Effect of angiotensin-converting enzyme inhibitor on cardiopulmonary baroreflex sensitivity in patients with acute myocardial infarction

Effect of Angiotensin-Converting Enzyme Inhibitor on Cardiopulmonary Baroreflex Sensitivity in Patients With Acute Myocardial Infarction Makoto Hikosaka, MD, Fumio Yuasa, MD, Reisuke Yuyama, MD, Masayuki Motohiro, MD, Jun Mimura, MD, Akihiro Kawamura, MD, Tsutomu Sumimoto, MD, Tetsuro Sugiura, MD, and Toshiji Iwasaka, MD eurohumoral excitatory state results from abnormality of baroreflexes and reduced tonic restraint N of baroreflexes leads to neurohumoral excitation. The 1

cardiopulmonary baroreflexes originate mainly from the heart2 and modulate systemic vascular resistance, plasma catecholamines, and plasma renin activity.3,4 Previous studies have reported that cardiopulmonary baroreflexes are depressed after acute myocardial infarction (AMI) and improve gradually from the initial impairment.5,6 Angiotensin-converting enzyme (ACE) inhibitors improve survival of AMI7,8 and have been shown to modify cardiopulmonary baroreflexes in patients with congestive heart failure.9 However, the effect of ACE inhibitors on cardiopulmonary baroreflexes in patients with AMI is yet to be determined. Therefore, the present study was performed to evaluate the effect of the ACE inhibitor quinapril on cardiopulmonary baroreflexes in patients with AMI. •••

TABLE 1 Clinical Characteristics and Cardiopulmonary Baroreflex Sensitivity Patient No.

Age (yrs) & Sex

Location

EF (%)

CP at Day 5 (%)

CP at Day 10 (%)

⌬ CP (%)

Placebo Group 1 2

53/M 53/M

A A

62 39

28.7 7.0

66.5 26.8

37.8 19.8

3 4

62/M 75/M

A A

55 56

9.3 14.3

26.3 39.8

17.0 25.5

5 6 7 8 9 10 11 12 13 14 15 Mean ⫾SD

60/M 79/F 55/M 75/M 71/M 51/M 64/M 67/M 47/M 55/M 70/M 62 ⫾10

A I I A I A A A A A I

51 80 59 59 69 60 52 67 61 75 32 58 ⫾12

9.0 14.2 22.3 15.3 8.7 12.8 14.5 18.9 11.9 16.1 6.4 14.0 ⫾6.0

30.4 39.1 28.2 30.0 22.1 38.5 34.7 32.4 54.0 19.0 22.9 34.0 ⫾12.6

21.4 24.8 5.9 14.7 13.3 25.7 20.2 13.5 42.1 2.9 16.5 20.1 ⫾10.4

We studied 30 consecutive patients (27 men and 3 women) who were admitted to the coronary care unit with a first Q-wave AMI (anterior wall, 19 patients; inferior wall, 11 patients) and fulfilled the following criteria: (1) admission to the coronary care unit ⬍6 hours from onset of symptoms; (2) 1-vessel disease; (3) successful primary percutaneous transluminal coronary angioplasty (residual diameter stenosis ⬍50%) of a totally occluded infarct-related artery (Thrombolysis In Myocardial Infarction flow grade 0) ⬍12 hours from symptom onset; (4) no history of AMI, renal failure, or other major cardiovascular diseases, and (5) no clinical sign of heart failure or myocardial ischemia during the study period. Calcium antagonists, ␤ blockers, and nitrates were given according to the clinical needs but were withdrawn at least 48 hours before the study. All subjects gave their informed consent before the study. This study complies with the Declaration of Helsinki and the protocol was approved by the Ethical Committee of Kansai Medical University. Cardiopulmonary baroreflex provocation with lower body negative pressure was performed 5 days after the onset of AMI, and patients were randomly

A ⫽ anterior; CP ⫽ cardiopulmonary baroreflex sensitiviy; ⌬CP ⫽ the amount of increase in cardiopulmonary baroreflex sensitivity; EF ⫽ left ventricular ejection fraction; I ⫽ inferior.

From The Second Department of Internal Medicine, Kansai Medical University, Osaka; and Kochi Medical School, Kochi, Japan. This work was supported by Yoshitomi Pharmaceutical Industries, Tokyo, Japan. Dr. Hikosaka’s address is: CCU, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi City, Osaka, Japan, 570-8507. Manuscript received March 16, 2000; revised manuscript received and accepted June 9, 2000.

assigned to 2 groups: 15 patients received the oral ACE inhibitor quinapril at a dosage of 10 mg once daily for 5 consecutive days, and 15 patients received placebo orally once daily for 5 consecutive days. After a 5-day period, cardiopulmonary baroreflex provocation was repeated. Cardiopulmonary baroreflex prov-

©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 86 December 1, 2000

Quinapril Group 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Mean ⫾SD

63/F 58/M 65/M 56/M 37/M 71/M 61/M 63/M 62/M 58/M 66/M 49/M 53/F 50/M 65/M 58 ⫾8

A I I A I A A A I A I A I I A

55 51 63 69 59 42 59 63 79 44 66 53 73 52 38

15.7 11.5 16.7 6.9 39.6 16.8 13.8 14.6 10.3 19.0 21.0 19.4 15.8 22.3 13.3

43.9 79.6 28.0 18.2 67.0 54.4 62.0 37.0 43.7 174.3 62.0 59.3 54.6 64.5 25.2

28.2 66.1 11.3 11.3 27.4 37.6 48.2 22.4 33.3 155.3 41.0 39.9 38.8 42.2 11.9

58 ⫾12

17.1 ⫾7.4

58.2 ⫾36.4

41.1 ⫾35.1

0002-9149/00/$–see front matter PII S0002-9149(00)01209-1

1241

Care Corp, Irvine, California) through a Swan-Ganz catheter inserted from the internal jugular vein. Heart rate was calculated from the electrocardiogram. Blood samples for measurements of plasma noradrenaline and renin activity were obtained in both groups from the arterial line before cardiopulmonary baroreflex sensitivity assessment at days 5 and 10. Plasma noradrenaline was measured by high-performance liquid chromatography with electrochemical detection. Fractions from the highperformance liquid chromatography effluent containing tritium-labeled noradrenaline were assayed by liquid scintillation spectroscopy.11 Plasma renin activity was measured FIGURE 1. Changes in mean arterial pressure (mBP), heart rate, central venous presby radioimmunoassay.12 sure (CVP), and forearm vascular resistance (FVR) induced by lower body negative Results are expressed as mean pressure (–10 mm Hg) in the quinapril group (n ⴝ 15) and the placebo group (n ⴝ value ⫾ SD. Significance was estab15) studied at day 5 (open bars) and day 10 (hatched bars) after acute myocardial lished at p ⬍0.05. Unpaired 2-tailed t infarction. Data are expressed as mean ⴞ SD. *p <0.01 quinapril versus placebo test or chi-square analysis was used group. for comparison of unpaired sample. Two-way analysis of variance and Bonferoni’s test were used to evaluate the differences between the 2 groups at days 5 and 10. Analysis of covariance adjusting for age was performed to compare the 2 groups. Clinical characteristics and cardiopulmonary baroreflex sensitivity of all patients are reported in Table 1. Although there was no significant difference in central venous pressure between the 2 groups at day 10, changes in forearm vascular resistance during lower body negative pressure was significantly larger in the quinapril group than in the placebo group (12.3 ⫾ 6.2 vs 5.2 ⫾ 3, p ⬍0.05) (Figure 1). There was no significant difference in cardiopulmonary FIGURE 2. Change in cardiopulmonary baroreflex sensitivity from days 5 to 10 baroreflex sensitivity between the 2 after acute myocardial infarction in the quinapril group (n ⴝ 15, open circles) and in the placebo group (n ⴝ 15, closed circles). Cardiopulmonary baroreflex groups at day 5. Cardiopulmonary sensitivity increased significantly from days 5 to 10 in both groups. *p <0.01 baroreflex sensitivity increased signifiversus day 5. †p <0.05 quinapril versus placebo group. cantly from days 5 to 10 in both groups (quinapril group, 17 ⫾ 7% to 58 ⫾ 36%; placebo group, 14 ⫾ 6% to 34 ⫾ 13%), ocation was performed by applying lower body neg- but cardiopulmonary baroreflex sensitivity in the ative pressure to ⫺10 mm Hg. Data were collected quinapril group was significantly higher than that in during 2 minutes of the stimulus. Cardiopulmonary the placebo group at day 10 (Figure 2). Moreover, the baroreflex sensitivity was expressed as percent change amount of increase in cardiopulmonary baroreflex in forearm vascular resistance from rest to application sensitivity from days 5 to 10 was significantly larger of lower body negative pressure. Forearm blood flow in the quinapril group than in the placebo group (41 ⫾ was measured by a standard mercury-in-silastic strain- 35% vs 20 ⫾ 10%, p ⬍0.05). Although cardiopulmogauge plethysmography technique.10 Forearm vascu- nary baroreflex sensitivity had no significant relation lar resistance was calculated by dividing mean blood to left ventricular ejection fraction, infarct site, and pressure (mm Hg) by forearm blood flow (ml/min/ maximum creatine phosphokinase, cardiopulmonary 100 ml of forearm volume). Central venous pressure baroreflex sensitivity was inversely related to age (r ⫽ was recorded using a Baxter transducer (Baxter Health ⫺0.4, p ⬍0.05). However, when adjusted for age, 1242 THE AMERICAN JOURNAL OF CARDIOLOGY姞

VOL. 86

DECEMBER 1, 2000

there was a significant difference in cardiopulmonary baroreflex sensitivity between the 2 groups at day 10 (p ⬍0.05). There were no significant differences in plasma noradrenaline and renin activity between the 2 groups at day 5. Plasma noradrenaline and renin activity did not change significantly from days 5 to 10 in the placebo group, but plasma noradrenaline decreased significantly (416 ⫾ 200 to 331 ⫾ 170 pg/ml) and plasma renin activity increased significantly (1.9 ⫾ 1.6 to 6.5 ⫾ 5.9 ng/ml/hour) at day 10 in the quinapril group (p ⬍0.05). •••

We evaluated cardiopulmonary baroreflex sensitivity twice in the early phase of AMI and found that cardiopulmonary baroreflex sensitivity gradually improved (from days 5 to 10) after AMI, which was consistent with results of Grassi et al.6 However, the improvement in cardiopulmonary baroreflex sensitivity was greater in the quinapril group than in the placebo group. These findings indicate that quinapril treatment has a favorable effect on the improvement of cardiopulmonary baroreflex sensitivity after AMI. Both arterial and cardiopulmonary baroreflexes exert tonic restraint over sympathetic outflow, but the major defect is in the cardiopulmonary baroreflex control and not in the arterial baroreflex control of sympathetic activity in patients with heart failure.9,13 The technique used in the present study—lower body negative pressure— causes a change in central venous pressure without a significant change in arterial pressure, thus isolating the 2 sets of reflexes. The mechanism responsible for the improvement in cardiopulmonary baroreflex sensitivity after quinapril treatment is not entirely clear. Angiotensin II facilitates noradrenaline release from the sympathetic nerve endings.14 Animal studies have indicated that angiotensin II acts centrally to attenuate baroreflex control of the sympathetic activity.15,16 Furthermore, the increase in baroreflex sensitivity was associated with a reduction of angiotensin II in the area postrema.17 Although we did not measure angiotensin II levels before and after quinapril treatment to confirm the blockade of its formation, this probably occurred because plasma renin activity increased after quinapril treatment. Therefore, the reduction in circulating angiotensin II level most likely is responsible for the improvement in cardiopulmonary baroreflex sensitivity after quinapril treatment. Moreover, the ACE inhibitor not only decreases angiotensin II but also increases local concentrations of bradykinin. Considering the fact that central administration of bradykinin increases baroreflexes,18 this may be another mechanism accounting for the improvement in cardiopulmonary baroreflex sensitivity after quinapril treatment. Plasma noradrenaline levels depend not only on noradrenaline secretion, but also on tissue clearance and a reuptake process. Plasma noradrenaline has been shown to correlate strongly with direct intraneuronal recordings of sympathetic activity in patients with various diseases.19,20 Although we cannot exclude the possibility that the vasodilating effect of the

ACE inhibitor increased the tissue clearance process of plasma noradrenaline, the reduction in plasma noradrenaline is likely to represent a beneficial effect of ACE inhibitor treatment in patients with AMI. In this study, although not statistically significant, there were more anterior wall than inferior wall AMIs in the placebo group than in the quinapril group. Autonomic nerves are not distributed uniformly within the myocardium. Depending on localization, myocardial injury can produce different patterns and degrees of autonomic nervous system activation. However, the improvement in cardiopulmonary baroreflex sensitivity can occur even with necrotic destruction of cardiac receptors because neural plasticity may allow the remaining receptors to have greater importance with time. In conclusion, quinapril treatment improved cardiopulmonary baroreflex control of sympathetic activity and reduced sympathetic activity after uncomplicated AMI. The inhibitory effect of quinapril on sympathetic nerve activity may, at least in part, contribute to the known beneficial effects of ACE inhibitors on survival in patients with uncomplicated AMI.

1. Abboud FM, Thames MD, Mark AL. Role of cardiac afferent nerves in

regulation of circulation during coronary occlusion and heart failure. In: Abboud FM, Fozzard HA, Gilmore JP, Reis DJ, eds. Disturbances in Neurogenic Control of the Circulation. Bethesda, MD: American Physiological Society, 1981:65– 86. 2. Grassi G, Giannattasio C, Cuspido C, Bolla GB, Cleroux J, Ferrazzi P, Fiocchi R, Mancia G. Cardiopulmonary receptor regulation of renin release. Am J Med 1988;84(3A):97–104. 3. Abboud FM, Eckberg DL, Johansen UJ, Mark AL. Carotid and cardiopulmonary baroreceptor control of splanchnic and forearm vasoconstrictor resistance during venous pooling in man. J Physiol (Lond) 1979;286:173–184. 4. Grassi G, Gavazzi C, Cesura M, Picotti GB, Mancia G. Changes in plasma catecholamines in response to reflex modulation of sympathetic vasoconstrictor tone by cardiopulmonary receptors. Clin Sci 1985;68:503–510. 5. Mark AL, Mancia G. Cardiopulmonary baroreflexes in humans. In: Shepherd JT, Abboud FM, ed. Handbook of physiology, The Cardiovascular System. vol III. Part 2. Bethesda, MD: American Physiological Society, 1983:795– 814. 6. Grassi G, Giannattasio C, Seravalle G, Osculati G, Valagussa F, Zanchetti A, Mancia G. Cardiopulmonary receptor and arterial baroreceptor reflexes after acute myocardial infarction. Am J Cardiol 1992;69:873– 878. 7. The Acute infarction Ramipril Efficacy (AIRE) Study Investigators. Effects of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;432:821– 828. 8. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico. GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after acute myocardial infarction. Lancet 1994;343:1115–1122. 9. Dibner-Dunlop ME, Smith ML, Kinugawa T, Thames MD. Enalaprilat augments arterial and cardiopulmonary baroreflex control of sympathetic nerve activity in patients with heart failure. J Am Coll Cardiol 1996;27:358 –364. 10. Hokanson DE, Sumner DS, Standness E. An electrically calibrated plethysmograph for direct measurement of limb blood flow. IEEE Trans Biomed Eng 1975;22:21–25. 11. Keller R, Ove A, Medford I, Adamas RN. Liquid chromatogaraphic analysis of catecholamines. Life Sci 1976;19:995–1004. 12. Sowers JR, Gloub MS, Eggena PH, Catagnia RA. Influence of sodium hemostasis on dopamine modulation of aldosterone renin and prolactin in man. J Clin Endocrinol Metab 1982;54:121–126. 13. Dibner-Dunlap ME, Thames MD. Control of sympathetic nerve activity by vagal mechanoreflexes is blunted in heart failure. Circulation 1992;86:1929 – 1934. 14. Reid IA. Interactions between ANG II, sympathetic nervous system, and baroreceptor reflexes in regulation of blood pressure. Am J Physiol 1992;262: E763–E778. 15. Schmid PG, Guo GB, Abboud FM. Different effect of vasopressin and angiotensin II on baroreflexes. Fed Proc 1985;44:2388 –2392. 16. Hayashi J, Takeda K, Kawasaki S, Nakamura Y, Oguro M, Nakata T, Tanabe

BRIEF REPORTS

1243

S, Lee LC, Sasaki S, Nakagawa M. Central attenuation of baroreflex by angiotensin II in normotensive and spontaneously hypertensive rats. Am J Hypertens 1988;1:15S-22S. 17. Joy MD, Lower RD. Evidence that the area postrema mediates the central cardiovascular response to angiotensin II. Nature 1970;228:1301–1304. 18. Gerken VM, Santos RA. Centrally infused bradykinin increases baroreceptor reflex sensitivity. Hypertension 1992;19(suppl II):II-176 –II-181.

19. Ferguson DW, Berg WJ, Sanders JS. Clinical and hemodynamic correlates of sympathetic nerve activity in normal humans and patients with heart failure: evidence from direct microneurographic recordings. J Am Coll Cardiol 1990;16: 1125–1134. 20. Morlin C, Wallin BG, Eriksson BM. Muscle sympathetic activity and plasma noradrenaline in normotensive and hypertensive man. Acta Physiol Scand 1983; 119:117–121.

Factors Associated With Preventable Out-of-Hospital Nontraumatic Cardiac Arrest Takayuki Fujita, MD, Kazuo Kimura, MD, Toshiyuki Ishikawa, MD, Masami Kosuge, Makoto Shimizu, MD, Mitsugi Sugiyama, MD, Osamu Tochikubo, MD, and Satoshi Umemura, MD ecause ⬍20% of patients who have out-of-hospital cardiac arrest (CA) survive to discharge, adB mission to a hospital before the onset of CA is crucial. 1

More than half of all sudden deaths due to coronary heart disease are caused by ventricular fibrillation.2 This study was designed to identify factors associated with preventable out-of hospital CA, defined as CA that developed ⱖ1 hour after symptom onset. •••

The Department of Emergency Medicine, Yokohama City University Hospital, was established in 1989. It is involved in the management of virtually all out-of-hospital cases of CA occurring in a well-defined area with a population of approximately 750,000. From January 1, 1989 to March 31, 1997, 1,228 patients were admitted because of nontraumatic CA. All patients met the criteria for sudden death as defined by Kuller et al2 (death within 24 hours from onset of symptoms and ability to function in the community for ⬎24 hours before death). Information on patients was obtained immediately after admission from families, emergency medical technicians, persons near the patients at symptom onset, or the patients’ regular physician by a physician at our institute. Serum chemical analysis, chest X-rays, and transthoracic echocardiography were also performed. If aortic dissection or pulmonary embolism was suspected at examination, transesophageal echocardiography or computed tomography scanning was performed to rule out the possibility of acute coronary syndrome (ACS). In patients with equivocal diagnoses, necropsy was performed. Consequently, the diagnosis of ACS was established in 386 patients (32%) (279 men and 107 women; mean age [⫾SD], 66 ⫾ 12 years, range 27 to 93) who met ⱖ1 of the following criteria: (1) symptoms suggesting myocardial ischemia before CA (excluding patients with a suspected diagnosis of aortic dissection or pulmonary embolism); (2) ST-segment elevation of ⱖ0.2 mV in From the Department of Cardiology, Yokohama City University Medical Center, Yokohama, Japan. Dr. Kimura’s address is: The Department of Cardiology, Yokohama City University Medical Center, 4-57, Urafune-cho, Minami-ku, Yokohama 232-0024, Japan. Manuscript received March 16, 2000; revised manuscript received and accepted June 5, 2000.

1244

©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 86 December 1, 2000

MD,

ⱖ2 leads on electrocardiogram obtained after resumption of spontaneous rhythm; and (3) fresh coronary thrombi associated with major epicardial coronary arteries on necropsy. ACS was diagnosed by medical history only in 231 patients, by electrocardiograms only in 48, by necropsy only in 35, and by ⱖ2 of the criteria described above in 72 patients. Unstable angina was defined as crescendo angina (severe, prolonged, or frequent) superimposed on a pre-existing pattern of relatively stable angina pectoris or angina pectoris of recent onset (usually within 1 month). Symptom onset was quantified on a scale from 1 to 8 METs according to generally accepted values.3 Time of symptom onset was defined as when symptoms occurred suddenly and persisted until arrest. Time of arrest was defined as when complete loss of muscular strength and responsiveness was witnessed. The presence or absence of the following risk factors were recorded: hypertension (currently or previously requiring treatment) and diabetes mellitus treated by diet, drugs, or insulin, or a fasting blood sugar level ⬎120 mg/dl irrespective of treatment. Ischemic heart disease was diagnosed if the patient had a history of angina pectoris or myocardial infarction. To calculate an approximate least-square (fitted) curve when 2 harmonics (cycles) were postulated, and to determine the times of maximum and minimum values, the Memcalc program4 was used for nonlinear least-squares regression analysis (Mem Calc 200/1,000 program, GMS Co., Ltd., Tokyo, Japan). Baseline data are presented as percentages or as mean ⫾ SDs. Differences in the distribution of selected variables were examined with the chi-square test. Multivariate logistic regression analysis was performed to assess the combined effects of variables on the interval from symptom onset to out-of-hospital CA. A p value of ⬍0.05 was considered statistically significant. Among the 386 patients who had out-of-hospital CA caused by ACS, there was a seasonal trend characterized by peak incidence in winter and lowest incidence in summer (Figure 1). In 339 of 386 patients (88%), the time of symptom onset was established (Figure 2); the circadian rhythm had primary peak 0002-9149/00/$–see front matter PII S0002-9149(00)01210-8