelium-indepenonary blood flow. Of 13 patients who re- dent agents adenosine (Aden) and nitroglycerin (NTG) in 31 normotensive, nondiabetic subjects with normal coronary angiogmms. ACh 1 = 0.15 pg/min ceived the 30 yglmin acetylcholine infu- ACh; ACh2 = 1.5 pg/min ACh; ACh3 = 15 pg/min ACh; AChP = Peak resion, 10 had a greater response when sponse to ACh3 or to ACh4 (30 pg/min). compared with the 15 tiglmin infusion (resulting in an additionaf45 + 18 SE% increase in coronary blood flow), although re- trend toward a greater response to nitroglycerin comsponses to the 2 doses were not significantly differ- pared with acetylcholine (p = 0.07). ent. However, responses to the 2 highest doses of In this referral normal population, only 1 of 31 acetylcholine ( 15 and 30 pg/min) were significantly patients had an adenosine (endothelium-indepengreater than responses to 0.15 and 1.5 pg/min (p dent) response < 150% increase in coronary blood < 10m6). Minor (although not statistically signifi- flow (equivalent to flow reserve <2.5: 1) . However, cant) coronary artery dilatation occurred with each 12 patients had an acetylcholine (endothelium-deof the 4 infusion rates of acetylcholine used ( 1.1 t pendent) response <150% increase in coronary 1.0, 2.5 ? 1.5, 3.6 t 2.0, and 3.2 + 2.0 SE% di- blood flow. Ten of the 12 had an abnormal lipid proameter increase, respectively). Peak epicardial di- file defined by 1 or more of the following: elevated latation occurred during an infusion rate of 15 pg/ total cholesterol ( 2220 mg/dl) , elevated low-denmin. Only 2 of 13 patients receiving 30 pg/min had sity lipoprotein cholesterol (2 130 mg/dl), dean increase in coronary artery diameter greater than creased high-density lipoprotein cholesterol ( <40 that observed during the 15 pg/min infusion rate. mg/dl), elevated lipoprotein(a) ( 230 mg/dl) . Peak response to serial increasing bolus infusions However, linear regression analysis revealed no sigof adenosine was 237 ? 11 SE% increase in coro- nificant correlations between these lipid components nary blood flow above baseline (see Figure 1). Of and abnormal endothelium-dependent vasodilation the 3 bolus doses of adenosine used, the peak re- in this cohort. Similarly, increasing age, male gensponse occurred after 8 pg in 7 (23%), after 16 pg der, black race, and current tobacco use did not exin 15 (48%), and after 20 ,zg in 9 (29%). The 16 plain abnormal vasoreactivity. Our study demonstrates the expected range of pg dose resulted in a group average that was 9% and 20% higher than the 20 and 8 pg doses, respectively, findings for coronary blood flow augmentation secalthough these differences were not statistically sig- ondary to endothelium-dependent and endotheliumnificant. In this referral normal group, the peak ace- independent coronary vasodilation in a referral nortylcholine response was 90% of the peak adenosine mal cardiac population using intracoronary Doppler response. This is alternatively described as the en- velocity recordings via a guidewire. This technique dothelium-dependent to endothelium-independent uses a miniature Doppler-tipped wire configured relaxation ratio. In response to a mean nitroglycerin similarly to an angioplasty wire, allowing placement dose of 188 + 57 SD pg, peak response was 272 -+ in most segments of the epicardial coronary arteries. 24 SE% increase in coronary blood flow above base- We found that on average, coronary blood flow inline. After nitroglycerin, percent increase in coronary creases in referral normal patients by >200% or triartery diameter at the site of flow velocity measure- ple the basal flow in response to the endotheliumments was 25 2 3 SE% (p = 0.0001) . There were independent agents adenosine and nitroglycerin and no statistically significant differences in peak blood in response to the endothelium-dependent agent aceflow responses to acetylcholine, adenosine, or nitro- tylcholine. However, some referral normal subjects glycerin among these subjects, although there was a demonstrate mildly to even markedly depressed reBRIEF REPORTS 1243
sponses to acetylcholine. Although this reference referral normal subjects with endothelial dysfuncgroup had normal coronary angiograms, referral due tion is necessary to assessthe potential cardiovasto chest pain sets these patients apart from a purely cular risk of this finding in a presumed low-risk population. voluntary group with normal coronary arteries. Much has been written about vasodilation of diseased and “control” human coronary arteries using an intravascular Doppler mounted catheter of the 1. Celermajer DS, Sorensen KE, Spiegelholter DJ, Georgakopoulos D, RobinMillar Velocimeter (Houston, Texas) type.11-14Be- son J, Deanfield JE. Aging is associated with endothelial dysfunction in healthy years before the age-related decline in women. J Am Coil Cardiol cause of its catheter-based configuration, only prox- men 1994;24:471-476. imal straight segments of the coronary arteries may 2. Treasure CB, Klein L, Vita JA, Manoukian SV, Renwick GH, Selwyn AP, be safely and easily accessed with this technique. Ganz P, Alexander RW. Hypertension and left ventricular hypertrophy are associated with impaired endothelium mediated relaxation in human coronary This technique is also subject to a greater likelihood resistance vessels. Circulation 1993;87:86-93. of artifact and poorer signal quality secondary to the 3. Zeiher A, Drexler H, Wollschlager H, Just H. Modulation of coronary vasize and relative inflexibility of the catheter and dif- somotor tone in humans: progressive endothelial dysfunction with different stages of coronary atherosclerosis. Cimdation 1991;83:391-401, ficulty in ensuring coaxial positioning. With use of early 4. Drexler H, Zeiher AM. Endothelial function in human coronary arteries in this technique, endothelium-dependent and endothe- viva: focus on hypercholesterolemia. Hypertension 199 1;18( suppl):II-90-11. lium-independent vasodilation has been reported in 99. 5. Herrington DM, Braden GA, Williams JK, Morgan TM. Endothelial depencontrol subjects defined variou~ly.~‘-‘~ In some dent coronary vasomotor responsiveness in postmenopausal women with and cases, mild coronary disease in the study vessel and/ without estrogen replacement therapy. Am J Cardiol 1994;73:951-952. JE, Rossen JD, Oskarsson HJ, Minor RL Jr, Lopez AG, Winniford or severe disease in another vessel were allowed. 6.MD.Quillen Acute effect of cigarette smoking on the coronary circulation: constriction Hypertension, hyperlipidemia, hyperglycemia, and of epicardial and resistance vessels. JAm Cob Cnrdiol 1993;22:642-647, current tobacco use are commonly seen in previously 7. Vita J, Treasure C, Nabel E. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation 1990;8 1:49 l-497. reported control subjects. 8. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990’s. Our study describes coronary relaxation proper- Nature 1993; 362:801-809. 9. Brown BG, Zhao X-Q, Sacco DE, Albers JJ. Lipid lowering and plaque ties in a referral normal population, which we de- regression: new insights into prevention of plaque disruption and clinical events fined simply as normotensive nondiabetic subjects in coronary disease. Circulation 1993;87:1781- 1791. without angiographic coronary artery disease. Our 10. Haskell WL, Alderman EL, Fair JM, Maron DJ, Mackey SF, Superko R, PT, Johnstone IM, Champagne MA, Krauss RM, Farquhar JW. Effects study suggests that an optimal intracoronary adeno- Williams of intensive multiple risk factor reduction on coronary atherosclerosis and clinsine bolus infusion is 16 pg. Similarly, an optimal ical cardiac events in men and women with coronary artery disease: the Stanford intracoronary acetylcholine infusion rate appears to Coronary Risk Intervention Project (SCRIP). Circulation 1994;89:975-990. 11. Wilson RF, Laughlin DE, Ackell PH, Chilian WM, Holiday MD, Hartley be 30 pglmin. We found that 39% of referral normal CJ, Armstrong ML, Marcus ML, White CW. Transluminal, subselective measubjects had evidence of endothelial dysfunction, de- surement of coronary artery blood flow velocity and vasodilator reserve in man. 1985;72:82-92. fined as reduced endothelium-dependent relaxation Circulation 12. Houghton JL, Frank MJ, Carr AA, van Dohlen Tw, Prisant LM. Relations ( < 150% increase in coronary blood flow above among impaired coronary flow reserve, left ventricular hypertrophy and thallium perfusion defects in hypertensive patients without obstructive coronary artery baseline). In a referral normal cardiac population, endothelium-independent coronary relaxation is nearly always normal, but endothelium-dependent relaxation may be depressed in a significant proportion of patients. Further study of the natural history of
Testosterone Joseph M. Zmuda,
Decreases
MS, Paul D. Thompson,
genetic control and have proved remarkably resistant to therapeutic manipulations.’ Of the commonly From the Divisions of Cardiology, The University of Pittsburgh, Pittsburgh, Pennsylvania and The Miriam Hospital and Brown University, InProvidence, Rhode Island This study was sup orted by National stitutes of Health Grant Ht.28467 and gifts Prom the Miriam Foundation, the Haire family, Wrlliam Jakober, and the McNulty family. Dr. Thompson’s address is: Preventive Cardiology, Suite 12 12, Kaufmann Building, University of Pittsburgh Medical Center, 200 lothrop Street, Pittsbur h, Pennsylvania. Manuscript received November 29, 9, 1996. 1995; revise f manuscript received and acceptedjanuary
0 1996 by Excerpta Medica, All rights reserved.
Inc
Lipoprotein(a)
MD, Roberta
ipoprotein (a) [ Lp (a)] has recently emerged as L an important risk factor for atherosclerotic car,diovascular disease.’ Lp (a) levels are largely under
1244
disease. J Am CoU Cardiol 1990;15:43-51. 13. Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolemic patients by Larginine. Lancer 1991;338:1546-1550. 14. Egashira K, Hirooka Y, Kai H, Sugimachi M, Suzuki S, Inou T, Tokeshita A. Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia. Circulation 1994;89:2519-2524.
Dickenson,
in Men
BS, Linda L. Bausserman,
PhD
used lipid-lowering medications, only high-dose niacin appears to reduce Lp(a) levels.2 Others have demonstrated that estrogen 3 and the anabolic-androgenie steroid stanozolo14 reduce Lp (a) concentrations in postmenopausal women, but to our knowledge, the effect of androgenic hormone administration on Lp(.a) in men has not been examined. Testosterone is normally aromatized to estradiol, and peripheral aromatization of testosterone is the major source of circulating estrogen in men.5 We recently examined the effect of testosterone aromatization on serum lipid and lipoprotein levels in men by administering testosterone alone or in combination with the aromatase inhibitor testolactone.6 Recent reports that 0002-9149/96/s 15.00 PII SOOO2-9149(96)001769
agents: a report from the NHLBl Thrombolysis in Myocardial infarction (TIMI ) trial. JAm Coil Cardiol 1985;2:495-502. 11. “on Ersen R. Schmidt W, Uebis R, Edelman B, Effert S, Sinly J, Rau G. Myocardial infarction and thrombolysis: electrocardiographtc short term and long term results using precordial mapping. Br Hecrrt J 1985;54: 6-10. 12. Savage RM. Wagner GS, Ideker RE. Podolsky SA, Hackel DB. Correlation of postmortem anatomic findings with electrocardiographic changes in patients with typical anterior and posterior infarct\. Ciwu/atr,,rr 1917;55:279-285. 13. Palmeri ST, Harrison DG, Cobb FR. Morris KG, Harrell FE, ldeker R. Selvester RH, Wagner GS. A QRS scormg system for assessmg left ventricular function after myocardial infarction. N Efzg/ .I Med 1982; 306:4-9. 14. Schaper J. Ultrastructural arpects of ixhemia and reperfwion in canine and human heart. In: Effen S, van Essen R. eds. Thrombolysis: Fact\ and Hope\. Darmstadt, Germany: Steinkopff, 1986: l-53. 15. Vermeer F, Simoons ML, Bbr FW, Tijssen JGP. van Domburg RT. Serruys PW, Verheugt FWA, Res JCJ, de Zwaan C. van der Laarw A, Krauss XH, Lubsen J, Hugenholtz PG. Which patients benefit mobt from early thrombolytic therapy with intracoronary streptokinase? Cir-culution 1986; 74: 1379- 1389. 16. Hindman N, Grande P, Harrell FE, Anderson C, Harrison D, ldcker RE, Selvester RH. Wagner GS. Relation between electrocardiographic and entymatic method? of estimatmg acute myocardial Infarct \ire. Arrr .I c‘w&/ 1986;58:31-35. 17. Swedberg K. Held P, KJekskes J. Rasmussen K, Rydm L. Wedel H. on behalf of the CONSENSUS II Study Group. Effect\ of the early administration of enalapril on mortality in patient5 with acme myocardial infarction. N &~1 .I Med 1992;327:678-684. 18. Nabel EC, Top01 EJ, Galeana A, Ellis SG, Bates ER, Werns SW. Walton JA, Muller DW, Schwaiger M, Pitt B. A randomized placebo-controlled trial of combined early intravenous captopril and recombinant tissue-type plasmmogen activator therapy in acute myocardial infarction. J Am Co// Colz/k~/ 1991;11:467-473. 19. Kingma JH. van Gilst WH, Peels CH. Dambrink JH, Verheugt FW. Wielenga RP. Acute intervention with captopril during thrombolysis in patients with first anterior myocardial infarction: results from the Captopril and Thromholyqis Study (CATS). Eur Heart J 1994: 15:898-907.
Coronary Vasomotor Function in a Normotensive, Nondiabetic Referral Population With Normal Coronary Arteriograms Jan L. Houghton,
MD, Vivienne
David
E. Smith, MD, Warren M. Breisblatt, MD, Nancy S. Strogatz, PhD, and Albert A. Carr, MD
oronary vasomotor function, defined as potential for vasorelaxation and augmentation of coronary C blood flow, is adversely affected by multiple factors, including increased age, systemic hypertension, left ventricular hypertrophy, hyperlipidemia, atherosclerosis, estrogen deficiency, diabetes mellitus, and longterm use of tobacco.‘-7 Pathophysiology of acute coronary syndromes, vasospastic angina, and progression of atherosclerosis all appear to be linked to coronary endothelial dysfunction and depressedcapacity for coronary relaxation.8-10The purpose of this study was to define the reference range for pharmacologically induced coronary vasodilation in a healthy referral cardiac population composed of normotensive, nondiabetic subjects with normal coronary arteriograms that From the Division of Cardiology, Albany Medical College, Albany, New York. This study was supported by Grant HE0262 from the National Heart, lung, and Blood Institute, Bethesda, Maryland. Dr. Houghton’s address is: Division of Cardiology, A-44, Albany Medical College, New Scotland Avenue, Albany, New York 12208 Manuscript received September 13, 1995; revised manuscript received and accepted January 1 1, 1996.
0 1996 by Excerpta Medica, All rights reserved.
Inc.
L. Henches,
BSN,
showed no angiographic evidence of atherosclerosis. This population is hereafter referred to as referral normal. Intracoronary Doppler measurementsof coronary blood flow velocity and quantitative coronary angiography were used to study 3 indicators of coronary vasomotor function: endothelium-dependent vasodilator response to intracoronary acetylcholine, endothehum-independent vasodilator response to intracoronary adenosine, and endothelium-independent vasodilator response to intracoronary nitroglycerin. ... Patients were recruited for the study after clinical referral for cardiac catheterization to evaluate chest pain. This investigation is part of a larger study whose purpose is to examine the influence of hypertension, left ventricular hypertrophy, hemodynamitally insignificant atherosclerosis, gender, and ethnicity on coronary vascular relaxation. Patients were excluded from the study because of a prior history of myocardial infarction, balloon angioplasty, bypass surgery, significant valvular heart disease, or other serious medical disorder. Vasoactive cardiac 0002.9 149/96/$15.00 PII SOOO2-9 149(96)00173-7
1241
lowed by baseline recording of coronary flow velocity. Adenosine was administered in 8, 16, and finally I 20 yg bolus infusions through the guiding catheter. Number Characteristics After return to baseline values, an infusion monorail catheter was advanced over the Doppler wire and 15 (48%) Tobacco use 9 (29%) Hyperlipidemio placed near the tip of the guiding catheter. Baseline 135 + 34 LDLcholesterol (mg/dl) recordings of coronary flow velocity were obtained 44t 10 HDL cholesterol (mg/dl) and followed by 2-minute graded infusions of ace34 + 24 WI (w/4 tylcholine (lo-*, 10p7, low6 mol/L) through an in27 2 6 Body mass index (kg/m’) fusion catheter via a syringe pump (Medfusion, Du62 2 10% Ejection fraction 101 2 17 LVMI (g/m’) luth, Georgia). This corresponded to 0.15,, 1.5, and 0.4 k 0.08 Relative wall thickness 15 pglmin of acetylcholine. Thirteen subjects (42%) 95 k 9 Mean arterial pressure (mm Hg) received twice the usual peak dose (30 pg/min or 95% 15 Serum glucose (mg/dl) 2.0 X lop6 mol/L) to evaluate an aggressive dosing Values are expressedes mecln2 SDor number(%I. protocol in normal patients. Coronary angiography HDL = highdensity lipoprotein; LDL = low-density lipoprotein; Lp(a) = lipswas repeated at the end of each graded infusion of protein(a); LVMI = left ventricular ~BII index. acetylcholine. Finally, 100 to 300 pg of nitroglycerin was administered by bolus infusion through the medications were withheld for 2 12 hours before car- guiding catheter and followed by coronary angiogdiac catheterization. Current tobacco smokers ab- raphy. Coronary artery diameter was measured with stained from smoking for ~8 hours. electronic digital calipers at the site of velocity mea... surements in response to each vasoactive drug inCoronary vascular function was tested in the fol- fusion. Peak coronary blood flow in response to the lowing manner: a 0.018-inch Doppler-tipped guide- endothelium-dependent and endothelium-indepenwire (Cardiometrics Flo-Wire [Mounain View, Cal- dent agents was calculated as the product of peak ifornia]) was placed in the proximal to midportion coronary flow velocity and cross-sectional area at the of the left anterior descending or circumflex arteries. site of velocity measurements. Percent increase Baseline coronary angiography was performed, fol- above baseline was calculated for each drug infusion. TABLE I Characteristics of 3 1 Normotensive Nondiabetic Subjects With Normal Coronary Angiograms
TABLE II Individual Clinical and Coronary Vasorelaxation
Properties of 3 1 Patients
Patient Number
Age (yd & Sex
Race
MAP
Total Chol.
LDL Chol.
HDL Chol.
LP(a)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31
45F 46M 53F 45M 31M 44F 46F 47M 37M 60M 37M 33M 31M 43M 56F 54F 37M 56M 67M 67M 43M 42F 6OF 37M 33F 42F 43F 43F 35M 63M 5OF
w W w W W w W W W w W W W W W W W W W W W B B B B B B B B B B
103 86 86 89 108 93 89 92 86 112 112 102 101 84 91 85 92 96 100 86 102 100 86 89 112 75 100 99 92 103 93
212 181 225 205 164 220 210 184 232 175 156 135 188 194 280 249 202 201 259 256 205 207 221 179 158 167 184 156 231 164 201
126 120 150 156 109 149 152 121 175 87 112 81 109 133 200 193 150 145 184 182 148 121 143 117 81 96 111 88 190 121 130
48 38 40 39 45 63 43 43 41 36 35 43 65 36 32 36 43 41 48 52 41 36 51 52 69 49 42 54 26 34 58
20 44 4 34 9 35 18 18 6 25 1 34 49 32 4 44 5 16 75 50 39 73 61 61 42 29 44 90
moss index
(kg/m’);
CBF = coronaty
BMI = body
blood
fl ow; ETT = exercise
: 0 0 0 + 0 0 + + + + 0 i 0 i 0 0 : A + A 0 : + treadmill
low-densitylipoprotein cholesterol(mg/dl); Lp(a)= lipoprotein(a) (mg/dl); MAP =
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THE AMERICAN JOURNAL OF CARDIOLOGY@’
Tob.
VOL. 77
BMI
Positive Thallium or ETT
45 29 30 26 28 25 29 29 27 32 30 30 26 21 31 24 24 24 22 23 25 26 25 33 21 24 31 42 24 26 16
Adenosine
NTG
260 85 174 138 21 258 212 86 409 182 241 306 15 105 500 104 272 437 386 38 233 112 98 143 293 265 277 204 338 127 247
246 122 301 345 217 211 229 263 157 167 201 245 268 186 348 184 277 269 253 185 192 225 350 322 310 186 184 217 258 201 228
166 183 193 362 156 152 143 494 214 199 302 70 188 466 209 254 238 474 273 313 245 390 192 441 234 155 539 399 266 285
0 0 0 0 + 0 0 + 0 + 0 0 0 + + ; 0 0 0 0 0 0 0 0 + 0 0 0
test; HDL Chol.
meon arterial
Percent increase in CBF Acetylcholine
pressure
= high-density
lipoprotein
(mm Hg); NTG
= nitroglycerin;
JUNE 1, 1996
cholesterol
(mg/dlJ;
Tob. = tobacco
LDL Chol. use.
=
Thirty-one normotensive nondiabetic SWsubjects with normal coronary arteries were studied over a period of 2 years. The 0 h wosubjects included 10 black and 21 white s patients, of whom 13 were women and 18 f! awere men. Mean age -+ SD was 46 years d + 10. Important clinical variables are 9 a; 300listed in Table I as summary data for the S study group. Table II presents clinical and e test results for individual patients. Figure u zoos 0 1 demonstrates peak percent increase in B coronary blood flow in response to graded i? ‘O”0 or bolus infusion of acetylcholine, adenI osine, and nitroglycerin. e o! 8 0 s Peak response to acetylcholine infusion in this cohort resulted in a 212 t 22 _--1w; . , . , . , . , . , . , SE% increase in coronary blood flow ACb2 AChl At33 ACLP Adem NT72 above baseline (see Figure 1) , primarily through vasodilation of the microcirculaFIGURE 1. Percent increase in coronary blood flow (mean ? SD) in the left antion. This corresponds to a greater than k rror * descending or circumflex artery in response to raded infusion of the enthreefold increase above the baseline cor- dothelium-dependent agent acetylcholine (ACh) and # e endothelium-indepenonary blood flow. Of 13 patients who re- dent agents adenosine (Aden) and nitroglycerin (NTG) in 31 normotensive, nondiabetic subjects with normal coronary angiogmms. ACh 1 = 0.15 pg/min ceived the 30 yglmin acetylcholine infu- ACh; ACh2 = 1.5 pg/min ACh; ACh3 = 15 pg/min ACh; AChP = Peak resion, 10 had a greater response when sponse to ACh3 or to ACh4 (30 pg/min). compared with the 15 tiglmin infusion (resulting in an additionaf45 + 18 SE% increase in coronary blood flow), although re- trend toward a greater response to nitroglycerin comsponses to the 2 doses were not significantly differ- pared with acetylcholine (p = 0.07). ent. However, responses to the 2 highest doses of In this referral normal population, only 1 of 31 acetylcholine ( 15 and 30 pg/min) were significantly patients had an adenosine (endothelium-indepengreater than responses to 0.15 and 1.5 pg/min (p dent) response < 150% increase in coronary blood < 10m6). Minor (although not statistically signifi- flow (equivalent to flow reserve <2.5: 1) . However, cant) coronary artery dilatation occurred with each 12 patients had an acetylcholine (endothelium-deof the 4 infusion rates of acetylcholine used ( 1.1 t pendent) response <150% increase in coronary 1.0, 2.5 ? 1.5, 3.6 t 2.0, and 3.2 + 2.0 SE% di- blood flow. Ten of the 12 had an abnormal lipid proameter increase, respectively). Peak epicardial di- file defined by 1 or more of the following: elevated latation occurred during an infusion rate of 15 pg/ total cholesterol ( 2220 mg/dl) , elevated low-denmin. Only 2 of 13 patients receiving 30 pg/min had sity lipoprotein cholesterol (2 130 mg/dl), dean increase in coronary artery diameter greater than creased high-density lipoprotein cholesterol ( <40 that observed during the 15 pg/min infusion rate. mg/dl), elevated lipoprotein(a) ( 230 mg/dl) . Peak response to serial increasing bolus infusions However, linear regression analysis revealed no sigof adenosine was 237 ? 11 SE% increase in coro- nificant correlations between these lipid components nary blood flow above baseline (see Figure 1). Of and abnormal endothelium-dependent vasodilation the 3 bolus doses of adenosine used, the peak re- in this cohort. Similarly, increasing age, male gensponse occurred after 8 pg in 7 (23%), after 16 pg der, black race, and current tobacco use did not exin 15 (48%), and after 20 ,zg in 9 (29%). The 16 plain abnormal vasoreactivity. Our study demonstrates the expected range of pg dose resulted in a group average that was 9% and 20% higher than the 20 and 8 pg doses, respectively, findings for coronary blood flow augmentation secalthough these differences were not statistically sig- ondary to endothelium-dependent and endotheliumnificant. In this referral normal group, the peak ace- independent coronary vasodilation in a referral nortylcholine response was 90% of the peak adenosine mal cardiac population using intracoronary Doppler response. This is alternatively described as the en- velocity recordings via a guidewire. This technique dothelium-dependent to endothelium-independent uses a miniature Doppler-tipped wire configured relaxation ratio. In response to a mean nitroglycerin similarly to an angioplasty wire, allowing placement dose of 188 + 57 SD pg, peak response was 272 -+ in most segments of the epicardial coronary arteries. 24 SE% increase in coronary blood flow above base- We found that on average, coronary blood flow inline. After nitroglycerin, percent increase in coronary creases in referral normal patients by >200% or triartery diameter at the site of flow velocity measure- ple the basal flow in response to the endotheliumments was 25 2 3 SE% (p = 0.0001) . There were independent agents adenosine and nitroglycerin and no statistically significant differences in peak blood in response to the endothelium-dependent agent aceflow responses to acetylcholine, adenosine, or nitro- tylcholine. However, some referral normal subjects glycerin among these subjects, although there was a demonstrate mildly to even markedly depressed reBRIEF REPORTS 1243
sponses to acetylcholine. Although this reference referral normal subjects with endothelial dysfuncgroup had normal coronary angiograms, referral due tion is necessary to assessthe potential cardiovasto chest pain sets these patients apart from a purely cular risk of this finding in a presumed low-risk population. voluntary group with normal coronary arteries. Much has been written about vasodilation of diseased and “control” human coronary arteries using an intravascular Doppler mounted catheter of the 1. Celermajer DS, Sorensen KE, Spiegelholter DJ, Georgakopoulos D, RobinMillar Velocimeter (Houston, Texas) type.11-14Be- son J, Deanfield JE. Aging is associated with endothelial dysfunction in healthy years before the age-related decline in women. J Am Coil Cardiol cause of its catheter-based configuration, only prox- men 1994;24:471-476. imal straight segments of the coronary arteries may 2. Treasure CB, Klein L, Vita JA, Manoukian SV, Renwick GH, Selwyn AP, be safely and easily accessed with this technique. Ganz P, Alexander RW. Hypertension and left ventricular hypertrophy are associated with impaired endothelium mediated relaxation in human coronary This technique is also subject to a greater likelihood resistance vessels. Circulation 1993;87:86-93. of artifact and poorer signal quality secondary to the 3. Zeiher A, Drexler H, Wollschlager H, Just H. Modulation of coronary vasize and relative inflexibility of the catheter and dif- somotor tone in humans: progressive endothelial dysfunction with different stages of coronary atherosclerosis. Cimdation 1991;83:391-401, ficulty in ensuring coaxial positioning. With use of early 4. Drexler H, Zeiher AM. Endothelial function in human coronary arteries in this technique, endothelium-dependent and endothe- viva: focus on hypercholesterolemia. Hypertension 199 1;18( suppl):II-90-11. lium-independent vasodilation has been reported in 99. 5. Herrington DM, Braden GA, Williams JK, Morgan TM. Endothelial depencontrol subjects defined variou~ly.~‘-‘~ In some dent coronary vasomotor responsiveness in postmenopausal women with and cases, mild coronary disease in the study vessel and/ without estrogen replacement therapy. Am J Cardiol 1994;73:951-952. JE, Rossen JD, Oskarsson HJ, Minor RL Jr, Lopez AG, Winniford or severe disease in another vessel were allowed. 6.MD.Quillen Acute effect of cigarette smoking on the coronary circulation: constriction Hypertension, hyperlipidemia, hyperglycemia, and of epicardial and resistance vessels. JAm Cob Cnrdiol 1993;22:642-647, current tobacco use are commonly seen in previously 7. Vita J, Treasure C, Nabel E. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation 1990;8 1:49 l-497. reported control subjects. 8. Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990’s. Our study describes coronary relaxation proper- Nature 1993; 362:801-809. 9. Brown BG, Zhao X-Q, Sacco DE, Albers JJ. Lipid lowering and plaque ties in a referral normal population, which we de- regression: new insights into prevention of plaque disruption and clinical events fined simply as normotensive nondiabetic subjects in coronary disease. Circulation 1993;87:1781- 1791. without angiographic coronary artery disease. Our 10. Haskell WL, Alderman EL, Fair JM, Maron DJ, Mackey SF, Superko R, PT, Johnstone IM, Champagne MA, Krauss RM, Farquhar JW. Effects study suggests that an optimal intracoronary adeno- Williams of intensive multiple risk factor reduction on coronary atherosclerosis and clinsine bolus infusion is 16 pg. Similarly, an optimal ical cardiac events in men and women with coronary artery disease: the Stanford intracoronary acetylcholine infusion rate appears to Coronary Risk Intervention Project (SCRIP). Circulation 1994;89:975-990. 11. Wilson RF, Laughlin DE, Ackell PH, Chilian WM, Holiday MD, Hartley be 30 pglmin. We found that 39% of referral normal CJ, Armstrong ML, Marcus ML, White CW. Transluminal, subselective measubjects had evidence of endothelial dysfunction, de- surement of coronary artery blood flow velocity and vasodilator reserve in man. 1985;72:82-92. fined as reduced endothelium-dependent relaxation Circulation 12. Houghton JL, Frank MJ, Carr AA, van Dohlen Tw, Prisant LM. Relations ( < 150% increase in coronary blood flow above among impaired coronary flow reserve, left ventricular hypertrophy and thallium perfusion defects in hypertensive patients without obstructive coronary artery baseline). In a referral normal cardiac population, endothelium-independent coronary relaxation is nearly always normal, but endothelium-dependent relaxation may be depressed in a significant proportion of patients. Further study of the natural history of
Testosterone Joseph M. Zmuda,
Decreases
MS, Paul D. Thompson,
genetic control and have proved remarkably resistant to therapeutic manipulations.’ Of the commonly From the Divisions of Cardiology, The University of Pittsburgh, Pittsburgh, Pennsylvania and The Miriam Hospital and Brown University, InProvidence, Rhode Island This study was sup orted by National stitutes of Health Grant Ht.28467 and gifts Prom the Miriam Foundation, the Haire family, Wrlliam Jakober, and the McNulty family. Dr. Thompson’s address is: Preventive Cardiology, Suite 12 12, Kaufmann Building, University of Pittsburgh Medical Center, 200 lothrop Street, Pittsbur h, Pennsylvania. Manuscript received November 29, 9, 1996. 1995; revise f manuscript received and acceptedjanuary
0 1996 by Excerpta Medica, All rights reserved.
Inc
Lipoprotein(a)
MD, Roberta
ipoprotein (a) [ Lp (a)] has recently emerged as L an important risk factor for atherosclerotic car,diovascular disease.’ Lp (a) levels are largely under
1244
disease. J Am CoU Cardiol 1990;15:43-51. 13. Drexler H, Zeiher AM, Meinzer K, Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolemic patients by Larginine. Lancer 1991;338:1546-1550. 14. Egashira K, Hirooka Y, Kai H, Sugimachi M, Suzuki S, Inou T, Tokeshita A. Reduction in serum cholesterol with pravastatin improves endothelium-dependent coronary vasomotion in patients with hypercholesterolemia. Circulation 1994;89:2519-2524.
Dickenson,
in Men
BS, Linda L. Bausserman,
PhD
used lipid-lowering medications, only high-dose niacin appears to reduce Lp(a) levels.2 Others have demonstrated that estrogen 3 and the anabolic-androgenie steroid stanozolo14 reduce Lp (a) concentrations in postmenopausal women, but to our knowledge, the effect of androgenic hormone administration on Lp(.a) in men has not been examined. Testosterone is normally aromatized to estradiol, and peripheral aromatization of testosterone is the major source of circulating estrogen in men.5 We recently examined the effect of testosterone aromatization on serum lipid and lipoprotein levels in men by administering testosterone alone or in combination with the aromatase inhibitor testolactone.6 Recent reports that 0002-9149/96/s 15.00 PII SOOO2-9149(96)001769