AT1 angiotensin II receptor inhibition in pacinginduced heart failure: Effects on left ventricular performance and regional blood flow patterns

Journal of Cardiac Failure Vol. 4 No. 4 1998

Experimental Studies

AT 1 Angiotensin II Receptor Inhibition in PacingInduced Heart Failure: Effects on Left Ventricular Performance and Regional Blood Flow Patterns MARK J. CLAIR, BS, R. STEPHEN KROMBACH, BA, JENNIFER W. HENDRICK, BS, WARD V. HOUCK, MD, LATHA HEBBAR, MD, FRCA, SCOTT B. KRIBBS, BS, GLORIA RIOS, MD, STEVE WHITEBREAD, BS, RUPAK MUKHERJEE, PhD, MARC de GASPARO, MD, FRANCIS G. SPINALE, MD, PhD Charleston, South Carolina; Basel, Switzerland

ABSTRACT Background: A T l angiotensin II (AT I Ang II) receptor activation has been shown to cause increased vascular resistance in the systemic (SVR), pulmonary (PVR), and coronary vasculature which may be of particular importance in the setting of congestive heart failure (CHF). The overall goal of this study was to examine the effects of acute AT 1 Ang II receptor inhibition on left ventricular (LV) pump function, systemic hemodynamics, and regional blood flow patterns in the normal state and with CHF, both at rest and with treadmill-induced exercise. M e t h o d s and Results: Pigs (25 kg) were instrumented to measure cardiac output (CO), SVR, and PVR, and LV myocardial blood flow distribution in the conscious state and were assigned to one of two groups: (1) pacing-induced CHF (240 bpm for 3 weeks, n = 6) or (2) sham controls (n = 5). Measurements were obtained at rest and after treadmill exercise (15 ° for 10 minutes). Studies were repeated 30 minutes after intravenous infusion of a low (1.1 mg/kg) or high (125 mg/kg) dose of the AT~ Ang II antagonist, valsartan. The low dose of valsartan reduced the Ang II pressor response by approximately 50% but had a minimal effect on arterial pressure, whereas the high dose eliminated the Ang II pressor response and reduced resting blood pressure by approximately 20%. With CHF, CO was reduced at rest (2.5 -+ 0.2 v 3.9 -+ 0.1 L/rain) and with exercise (6.4 _+ 0.5 v 7.8 + 0.5 L/min) compared with controls (P < .05). Valsartan at the low and high dose increased resting CO by 28% in the control and CHF groups, but did not affect CO with exercise. Resting SVR in the CHF group was higher than controls (2,479 ± 222 v 1,877 _+ 65 dyne- s • cm -s, P < .05), but SVR fell to a similar degree with exercise (1,043 _+ 98 v 1,000 + 77 dyne • s • cm 5). The low and high dose of

From the Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina; and Pharmaceutical Division, Novartis, Basel, Switzerland. Supported by National Institutes of Health Grant HL-45024 (FGS), a Basic Research Grant from Ciba-Geigy (FGS), American Heart Association Grant-in-Aid (FGS), and an American Heart Association Medical Student Fellowship Award (SBK). Manuscript received March 27, 1998; revised manuscript received July 17, 1998; revised manuscript accepted August 13, 1998. Reprint requests: Francis G. Spinale, MD, PhD, Cardiothoracic Surgery and Physiology, Medical University of South Carolina, Charleston, SC 29425-2279. Copyright © 1998 by Churchill Livingstone ® 1071-9164/98/0404-000758.00/0

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valsartan reduced resting SVR by more than 30% in both the control and CHF groups. PVR was increased by more than twofold in the CHF group at rest. The high dose of valsartan reduced resting PVR with CHF, but had no further effect with exercise. LV myocardial blood flow was reduced with pacing CHF, particularly with exercise. With exercise and CHF, a low or high dose of vaisartan reduced coronary vascular resistance, but LV myocardial blood flow remained reduced from normal values. Conclusions: Heightened AT 1 Aug II receptor activity occurred in this model of CHF, which contributed to alterations in systemic hemodynamics and vascular resistive properties. By using a low dose of a selective AT 1 Aug II receptor antagonist reduced SVR, PVR, and coronary vascular resistive properties and therefore may provide beneficial effects in a setting of CHF. Key words: heart failure, left ventricular, hemodynamics, angiotensin II, exercise, blood flow, vascular resistance.

Functional characteristics of severe congestive heart failure (CHF) include left ventricular (LV) pump dysthnction, alterations in systemic hemodynamics, and increased neurohormonal system activation (1-6). With the development of CHF, increased production of angiotensin II (Aug II) occurs with resultant activation of the AT 1 Aug II receptor system (2,6,7). Abundant AT 1 Ang ]I receptors have been located within numerous vascular beds, including the pulmonary and coronary vasculature, and activation of this receptor pathway causes vascular smooth muscle vasoconstriction (7-12). Thus, heightened AT I Aug II receptor activation with CHF will cause increased vascular resistive properties which in turn may exacerbate the LV pump dysfunction that occurs with the development of this disease process. Past clinical studies have clearly shown that angiotensin-converting enzyme (ACE) inhibition improves LV function and survival in the setting of CHF (13-15). However, ACE inhibition has been shown to produce multiple effects within the vasculature, which include prevention of Aug II formation, potentiation of bradykinin levels, and modulation of nitric oxide production (16-21). Whether specific interruption of AT 1 Aug II receptor activity in the setting of CHF influences regional blood flow patterns remains unclear. Accordingly, the overall goal of this study was to determine the effects of AT 1 Aug II receptor inhibition on LV function, hemodynamics, and regional blood flow patterns in the normal state and after the development of CHF, both at rest and with treadmill-induced exercise. Chronic rapid pacing in animals has been clearly shown to produce LV functional and neurohormonal characteristics similar to that of the clinical spectrum of CHF (9,22-30). Specifically, this laboratory and others have shown previously that the development of pacinginduced CHF is accompanied by LV dilation and activation of several neurohormonal axes, such as the reninangiotensin pathway (22,27,29). In this model of CHF, the increased neurohormonal system activity is paralleled by increased systemic (SVR), pulmonary (PVR),

and coronary vascular resistance (9,22-28). For example within the coronary vasculature, the development of pacing-induced CHF is associated with diminished myocardial blood flow reserve (25). Within the pulmonary vasculature, a heightened vasoconstrictive response to Aug II has been reported with the development of pacinginduced CHF (9). In light of these past findings, this study was designed to test the hypothesis that AT 1 Aug II receptor inhibition will influence LV pump function, systemic hemodynamics, and regional blood flow patterns in the setting of pacing-induced CHF, particularly during treadmill-induced exercise. The development of specific AT~ Aug II receptor antagonists have provided a means to more selectively inhibit the physiological events that are mediated by Aug II (31-34). AT 1 Aug II receptor block has been shown to produce significant changes on resting blood pressure and SVR in patients with CHF (31). This study was designed to examine the potential effects of the acute administration of the AT 1 Aug II receptor antagonist, valsartan (32), by using two dosing regimens: a low dose that would produce minimal effects on resting blood pressure and a high dose that would significantly reduce resting blood pressure. Through this approach, whether the effects of valsartan infusion on LV function and regional blood flow were attributed to specific inhibition of the AT 1 Ang II receptor transduction system, a reduction in systemic loading conditions, or both of these factors could be more carefully defined.

Materials and Methods Dose Selection Studies Six male Yorkshire pigs (25 kg) were chronically instrumented to measure arterial blood pressure in the conscious state. The pigs were anesthetized with isoflurane (3%/1.5 L/min) and a mixture of nitrous oxide and oxygen (50:50), intubated with a cuffed endotracheal

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160 q /

Basal Angiotensin II infusion

140 *+

120 -IE

E 100

13_ 1E

<

g

80

60

40

20

Control

Low Dose AT1-BIock (1.1 mg/kg)

High Dose AT1-BIock (125 mg/kg)

Fig. 1. The dosing strategy for developing a low dose and high dose protocol for the AT 1 angiotensin II (Ang II) receptor antagonist, valsartan, was based on changes in mean arterial pressure under basal conditions and after an Ang II pressor challenge. Mean arterial pressure in chronically instrumented conscious pigs (n = 6) significantly increased from basal conditions after a bolus infusion of Ang II (10 /xg). An infusion of 1.1 mg/kg of valsartan resulted in a slight fall in basal resting blood pressure (P = .1l) and significantly reduced the Ang II pressor response. After an infusion of 125 mg/kg of valsartan, a stable reduction in resting blood pressure of approximately 20% was achieved and associated with a complete elimination of the Ang II pressor response. These low and high dosage regimens were used to examine systemic hemodynamics and regional blood flow in the control and congestive heart failure (CHF) states, at rest and with exercise. *P < .05 v basal state; *P < .05 v control state; *P < .05 v low dose of valsartan.

tube, and ventilated at a flow rate of 22 mL/kg/min and a respiratory rate of 15 resp./min. With a left thoracotomy, the thoracic aorta was exposed and a catheter connected to a vascular access port (model GPV, 9F; Access Technologies, Skokie, IL) advanced into the aorta and sutured in place. The access port was buried in a subcutaneous pocket over the thoracolumbar fascia and the thoracotomy closed. After a recovery period of 7 to 10 days, the animals were returned to the laboratory for initial baseline and Ang II pressor response studies. For these studies, the animals were sedated with an oral dose of diazepam (20 mg, Valium; Hoffmann-La Roche, Nutley, NJ) and placed in a custom-designed sling, which allowed the animal to rest comfortably. All studies were performed in the conscious state without additional use of sedation. The vascular access port was entered using a 12-gauge Huber needle (Access Technologies) containing dual access sites and basal, resting arterial pressure, and heart rate were recorded. Pressure readings from the fluid-filled aortic catheter were obtained by using an externally calibrated transducer (Statham P23ID; Gould, Oxnard, CA). The pressure waveforms were recorded by using a multichannel recorder (Hewlett Packard, Houston, TX) and were digitized on a computer for subse-

quent analysis at a sampling frequency of 250 Hz (80386 processor; Zenith Data Systems, St. Joseph, MO). After these baseline measurements, a bolus infusion of Ang II (10 /xg; Sigma, St. Louis) was administered and measurements repeated 5 minutes after the Ang II infusion. This dose of Ang II was determined in preliminary dose-response studies to yield a maximal blood pressure effect (35). The animals were allowed to recover from the pressor studies for 48 hours and then returned to the laboratory for the valsartan dose determination protocols. In these studies, a loading dose of valsartan (Novartis, Basel, Switzerland) was administered and immediately followed by a constant infusion for 30 minutes, at which time hemodynamic measurements were performed. The Ang II pressor response test was repeated immediately after the 30-minute infusion. The lag times between control and the different dosages of valsartan were equivalent. A bolus infusion of 1 mg/kg of valsartan followed by a continuous maintenance infusion of 0.003 mg/kg/min (1. l mg/kg total delivery) resulted in a slight fall in basal resting blood pressure, but significantly reduced the Ang II pressor 2 response (Fig. 1). Infusions of < 1 mg/kg of valsartan did not reliably inhibit the Ang II pressor response in this chronically instrumented por-

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cine preparation. With an infusion of 75 mg/kg followed by a continuous infusion of 50 mg/kg of valsartan (125 mg/kg total delivery), a consistent reduction in resting blood pressure of 20% could be achieved and was associated with a complete elimination of the Ang II pressor response (Fig. 1). At infusions of >-100 mg&g of valsartan, a significant and rapid fall in resting blood pressure occurred and was associated with hemodynamic instability and tachycardia. These dosage regimens were identified as the low (1.1 mg/kg) and high (125 mg/kg) dosage protocols and were used in the experimental design described in the following section.

Model of CHF and Exercise Instrumentation and Experimental Design. Eleven age- and weight-matched Yorkshire pigs (25 kg) were anesthetized and a left thoracotomy performed, as described previously. Catheters connected to vascular access ports were placed in the thoracic aorta, pulmonary artery, and left atrium. The access ports were then placed in a subcutaneous pocket. A 20-ram flow probe (Transonics, Ithica, NY) was placed around the pulmonary artery immediately distal to the pulmonary artery catheter and the electrical connection exteriorized through the thoracolumbar fascia. A shielded stimulating electrode was sutured onto the left atrium, connected to a modified programmable pacemaker (model 8329; Medtronic, Inc., Minneapolis, MN), and buried in a subcutaneous pocket. The thoracotomy was closed in layers and the pleural space evacuated of air. After a 14 to 21 day recovery from the surgical procedure, the animals were then randomly assigned to one of two groups: (1) chronic rapid pacing at 240 bpm for 21 days (n = 6) or (2) sham-instrumented controls (n = 5). This laboratory has shown previously that chronic rapid atrial pacing reliably causes LV dilation and pump dysfunction within a 21-day period (25,27). Cardiac auscultation and electrocardiograms were performed frequently during the pacing protocol to ensure proper operation of the pacemaker and the presence of 1:1 conduction. At the completion of the pacing protocol, the animals were returned to the laboratory and the pacemaker deactivated (pacing group only). These series of studies were performed 30 minutes and 8 hours after pacemaker deactivation. To confirm that the period after pacemaker deactivation did not result in changes in LV size or function, a time course study was performed in five pigs with pacing-induced CHF. Briefly, the pigs underwent 3 weeks of rapid atrial pacing at 240 bpm and then returned to the laboratory. The pacemaker was deactivated and LV echocardiography was obtained at 30 minutes and repeated at 12 hours after pacemaker deactivation. LV end-diastolic dimension was unchanged after 12 hours compared with 30 minutes (5.2 -+ 0.1 v 5.1 -+ 0.1

cm, respectively). Similarly, LV fractional shortening was not different between 30 minutes and at 12 hours after pacemaker deactivation (28 _+ 2 v 27 _+ 2%, respectively). Thus, these results demonstrated that LV function remained stable over the elapsed period of time over which these series of studies were performed. After a 1 hour stabilization period, basal resting hemodynamics were recorded, microspheres injected, and plasma collected. Measurements were then repeated with treadmill-induced exercise. After the initial treadmill study, the animals were allowed a recovery period (1-3 hours) until hemodynamics and heart rate had returned to basal resting values. Measurements were then repeated at rest and with treadmill exercise after the low dose infusion of valsartan. The valsartan infusion was then terminated and a second recovery period (1-3 hours) was observed until hemodynamics returned to steady state resting levels. Afterward, measurements were obtained under resting conditions and with treadmill exercise after the high dose infusion of valsartan. The baseline and treadmill testing protocols were initiated immediately after the valsartan infusion. Thus, each animal (normal control or pacing-induced CHF) was studied under six measurement conditions. After the final set of measurements, the animals were euthanized with an overdose of pentobarbital (1,000 mg) and tissue obtained for fluorescent microsphere measurements. All animals were treated and c a r e d f o r in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (National Research Council, Washington, DC, 1996).

Measurements at Rest and With Exercise. Twodimensional and M-mode echocardiographic studies (ATL Ultramark VI, 2.25 MHz transducer; Bothell, WA) were used to image the LV from a right parasternal approach (25,30). LV fractional shortening was calculated as (end-diastolic dimension - end-systolic dimension)/end-diastolic dimension and was expressed as a percentage. The access ports were entered and pressures obtained by using the externally calibrated transducers described previously and the readings were digitized on a computer for subsequent analysis at a sampling frequency of 250 Hz (80486 processor; Zenith Data Systems). The flow probe was connected to a digital flowmeter (model T106; Transonics) and digitized on a computer for processing. From the digitized flow signal, stroke volume was computed on a beat-to-beat basis and averaged from a minimum of 25 ejections. PVR and SVR were computed as the mean pressure minus the left atrial pressure divided by cardiac output multiplied by the constant 80 to convert to resistance units of dynes per second per centimeter -5. From the arterial catheter, 30 mL of blood was drawn into chilled tubes containing EDTA (1.5 mg/mL) and centrifuged (2000 g for 10 min

Ang I1 Receptor Block in Heart Failure

at 4°C). The plasma was aliquoted into separate tubes the frozen in liquid nitrogen and stored at - 8 0 ° C for subsequent measurements of plasma renin activity, endothelin levels, or valsartan levels. Samples were also drawn from the pulmonary artery and atrial catheters and immediately measured for oxygen saturation and hemoglobin content (CO-Oximeter; Instruments Laboratory, Lawrence, MA). Systemic oxygen consumption (Vo2) was computed as the difference in arterial and pulmonary artery oxygen content divided by cardiac output. After the collection of the hemodynamic data and blood samples, fluorescent microspheres (3 × 106; Molecular Probes, Eugene, OR) of specific emission spectra were injected into the left atrium. A reference aortic blood sample was withdrawn at a rate of 7 mL/min, which was initiated 5 seconds before injection and continued for 120 seconds after injection. The pigs were then placed in custom-designed vests, which protected all connections, and the animals positioned in a modified treadmill containing balanced and calibrated pressure transducers. The pigs were then exercised at a treadmill workload of 3 miles/hour, at a 15 ° incline for a 10-minute interval. In preliminary studies from this laboratory, and consistent with past reports (36,37), this treadmill protocol resulted in a near-maximal heart rate for pigs. During the last minute of exercise, hemodynamics and blood samples were collected and microspheres delivered. Plasma renin activity was determined by computing angiotensin I production by using a radioimmunoassay (NEA-026; New England Nuclear, Boston, MA). The interassay variation for the plasma renin activity measurements was 15%. For the endothelin and Ang II assays, the plasma was first eluted over a cation exchange column (C-18 Sep-Pak; Waters Associates, Milford, MA) and reconstituted samples analyzed by high sensitivity radioimmunoassay (Amersham, Arlington Heights, IL). The interassay variation was 10% and the intraassay variation was 9% for the endothelin radioimmunoassay procedure. Plasma concentrations of valsartan were determined by an AT 1 Ang II receptor binding assay using smooth muscle cell membrane preparations, as described previously (34).

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spectrofluorimetry (Gilford Fluoro IV, Oberlin, OH). The fluorescent microspheres used in this study with respect to excitation/emission characteristics were: bluegreen, 428/457 nm; orange, 534/550 nm; red, 580/594 nm; and scarlet, 650/674 nm. These fluorescent microspheres were chosen because a spectral scan that conformed to a Gaussian distribution could be uniformly obtained, minimal spectral cross-over occurred, and it provided equivalent sensitivity (39,40). Because of these spectral characteristics, blood flow measurements were limited to four specific points: baseline, exercise, exercise with low dose valsartan infusion, and exercise with high dose valsartan infusion. Regional blood flow computations were determined by using the standard formula: Qm = (Ar X Am)/Qr. Where Qm is the blood flow in milliliters per minute, Ar is the fluorescence of the aortic reference sample, Am is the fluorescence of the tissue sample, and Qr is the withdrawal rate of the reference sample. Final blood flow values were normalized to sample weights and expressed as milliliter per minute per gram. Coronary vascular resistance was determined as the mean aortic pressure divided by LV myocardial blood flow and expressed as millimeters of mercury times minute per milliliter times gram.

Data Analysis Echocardiographic indices of LV function were compared between the control and pacing group by using a t-test. Systemic hemodynamic and regional blood flow measurements were compared among the treatment groups by using analysis of variance for repeated measures. If the analysis of variance revealed significant differences, pairwise tests of individual group means were compared by using Bonferroni probabilities. For comparisons of neurohormonal profiles, the Mann-Whitney test was used. All statistical procedures were performed by using the BMDP statistical software package (BMDP Statistical Software Inc., Los Angeles, CA). Results are presented as means _+ SEM. P < .05 was statistically significant.

Results Regional Blood Flow Measurements All of the tissue samples were fixed in 10% formaldehyde to facilitate slicing. Samples of approximately 3 to 5 were collected and prepared from 2.5×2.5 cm sections of the midregion of the LV free wall, basal regions of the lung, kidney, and gluteus maximus. The tissue samples were carefully weighed and then digested by using a potassium hydroxide solution, as previously described (38,39). The aortic blood samples were extracted by using an identical digest solution (38,39). The fluorescence of the extracted samples were determined by

After 3 weeks of chronic rapid pacing, all of the pigs in the untreated group showed clinical symptoms consistent with CHF, which included tachypnea, lethargy, and reduced appetite during the last week of rapid pacing. In the pacing-induced CHF group, LV end-diastolic dimension was increased (5.6 +- 0.3 v 4.0 -+- 0.1 cm, P < .05) and fractional shortening decreased (47 _+ 2 v 25 _+ 4%, P < .05) when compared with the sham control group. All of the pigs in the CHF group (n = 6) and in the sham control group (n = 5) successfully completed the infusion-treadmill study protocol.

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Journal of Cardiac Failure Vol. 4 No. 4 December 1998 Table 1. Systemic Hemodynamics, LV Pump Function, and Plasma Neurobormones With Pacing-Induced CHF Effects of Acute Valsartan Treatment Baseline Rest

Heart rate (bpm) Control CHF Pump function Stroke volume (mL) Control CHF Cardiac output (L/min) Control CHF Pressures Aorta (mmHg) Control CHF Pulmonary artery (mmHg) Control CHF Left atrium (mmHg) Control CHF Resistances Systemic (dyne • sec • cm -5) Control CHF Pulmonary (dyne • sec • cm -5) Control CHF Neurohormones Renin activity (ng • m E - 1 • h r - 1 ) Control CHF Endothelin (fmol/mL) Control CHF Angiotensin II (fmol/mL) Control CHF

Valsartan at 1.1 mg/kg Exercise

Rest

Exercise

Valsartan at 125 mg/kg Rest

Exercise

128 -- 9 162 _+ 11'

262 ± 9* 231 + 12"*

163 +- 12' 138 ± 9*

255 ± 10" 219 + 7**

167 + 8+ 147 ± 4*

271 + 8* 241 _+ 13"*

31.2 _+ 2.0 16.7 -+ 2.0*

32.2 _+ 0.6 27.9 ± 1.9"*

28.8 + 1.5 24.3 + 3.4*

29.6 ± 0.8* 31.8 -+ 3.4*

25.8 _+ 1.3t 21.9 _+ 1.8'

29.9 + 1.1" 28.9 + 4.5

3.9 ± 0.1 2.5 -+ 0.2*

7.8 -+ 0.5* 6.4 ± 0.5**

4.7 _+ 0.3* 3.2 + 0.3**

7.6 + 0.4* 6.4 +- 0.6**

4.3 +_ OAt 3.2 _+ 0.2t*

8.1 + 0.3* 6.7 + 0.8**

101 _+ 3 93 ± 2*

109 + 5* 95 + 5*

92 ± 4 80 -+ 6*

96 -+ 5* 85 -+ 5

84 ± 5* 76 -+ 6*

87 ± 4 t 82 + 5 t

18 ± 2 35 ± 3*

26 -+ 4* 34 +- 3*

19 -+ 2 28 _+ 4*

27 _+ 3* 32 _+ 4

15 ± 1 23 _+ 3t*

21 + 2 31 + 5*

11 ± 2 23 + 2*

9±2 17 ± 2**

7± 1 16 ± 3*

6-- 1 13 ± 3*

4 ± 1*§ 13 _+ 2**

6 ± 1" 14 ± 4*

1877 -+ 65 2479 _+ 222*

1043 4- 98* 1000 -+ 77*

1462 _+ 75* 1706 _+ 212*

953 -+ 32* 879 _+ 83*

1500 _+ 72* 1629 +_ 173'

143 _+ 31 395 _+ 36*

168 _+ 28 222 ± 27*

133 4- 25 337 ± 41'

218 _+ 18" 238 _+ 28*

144 + 34 290 _+ 30 **

142 ± 13 245 + 18'

4.2 _+ 0.6 26.0 4- 8.5*

12.6 -+ 3.2* 34.5 _+ 9.2**

7.6 ± 3.9 46.3 +- 16.5'

29.3 ± 14.7' 35.9 ± 10.6

33.5 ± 15.4 56.6 ± 13.0§

2.7 ± 0.5 9.7 ± 3.0*

3.8 ± 0.8 10.8 ± 2.9*

3.4 +_ 0.7 9.9 ± 1.7'

3.8 ± 0.8 9.5 ± 2.1'

6.0 -+ 0.6*§ 8.2 ± 1.2

5.8 + 0.7* 8.8 ± 1.4

30.1 -+ 6.6 113.5-+ 26.9*

35.9 ± 16.6 187.7 ± 76.9*

40.6 _+ 18.3 214.5 -+ 55.0*

114.9 ± 53.5* 282.8 ± 147.3

157.1 ± 73.9 *§ 254.0± 122.5

17.6 ± 5.0 100.2 ± 33.1'

11.7 ± 4.6* 100.9-+ 22.9***

802 ± 33 *t~ 888 ± 91"

* P < .05 v resting state; tp < .05 v respective baseline; *P < 0.05 v control; ~P < .05 v valsartan at 1.1 mg/kg. Pressures reported as mean values. Values are as means ± SEM. LV, left ventricular; CHF, congestive heart failure.

Systemic Hemodynamics and Neurohormonal Profiles: Effects of Acute AT1 Ang II Receptor Blockade Resting State.

H e m o d y n a m i c i n d i c e s in the n o r m a l

c o n t r o l state a n d w i t h p a c i n g - i n d u c e d C H F u n d e r c o n scious, a m b i e n t r e s t i n g c o n d i t i o n s are s u m m a r i z e d in

Resting State: Valsartan Treatment.

A f t e r the l o w

d o s e i n f u s i o n o f v a l s a r t a n (1.1 m g / k g ) , r e s t i n g h e a r t rate i n c r e a s e d b y 2 7 % in the c o n t r o l g r o u p b u t d e c r e a s e d b y 15% in the C H F g r o u p w h e n c o m p a r e d w i t h r e s p e c t i v e u n t r e a t e d values. In the c o n t r o l group, stroke v o l u m e r e m a i n e d u n c h a n g e d after the l o w d o s e o f v a l s a r t a n but

T a b l e 1. In the C H F group, r e s t i n g h e a r t rate w a s in-

i n c r e a s e d in the C H F group. C a r d i a c output i n c r e a s e d

c r e a s e d a n d stroke v o l u m e a n d cardiac o u t p u t w e r e re-

f r o m u n t r e a t e d v a l u e s in b o t h the c o n t r o l a n d C H F

d u c e d w h e n c o m p a r e d w i t h the c o n t r o l group. In the

g r o u p s . H o w e v e r , c a r d i a c o u t p u t r e m a i n e d l o w e r in the

C H F g r o u p , m e a n aortic p r e s s u r e w a s r e d u c e d and p u p

C H F g r o u p w h e n c o m p a r e d w i t h the c o n t r o l group. Al-

m o n a r y artery a n d left atrial p r e s s u r e i n c r e a s e d w h e n c o m p a r e d w i t h the c o n t r o l group. S V R a n d P V R u n d e r

t h o u g h m e a n aortic p r e s s u r e w a s u n c h a n g e d in the c o n -

a m b i e n t r e s t i n g c o n d i t i o n s w e r e i n c r e a s e d in the C H F

C H F g r o u p after the l o w d o s e o f valsartan. In the c o n t r o l

group. P l a s m a r e n i n activity w a s i n c r e a s e d b y m o r e t h a n s i x f o l d a n d e n d o t h e l i n levels b y m o r e t h a n t h r e e f o l d in

group, p u l m o n a r y artery a n d left atrial p r e s s u r e did n o t c h a n g e f r o m u n t r e a t e d values; h o w e v e r , b o t h o f t h e s e p r e s s u r e s significantly d e c l i n e d in t h e C H F g r o u p after a

the C H F g r o u p w h e n c o m p a r e d w i t h c o n t r o l values.

trol group, a significant r e d u c t i o n w a s o b s e r v e d in the

Ang II Receptor Block in Heart Failure

low dose of valsartan. Pulmonary and left atrial pressure remained higher in the CHF group when compared with the control group. SVR fell after a low dose of valsartan in both groups. PVR remained elevated in the CHF group when compared with the control group. Plasma renin activity and Ang II levels increased from respective untreated values in both the control and CHF groups, but there was a high degree of variability in this response. As a result, this increase in plasma renin activity and Ang II levels did not reach statistical significance (P = .20 and P = .22, respectively). Plasma endothelin levels remained unchanged from untreated baseline values. With this dose of valsartan, plasma levels were 4,671 _+ 715 nmol/L. After the high dose infusion of valsartan (125 mg/kg), the resting heart rate increased from untreated values in the control group. Resting heart rate was decreased in the CHF group when compared with respective untreated values, but this did not reach statistical significance (P = .27). In the control group, stroke volume was reduced after the high dose of valsartan but increased in the CHF group. Cardiac output increased from untreated values in both the control and CHF groups. However, cardiac output remained lower in the CHF group when compared with the control group. Mean aortic pressure declined in both groups after a high dose of valsartan. In the control group, pulmonary artery pressure remained unchanged but left atrial pressure fell from respective untreated values. In the CHF group, both pulmonary and left atrial pressures declined but remained increased when compared with respective control values. SVR fell to equivalent values in both groups after a high dose of valsartan. PVR fell in the CHF group but remained higher than the control group. In the control group, plasma renin, Ang II and endothelin levels increased from untreated baseline values after the high dose of valsartan. With the infusion of the high dose of valsartan, plasma compound levels were 376,539 _+ 28,227 nmol/L. Treadmill Exercise. Hemodynamic indices during treadmill exercise in the control and CHF groups are summarized in Table 1. In the CHF group, heart rate increased from resting values but remained lower than that achieved in the control group. In the control group, stroke volume remained unchanged from resting values with treadmill exercise but cardiac output increased by more than twofold. In the CHF group, treadmill exercise resulted in a significant increase in stroke volume and cardiac output from resting values; however, both remained reduced from control values. Mean aortic pressure increased in controls with treadmill exercise and remained unchanged from resting values in the CHF group. In the control group, pulmonary artery pressure increased with treadmill exercise with no change in left atrial pressure. In the CHF group, pulmonary artery pressure remained unchanged but left atrial pressure in-

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creased. SVR significantly fell with treadmill exercise in both groups. PVR remained higher in the CHF group. Systemic Vo2 significantly increased in the control group with exercise (7.2 + 0.7 to 20.8 -+ 2.6 mL O2/min/kg, P < .05). In the CHF group, systemic Vo2 increased from resting values with exercise (5.9 -+ 0.8 to 13.5 + 1.6 mL O2/min/kg, P < .05), but was significantly reduced from that achieved in the control group (P < .05). Plasma renin activity increased from basal resting values with treadmill exercise in both groups and remained higher in the CHF group. Plasma Ang II and endothelin levels did not change from basal levels with treadmill exercise. Treadmill Exercises Valsartan Treatment. The heart rate levels achieved with treadmill exercise were not affected by a low dose infusion of valsartan (1.1 mg/kg) in either the control or CHF groups. In the control group, stroke volume was reduced after a low dose of valsartan when compared with untreated exercise values. In the CHF group, stroke volume increased when compared with untreated exercise values. Cardiac output was unchanged from untreated exercise values in both groups. In the control group, aortic pressure fell from untreated exercise values. Systemic Vo2 was unchanged from untreated exercise values in both the control and CHF groups. In the control group, plasma renin activity was similar to untreated exercise values. However, in the CHF group plasma renin activity increased from untreated exercise values with a low dose of valsartan. Plasma endothelin levels were similar to untreated exercise values in both groups. Heart rate, stroke volume, and cardiac output levels that were achieved with treadmill exercise were not affected by a high dose of valsartan in either the control or CHF groups. However, aortic pressure was significantly reduced in both groups when compared with untreated exercise values. In the control group, SVR was reduced from untreated exercise values, as well as the low dose valsartan values. Plasma renin activity was higher in both the control and CHF groups after a high dose of valsartan when compared with respective untreated values, but the high variability associated with these observations resulted in no statistically significant differences (P = .25). Ang II levels increased in the control group with treadmill exercise and a high dose of valsartan. In the control group, plasma endothelin levels increased from untreated exercise values.

Regional Blood Flow Distribution: Effects of Valsartan Infusion Resting State. Steady-state resting blood flow values to specific circulatory beds in the control and CHF groups are summarized in Fig. 2. Under ambient resting

318

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Ang II Receptor Block in Heart Failure •

conditions, LV myocardial blood flow was reduced in the CHF group when compared with control values. Coronary vascular resistance was increased in the CHF group when compared with the control group (3,911 -+ 316 v 5,429 _+ 887 10 3 dyne • sec • cm -5 • g, P < .05, respectively). Pulmonary parenchymal flow and renal blood flow were reduced by more than 45% in the CHF group when compared with the control group. Skeletal muscle blood flow, as determined by blood flow to the gluteus maximus, was similar between the control and CHF groups. Treadmill Exercise. Changes in regional blood flow patterns after treadmill exercise in the control and CHF groups are summarized in Fig. 2. LV myocardial blood flow increased by more than threefold in the control group with exercise. In the CHF group, LV myocardial blood flow increased with exercise but was 48% lower than control values. Coronary vascular resistance was reduced in both the control and CHF groups with exercise when compared with resting values (1,180 _+ 198 v 1,922 _ 237 103 dyne • sec • cm -5 • g, P < .05, respectively) but remained higher in the CHF group (P < .05). Pulmonary parenchymal flow increased by more than threefold in the control group with exercise and was reduced in the CHF group. Renal blood flow increased by approximately twofold in the control state and was reduced from this value by 40% in the CHF group. With treadmill exercise, skeletal muscle blood flow increased from resting values in both the control and CHF groups but remained lower in the CHF group. Coronary vascular resistance was similar between the control and CHF groups after a low dose of valsartan (1,173 + 182 v 1,441 + 170 103 dyne • sec • cm -5 • g, respectively) and was lower in the CHF group when compared with untreated exercise values (P = .09). With the high dose of valsartan, myocardial blood flow values were similar to untreated exercise values in both groups. Coronary vascular resistance was lower in the CHF group after a high dose of valsartan when compared with untreated exercise values (1,399 -+ 147 10 3 dyne • sec • cm -5 • g, P = .07). After the high dose of valsartan, pulmonary parenchymal and skeletal muscle blood flow was reduced in the control group when compared with untreated exercise values. The percentage of change in regional blood flow values in the control and CHF groups after treadmill exercise are summarized in Fig. 3. In the untreated state, the increase in myocardial blood flow was significantly blunted in the CHF group. With the low and high dose of valsartan, the relative increase in myocardial blood flow was similar between the control and CHF groups. The percentage of change in pulmonary parenchymal flow was lower in the untreated CHF group with treadmill exercise when compared with control values. The relative increase in pulmonary parenchymal flow was similar

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319

between the control and CHF groups after the low dose of valsartan. After the high dose of valsartan, the relative increase in pulmonary parenchymal flow with exercise was reduced in the control group when compared with untreated values. The relative increase in renal and skeletal muscle blood flow were similar between the control and CHF groups and was not affected by valsartan treatment.

Discussion The relative contribution of AT 1 Ang II receptor activity to the alterations in hemodynamic profiles that occur in the setting of severe CHF are not fully understood. Accordingly, this study used a large animal model of pacing-induced CHF to examine the effects of acute AT 1 Ang II receptor block (by using valsartan) on hemodynamics and regional blood flow patterns. The new and unique findings of this study were: (1) a low dose of a selective AT a Ang II receptor antagonist reduced SVR, PVR, and coronary vascular resistive properties with CHF; (2) with treadmill exercise and CHF, a low or high dose of valsartan reduced coronary vascular resistance; and (3) the high dose of valsartan during treadmill exercise caused a reduction in pulmonary parenchymal flow and skeletal muscle blood flow and increased plasma endothelin levels. Thus, these findings suggest that heightened AT 1 Ang II receptor activity occurred in this model of CHF in both the resting and exercise state, which contributed to alterations in systemic hemodynamics and vascular resistive properties. This study builds on past reports by examining the specific and potentially dose-dependent effects of the AT~ Ang II receptor antagonist, valsartan, with respect to hemodynamic and regional blood flow patterns in both control pigs and after the development of pacing-induced CHF. For example, in human studies and animal models of hypertension, it has been shown that specific AT a Ang II antagonists can significantly reduce systemic blood pressure (31,33,41). Initial studies have shown that AT 1 Ang II receptor block can be safely instituted in patients with CHF (31). To our knowledge, this is the first study that has examined both hemodynamic and regional blood flow profiles at rest and with exercise after AT 1 Ang II receptor blockade in a model of CHF. In a previous study, Symons and Stebbins (42) reported that an acute infusion of losartan in control pigs reduced SVR and increased myocardial blood flow with treadmill exercise. In dogs with pacing-induced CHF, Cheng et al. (26) reported a significant increase in stroke volume after acute administration of losartan. An important objective of these studies was to examine the effects of valsartan at a dose that would provide adequate AT 1 Ang II receptor block but have minimal effect on systemic resting blood

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Fig. 3. The percentage of change in regional blood flow values from resting untreated baseline values was computed for the control and congestive heart failure (CHF) groups with treadmill exercise. The relative increase in myocardial blood flow was significantly blunted with treadmill exercise in the untreated CHF group. The relative increase in myocardial blood flow with exercise after either the low or high dose of valsartan were similar between the control and CHF groups. Pulmonary parenchymal flow was blunted in the untreated CHF group with exercise. The high dose of valsartan reduced pulmonary parenchymal flow in the control group. There were no differences in the relative magnitude of blood flow changes with treadmill exercise in the control or CHF group, regardless of valsartan treatment. *P < .05 v control; *P < .05 v untreated values; *P < .05 v low dose of valsartan.

pressure. This low dose of valsartan increased resting cardiac output in both the control and CHF states. Contributory factors for the increased cardiac output with the low dose of valsartan in the control state was a reduction in LV afterload (reduced SVR), as well as increased heart rate. In the CHF state, the increased resting cardiac output was associated with a reduction in resting ambient heart rate and left atrial pressure. A unique and important finding of this study was that with treadmill exercise, AT 1 Ang II receptor block improved relative LV myocardial blood flow from untreated values in the pacing-induced CHF group. Consistent with previous reports (25), this study showed that the development of pacing-induced CHF was associated with a significant reduction in myocardial blood flow at

rest. This reduction in myocardial blood flow occurred in the absence of a physical obstruction to flow and therefore was probably attributed to changes in vascular resistive properties of the coronary vascnlature. It has been reported previously that in patients with nonischemic cardiomyopathy, abnormalities in myocardial oxygen delivery/demand exist (43). Thus, the global reduction in LV myocardial blood flow with the development of pacing-induced CHF may significantly influence LV performance. The results of this study suggest that AT 1 Ang II receptor activity contributes to abnormalities in coronary vascular resistive properties in this model of pacinginduced CHF. In a study by Sudhir et al. (44) by using an anesthetized dog model, the effects of the ACE inhibitor enalaprilat on coronary blood flow was examined. In this

Ang II Receptor Block in Heart Failure

previous study, intracoronary administration of enalaprilat improved myocardial blood flow by approximately 19% when normalized to maximal flow achieved by adenosine. Interestingly, in that study, intracoronary administration of the AT 1 Ang II receptor antagonist losartan increased flow by 39% when compared with adenosine values. In patients with dilated cardiomyopathy, Foult et al. (12) showed that intracoronary administration of enalaprilat, which had no effect on systemic perfusion pressure, improved coronary sinus blood flow. Several previous reports have shown that a local renin-angiotensin pathway exists within the myocardial vasculature (10-12). In this study, the relative improvement in LV myocardial blood flow in the pacing-induced CHF group during treadmill exercise was achieved by using a low dose of valsartan in which coronary hydraulic effects (mean arterial pressure, atrial pressure) were unaffected. Taken together, the results from these previous studies and this study suggest that Ang II formation and subsequent AT 1 Ang II receptor activation significantly influence coronary vascular resistive properties in the setting of CHF. The goal of this study was to perform a comparative analysis between a low and high dose of AT 1 Ang II receptor block in a model of CHF with respect to hemodynamic and blood flow characteristics. However, it must be recognized that the reduction in systemic pressure may in and of itself influence blood flow, particularly coronary flow. Thus, whether the effects of AT 1 Ang II receptor block on myocardial flow observed in this study were selectively influencing AT 1 Ang II receptor activity in the coronary vasculature could not be directly assessed. To more carefully address this issue, intracoronary administration of the AT 1 Ang II receptor antagonist would be necessary and therefore must be recognized as a limitation of this study. With the development of CHF, pulmonary parenchymal flow was significantly reduced both at rest and with treadmill-induced exercise. These observations would suggest that inherent defects in the vasodilatory properties of the bronchial smooth muscle occurred with the development of pacing-induced CHF. With the low dose of valsartan treatment and treadmill exercise, bronchial flow decreased slightly in the normal state and increased slightly in the CHF state. However, at the high dose of valsartan and exercise, bronchial flow was significantly reduced in the control state. This was probably attributed to the fall in aortic perfusion pressure that occurred with the high dose of valsartan. These observations would suggest that the defects in bronchial flow that occur with pacing-induced CHF were probably not attributed to enhanced AT 1 Ang II receptor activity. With the development of pacing-induced CHF, renal blood flow was reduced both at rest and with exercise. Acute valsartan treatment at either the high or the low dose failed to

•

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321

increase renal blood flow with exercise. However, renal blood flow, particularly during exercise, was significantly influenced by autoregulatory factors that probably masked any effects of AT 1 Ang lI receptor block. Consistent with a previous study, the development of pacinginduced CHF was associated with abnormalities in skeletal muscle perfusion with treadmill exercise (23). Acute valsartan treatment did not increase skeletal muscle blood flow in the control or CHF states with treadmill exercise. This is probably because the major determinant of skeletal muscle flow during exercise is the local production of vasodilatory metabolites (45,46). In addition, the high dose of valsartan was associated with an absolute fall in blood pressure. Thus, the reduction in peripheral resistance with acute valsartan treatment with exercise may have been offset by a reduction in relative skeletal muscle perfusion pressures. Under ambient resting conditions, the development of pacing-induced CHF was associated with increased plasma renin activity. Treadmill-induced exercise was associated with increased plasma renin activity from basal values in both the control and CHF states. This increase in plasma renin activity with treadmill exercise in pigs is consistent with earlier studies (36,37). With acute valsartan treatment, plasma renin activity seemed to increase in a dose-dependent manner under ambient resting conditions and with exercise. This rise in plasma renin activity after acute AT 1 Ang II receptor block was not surprising and is consistent with interruption of the renin-angiotensin enzymatic pathway. With the development of pacing-induced CHF, increased plasma levels of the potent vasoactive peptide endothelin were observed. In patients with CHF, a relationship between circulating levels of endothelin and the degree of PVR has been reported (5,47). This study used a repeated observation design and therefore allowed for a paired comparison to be made. However, the sample size was small and therefore reduced the overall power of the study, particularly with certain comparisons such as neurohormonal values. Nevertheless, acute treatment with either the low or high dose of valsartan did not reduce plasma endothelin levels from untreated CHF values at rest or with exercise. However in the control state, the high dose of valsartan resulted in increased plasma endothelin levels at rest and with exercise. This increase in endothelin levels in the control state with the high dose of valsartan was probably the result of a reflexive response to the significant reduction in blood pressure. It must be recognized that any animal model will not fully represent the complex clinical spectrum of CHF. Specifically, the changes in LV myocardial structure that occur with pacing-induced CHF are not similar to clinical forms of CHF attributed to chronic ischemia or hypertensive disease (27,48). Nevertheless, this study showed that increased AT 1 Ang II receptor activity oc-

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Journal of Cardiac Failure Vol. 4 No. 4 December 1998

curred in this model of CHF in both the resting and exercise state, which contributed to alterations in systemic hemodynamics and vascular resistive properties. Using a low dose of a selective AT 1 Ang II receptor antagonist reduced SVR, PVR, and coronary vascular resistive properties. These results suggest that modulation of AT 1 Ang II receptor activity with CHF may provide beneficial effects to specific circulatory beds in the setting of CHF.

Acknowledgment

10.

11. 12.

13.

FGS is an Established Investigator of the American Heart Association. 14.

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