Angiotensin Infusion Effects on Left Ventricular Function

Angiotensin Infusion Effects on Left Ventricular Function • Assessment in Normal Subiects and an Patients with Coronary Disease Jesus A. Bianco, M.D.; Wa"en K. Laskey, M.D.; Dale G. Makey, M.D.; and Rex B. Shafer, M.D.

Radlonucllde multlgating of the cardiac cycle was employed to assess etlects of angiotensin infusion on left ventricular function. In sb: normal subjeds, angiotensin Infusion decreased heart rate (HR) from 7l ± SEM 2 to 57 ± 2 beats/miD (P < 0.001); wbDe systolic blood pressure (BP) increased from 119 ± 2 to 178 ± 1 mm II& (P < 0.001), and ejection fraction (EF) declined from 58 ± 1 to 47 ± 2 percent (P < 0.05). In contrast, in 11 normal subjects, supine exercise increased IIR

R adionuclide methods now permit accurate and

reproducible measurement of left and right ventricular ejection fractions. 1.2 They also allow evaluation of regional wall motion of the left and right ventricles. 3 Furthermore, radioisotopes have been used to assess left ventricular ( LV) function under exercise.u In patients with coronary-artery disease (CAD), exercise-induced ischemia is manifested by a fall or no change of the resting ejection fraction ( EF), and the appearance of regional wall motion abnormalities. Investigation of the response of the LV to acute arterial hypertension is of potential clinical benefit This is because afterload stress increases LV work and elevated myocardial oxygen requirements. 8 While cardiac catheterization data have been published in relation to the effect on LV function of systolic hypertension provoked by isometric exercise, 7 there is no information on the LV ejection fraction response to afterload augmentation produced by angiotensin infusion. The purpose of the present work employing radionuclide multigated scintigraphy was to compare the influence of acute arterial hypertension, evoked by angiotensin infusion, on LV performance in normal individuals and in patients with CAD. The investigation also included evaluation of the functional response to submaximal exercise.

•From the De~arbnents of Medicine (Cardiovascular Section) and Nuclear Medicine, Veterans Administration Medical Center and University of Minnesota, Minneapolis. Manuscript received November 2, 1978; revision accepted June27 &print requem: Dr. Shafer, VA Hospital, Minneapolis 55417

172

B~CO

ET AL

and systoUc BP by 55 and 49 percent, whereas EF increased from 64 ± 1 to 71 ± 1 (P < 0.001). In ten patients with CAD, angiotensin infusion produced no change in HR, increased systoUc BP by 34 percent, and decreased EF by 11 percent. Angiotensin infusion induced left ventricular depression in normal subjects and in patients with CAD. It cannot substitute for exercise . In intervention radionucllde ventriculography.

MATERIALS AND METIIODS

Scintigraphic determination of LV function has been reported in a separate publication from this laboratory.s Briefly, multiple gating of the cardiac blood-pool was carried out following the method of Burow et al. 9 Imaging commenced after the administration of 20 mCi oomtechnetium and in vivo red blood celllabeling. 10 The modified 40• left anterior oblique ( LAO) projection was used for best separation of the left ventricular chamber. A large field of view Anger camera was fitted with a low-energy all-purpose collimator. The camera was interfaced to a 32K minicomputer. Data acquisition was performed in the histogram mode using R-wave gating. The cardiac cycle was reconstructed utilizing 28 data frames. The average acquisition required 300,000 counts per frame. Framing rate was 0.04 to 0.02 sec per frame, in accordance to heart rate. For measurement of the LV ejection fraction, counts in the LV region-of-interest were computed in each frame using a semiautomatic computer program. The EF resulted from subtracting end-systolic counts from enddiastolic counts, and division by end-diastolic counts, after appropriate background subtraction. In an initial study in 24 patients with normal and abnormal hearts,s the correlation coefficient between scintigraphic and contrast angiographic (one-plane 30° right anterior oblique [RA01, Dodge method) EFs was 0.82 ( P 0.001, covariance = 0.04), comparing favorably with data of Folland et al. 11 Intervention studies, however, required shorter acquisition times ( < 2 minutes). A computer program was therefore developed to determine EFs in 75,000 counts-per-frame acquisitions. The validity of this procedure to measure EF was established by demonstrating an unchanged correlation with contrast angiography ( r = 0.85). The reproducibility of this technique to measure paired EFs within one hour's time was excellent ( n= 20, variation in ejection fraction units was ± SD 6 percent of the arithmetic mean). Regional LV wall motion abnormalities were reviewed jointly by three observers. Agreement was reached by consensus. Wall motion was scored as normal, hypokinetic, or dyskinetic (paradoxic pulsation).

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CHEST, 77: 2, FEBRUARY, 1980

Control Groups In 11 subjects without heart disease (age range 26 to 58 years), LV ejection fraction and wall motion were assessed at rest and during submaximal supine exercise. These individuals were normal volunteers or patients without heart disease as demonstrated by normal coronary arteries at the time of coronary angiography. The latter was performed to evaluate significance of chest pain. Additionally, six patients (age range 45 to 60 years) who underwent cardiac catheterization for suspected CAD, and who were found to have normal coronary arteries, were given angiotensin infusion. In these six patients, LV function was studied at rest and during angiotensin stress.

Patients with CAD The experimental group was comprised of ten patients with CAD and stable angina (age range 40 to 60 years) who did not have evidence of heart failure. All patients had significant coronary stenosis, ie, all had 70 percent stenosis of at least one coronary artery. None of the patients with CAD were on propranolol therapy. In addition, these patients were not on other medications which may have influenced the results. Specifically, they had not taken nitrates within four hours of the study.

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Experimental Protocol In 11 individuals without demonstrable CAD, bicycle supine exercise was conducted to increase both resting heart rate and systolic blood pressure by 60 to 70 percent. Similarly, in six additional subjects without CAD, an intravenous infusion of angiotensin II (Hypertensin) was administered to increase supine systolic blood pressure by 60 to 70 percent of the control values. The concentration of angiotensin II employed was 2J.g/min (range 1 to 3 ~g/min). In these two control groups, L VEF and wall motion were determined at rest, and during either supine submaximal exercise or the angiotensin infusion. The levels of heart rate and arterial pressure during the noted interventions were preselected to correspond to those expected in patients with CAD under identical experimental conditions. In ten individuals with CAD, the following sequence was followed. First, LV function was assessed under resting conditions. Subsequently, the patient was exercised to an endpoint corresponding to that achieved by the control subjects, in terms of heart rate and blood pressure. The LV ejection fraction and wall motion were determined at the preselected endpoint, under a steady work load. Angina or ST segment depression > 1 mm (and lasting for at least 80 msec) was seen in five of the ten patients. Acquisitions for the multigated study in the patients with angina lasted two minutes, after which, sublingual nitroglycerin was immediately administered. Patients then were allowed to rest for 20 minutes to

Table I --Data Ob~ Be/ore and Duri,.. E:cerdae in 11 Subject. JJ'itla-t C.4D Rest Heart rate (BPM)

Exercise

69±SEM1.0 107±1.0

p

<0.001

Systolic blood pressure (mm Hg)

128±2.0

191±2.0

<0.001

LV ejection fraction (percent)

64±1.0

71 ±1.0

<0.001

CHEST, 77: 2, FEBRUARY, 1980

Table 2---Dala Obklined Be/ore and Duri,.. A,..IOieiUin llln/ruioN in Sb Subject• .nt,._t CAD p

Rest

Angiotensin II

72±2

57±2

<0.001

Systolic blood pressure (mm Hg)

119±1

178±1

<0.001

LV ejection fraction (percent)

58±1

47±1

<0.05

Heart rate (BPM)

minimize residual exercise efFects. Following this recovery

period, an infusion of angiotensin was started to increase the systolic blood pressure to 175 to 180 mm Hg. At this level of arterial hypertension, the radioisotopic EF and wall motion were again obtained. All data are expressed as mean ± standard error of the mean ( SEM). To ascertain statistical significance paired ttests were calculated. An informed written consent was procured in all patients and normal subjects. REsULTS

Data obtained in 11 normal subjects are presented in Table 1. During exercise, the increases for heart rate and systolic blood pressure in this control group were 55 and 49 percent, respectively. The EF was augmented by 11 percent relative to the resting state. Table 2 reveals the percentage changes in six normal individuals receiving angiotensin infusion. Heart rate decreased by 21 percent, while blood pressure increased by 50 percent. The range of systolic blood pressures under angiotensin was 175 to 180 rom Hg; the diastolic pressures were between 70 and 120 rom Hg. The decrease in LV ejection fraction in this control group was 19 percent. In four of the six patients, the decline in EF was substantial, whereas in two patients it was within the limits of error of ejection fraction measurement. Results recorded in ten patients with significant CAD are shown in Table 3. Under the stress of exercise, the increase of heart rate was 63 percent, that of aortic pressure was 42 percent, and there was TableS-Data Obtained Be/ore E:cereiae, Duriq E:cereiH, and Duri,.. ..4,..1oteun II lnjudoN in Ten Patiena. IIIith CAD RA:.st

Exercise

P*

Angiotensin II P*

Heart rate (BPM) 68 ± 1 111 ± 1 <0.001 Systolic blood pressure (mm Hg) LV ejection fraction (percent)

131±1 186±2 <0.001

65±1

65±1

NS

76 ± 1

NS

175±1

<0.001

58±1

0.02

• As compared with control.

ANGIOHNSIN INFUSION EFFECTS 173

no change in EF. In contrast, angiotensin infusion evoked the following changes in these patients with CAD. Blood pressure increased by 34 percent, while EF fell by 11 percent. The range of blood pressures during angiotensin infusion was 160 to 190 mm Hg for the systolic, and 85 to 120 mm Hg for the diastolic pressures. DISCUSSION The inotropic effect of angiotensin is disputed. Positive 12 and negative 13 inotropic responses have been reported in isolated mammalian preparations. Data in. unanesthetized animals, in normal individuals, and in patients with heart disease are consistent with the idea that angiotensin infusion provokes a depression of LV function. 14-18 However, other investigators have found in man an increase in cardiac output and stroke work caused by administration of the drug. 19.2° These disparate results are best explained by the fact that in the latter investigations, LV function was indirectly assessed. That is, pump performance indices which were used could have been influenced by both cardiac and extra-cardiac factors. The findings in this study demonstrate that acute arterial hypertension, induced by angiotensin infusions, equally depresses LV ejection fraction in normal subjects and in patients with CAD. This effect of angiotensin stress on LV ejection fraction has not been previously documented and appears to reflect a greater increase in LV end-systolic volume, relative to end-diastolic volume, under conditions of angiotensin hypertension. 17 Our results additionally indicate that approximately 60 percent of normal individuals and patients with CAD will have a marked decline in LV ejection fraction as a response to angiotensin stress. The remaining 40 percent will exhibit a minimal response to such stress. Mechanisms by which angiotensin-mediated systolic hypertension produces a decrement in LV performance are several: ( 1) there is an increased impedance to LV ejection; 21 ( 2) there may be vagal depression of the myocardium, 22 as baroreceptors are stimulated by elevated arterial pressure; ( 3} coronary vasoconstriction may be a consequence of angiotensin action; 13•18.23 and ( 4) angiotensin may have, after all, a negative inotropic effect. 13•18 Any of these mechanisms, singly or in combination, will determine the extent of depression of LV performance in the individual under testing. This may account for the differences in experimental findings which were noted by investigators in the past. Finally, we observed a difference in heart rate response during angiotensin infusion between both 174 BIANCO ET AL

experimental groups. That is, in subjects without CAD we found the expected reflex bradycardia. In patients with CAD, this was not observed. Our experimental design, which was modified for the patients with CAD, is responsible for the discrepancy. In the normal subjects, exercise and angiotensin stresses were tested on separate occasions. However, in the patients with CAD, it is probable that residual enhanced sympathetic tone persisted after exercise, offsetting a reflex decrease in heart rate. Parenthetically, enhanced sympathetic drive in these patients likely precluded a more pronounced decrement in ejection fraction (Table 3). In summary, our data led to the following three major conclusions: (1) angiotensin-induced arterial hypertension equally depresses LV ejection fraction in normal subjects and in patients with CAD; (2} this effect of angiotensin is variable; and ( 3) the angiotensin infusion test cannot substitute for exercise in intervention radionuclide ventriculography. lb:FERENCES

1 Strauss HW, Pitt B: Evaluation of cardiac function and structure with radioactive tracer techniques. Circulation 57:645-654, 1978 2 Tobinick E, Schelbert HR, Henning H, et al: Right ventricular ejection fraction in patients with acute anterior and inferior myocardial infarction assessed radionuclide angiography. Circulation 57:1078-1084, 1978 3 Nichols AB, McKusick KA, Strauss HW, et al: Clinical utility of gated cardiac blood pool imaging in congestive left heart failure. Am J Med 65:785-793, 1978 4 Borer JS, Bacharach SL, Green MV, et al: Real-time radionuclide cineangiography in the noninvasive evaluation of global and regional left ventricular function at rest and during exercise in patients with coronary-artery disease. N Engl J Med 296:839-844, 1977 5 Berger HJ, Reduto LA, Johnstone DE, et al: Global and regional left ventricular response to bicycle exercise in coronary artery disease: Assessment by quantitiative radionuclide angiocardiography. Am J Med 66:13-21, 1979 6 Sonnenblick EH, Ross JR Jr, Braunwald E : Oxygen consumption of the heart-newer concepts of its multifaceted determination. Am J Cardiol22:328-336, 1968 7 Flessas AP, Connely GP, Handa S, et al: Effect of isometric exercise on the end-diastolic pressure, volumes, and function of the left ventricle in man. Circulation 53:839-844, 1976 8 Bianco JA, Makey DG, Laskey WK, et al: Radionuclide left ventricular dVI dt for the assessment of cardiac function in patients with coronary disease. J Nucl Med 20: 106, 1979 9 Burow RD, Strauss HW, Singleton R, et al : Analysis of left ventricular function from multiple gated acquisition cardiac blood pool imaging: Comparison to contrast angiography. Circulation 56:1024-1028, 1977 10 Pavel DG, Zimmer AM, Patterson VN: In vivo labeling of red blood cells with ee•Tc: A new approach to blood pool visualization. J Nucl Med 18:305-308, 1977

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11 Folland ED, Hamilton GW, Larson SM, et al: The radionuclide ejection fraction: A comparison of three radionuclide techniques with contrast angiography. J Nucl Med 18:1159-1166, 1977 12 Kobayashi M, Furukawa Y, Chiba S: Positive chronotropic and inotropic effects of angiotensin II in the dog heart. European J Pharmacol50:17-25, 1978 13 Downing SE, Sonnenblick EH: Effects of continuous administration of angiotensin II on ventricular performance. Am J Physiol 18:585-592, 1963 14 Olmstead F, Page IH: Hemodynamic aspects of prolonged infusion of angiotensin into unanesthetized dogs. Circ Res 16:140-149, 1965 15 Finnerty FA, Massaro GD, Chupkovich V, et al: Evaluation of the pressor, cardiac and renal hemodynamic properties of angiotensin II. Circ Res 9:256-263, 1961 16 Mueller HS, Gregory JJ, Gianelli S, et al : Systematic hemodynamic and myocardial metabolic effects of isoproterenol and angiotensin after open-heart surgery. Circulation 42:491-500, 1970

17 O'Rourke RA, Pegram B, Bishop VS : Variable effect of angiotensin infusion on left ventricular function. Cardiavase Res 6:240-247, 1972 18 Ronan JA Jr, Steelman RB, Schrank JP, et al : The angiotensin infusion test as a method of evaluating left ventricular function. Am Heart J 89:554-560, 1975 19 Yu PN, Luria MN, Finlayson JK: The effects of angiotensin on pulmonary circulation and ventricular function. Circulation 24 :1326-1337, 1961 20 Ross J Jr, Braunwald E: The study of left ventricular function in man by increasing resistance to ventricular ejection with angiotensin. Circulation 29:739-749, 1964 21 Sonnenblick EH, Downing SE: Mterload as a primary determinant of ventricular performance. Am J Physiol 204:604-612, 1963 22 Bianco JA, Freedberg LE, Powell JW: Influence of vagal stimulation on ventricular compliance. Am J Physiol 218: 264-269, 1970 23 Fowler NO, Holmes JC: Coronary and myocardial actions of angiotension. Circ Res 14:191-201, 1964

II World Conference on Lung Cancer Copenhagen-Malmo June 9-13, 1980

Arranged by: The International Association for The Study of Lung Cancer.

Conference Theme: to present a succinct evaluation of current knowledge related to prevention, diagnosis and treatment of lung cancer. Objectives: to examine the course of failures and success in each program area, thereby bringing into focus the primary needs for new approaches supported by ideas which emerge from this interaction between different specialities working in lung cancer in different countries. Structure: conferences, panels, symposia, round-table discussions, workshops, scientific and technical exhibitions and demonstrations. Topics: Prevention Epidemiology Respiratory Carcinogenesis Early Diagnosis and Staging Pathology

Surgery Radiotherapy Chemotherapy Immunotherapy Cellular Kinetics Lung Tumor Markers

CONFERENCE IS OPEN TO ANY PHYSICIAN, MEMBER OF THE HEALTH PROFESSION OR SCIENTIST WHO HAS AN INTEREST IN LUNG CANCER. For more information write: Linde Aile 48, DK-2720

CHEST, 77: 2, FEBRUARY, 1980

DIS CONGRESS SERVICE Copenhagen Vanlose, Denmark

ANGIOTENSIN INFUSION EFFECTS 175