Effects of Acute Angiotensin II Type 1 Receptor Antagonism and Angiotensin Converting Enzyme Inhibition on Plasma Fibrinolytic Parameters in Patients With Heart Failure
Background—Angiotensin converting enzyme (ACE) inhibition after myocardial infarction is associated with an improvement in plasma fibrinolytic parameters. The aim of the present study was to determine whether acute ACE inhibition and angiotensin II type 1 (AT1) receptor antagonism have similar effects in patients with heart failure.
Methods and Results—Twenty patients with moderately severe chronic heart failure received enalapril 10 mg and losartan 50 mg on 2 separate occasions in a single-blind, randomized, crossover design. Plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) antigen and activity were measured at baseline and 6 hours after the dose. Acute administration of losartan but not of enalapril reduced plasma t-PA (11%; P=0.003) and PAI-1 (38%; P<0.001) antigen concentrations, which was associated with increases in t-PA (29%; P=0.03) and decreases in PAI-1 (48%; P=0.01) activity. Changes in plasma fibrinolytic parameters were more marked during losartan treatment (P<0.02), with a 3-fold greater reduction in plasma PAI-1 antigen concentrations (P<0.05).
Conclusions—Acute AT1 antagonism in patients with heart failure is associated with a significant improvement in plasma fibrinolytic parameters that is greater than during ACE inhibition. These beneficial effects of AT1 antagonism and ACE inhibition would therefore appear to be mediated principally through suppression of angiotensin II.
It would be anticipated that high tissue plasminogen activator ( t-PA) concentrations would protect against subsequent coronary events. However, paradoxically, epidemiological studies of total t-PA (antigen) concentrations in patients with ischemic heart disease1 2 have observed a positive correlation with future coronary events. This may be explained by the concomitant elevation of plasminogen activator inhibitor type 1 (PAI-1), which complexes with t-PA and therefore causes an overall reduction in free t-PA “activity.”3 4 It is this free and unbound t-PA that is physiologically active and leads to endogenous fibrinolysis.
Several large-scale heart failure and post–myocardial infarction trials (VHEFT-II [Veterans Administration Heart Failure Trial II], SAVE [Survival And Ventricular Enlargement], SOLVD [Studies Of Left Ventricular Dysfunction], AIREX [Acute Infarction Ramipril Efficacy eXtension Study], TRACE [TRAndolapril Cardiac Evaluation], and SMILE [Survival of Myocardial Infarction: Long-term Evaluation]) have suggested a reduction in reinfarction rates in patients treated with ACE inhibitors. The mechanisms underlying this reduction in coronary thrombotic events are unknown. However, given that angiotensin II5 and bradykinin6 are known to induce the release of PAI-1 and t-PA, respectively, the benefits of ACE inhibitor therapy may be mediated through increases in bradykinin-induced t-PA release or a reduction in angiotensin II–mediated PAI-1 release or both. Indeed, the use of ACE inhibitors after myocardial infarction is associated with a decrease in PAI-1 concentrations and a potential increase in t-PA activity.7 8 However, the effects of ACE inhibition on plasma fibrinolytic factors have not been assessed in patients with heart failure, and it is unknown whether these beneficial effects are also seen with angiotensin II type 1 (AT1) receptor antagonism. The aim of the present study, therefore, was to determine whether acute ACE inhibition and AT1 receptor antagonism have similar effects in patients with heart failure.
Twenty patients with New York Heart Association (NYHA) grade II to III chronic heart failure and objective evidence of left ventricular impairment (left ventricular ejection fraction <40%, shortening fraction <20%, or left ventricular end-diastolic diameter >5.5 cm) were recruited with the approval of the local research ethics committee and in accordance with the Declaration of Helsinki. The written informed consent of each subject was obtained before entry into the study. No patient had previously received ACE inhibitor or AT1 receptor antagonist therapy or had a myocardial infarction within 3 months of the study. Concomitant therapy was omitted on the day of attendance.
Supine heart rate and blood pressure were monitored at intervals throughout each study with a semiautomated, noninvasive oscillometric sphygmomanometer9 (Takeda UA 751, Takeda Medical Inc).
Ten milliliters of blood was withdrawn from the antecubital fossa of the forearm and collected into acidified buffered citrate (Biopool Stabilyte for t-PA assays) and citrate (Monovette for PAI-1 assays) tubes and kept on ice before being centrifuged at 2000g for 30 minutes at 4°C. Platelet-free plasma was decanted and stored at −80°C before assay.10 Plasma PAI-1 and t-PA antigen and activities and atrial natriuretic peptide (ANP) concentrations were determined by ELISAs and a photometric method as previously described.11 12 All assays were performed by blinded independent operators.
Patients attended the clinic at 9 am and rested recumbent for 20 minutes before measurements were made. At 10 am, patients received a single-blind, randomized oral dose of enalapril 10 mg or losartan 50 mg followed by a light lunch at midday. After an additional 20-minute period of supine rest at 4 pm, repeated measurements were taken to coincide with peak plasma concentrations of the active metabolites (enalaprilat and E3174, respectively). To allow for a sufficient washout of enalaprilat and E3174, patients reattended 2 days later to undergo the same protocol but crossed over to receive the alternate therapy.
Data Analysis and Statistics
Data were examined by ANOVA and 2-tailed paired Student’s t test with Excel version 5.0 (Microsoft). All results are expressed as mean±SEM. Statistical significance was taken at the 5% level.
Patient characteristics are shown in Table 1⇓. Baseline predose hemodynamic, plasma ANP, and fibrinolytic parameters were similar on the 2 study days, with no significant differences (Table 2⇓) or time order effects.
After losartan therapy, plasma t-PA and PAI-1 antigen concentrations fell by 11% (P=0.003) and 38% (P<0.001), respectively (Table 2⇑; Figure⇓). Plasma t-PA activity increased by 29% (P=0.03), whereas PAI-1 activity fell by 48% (P=0.01). Enalapril therapy was associated with similar changes in fibrinolytic parameters (−6%, −14%, 21%, and −17%, respectively), but they were not statistically significant (P=0.1 to 0.4). Changes in plasma fibrinolytic parameters were more marked during losartan treatment (P=0.016; 2-way ANOVA, enalapril versus losartan), with a 3-fold greater reduction in plasma PAI-1 antigen concentrations (P=0.047; t test, enalapril versus losartan). There were no significant effects on plasma ANP concentrations (Table 2⇑).
We have shown that acute AT1 receptor antagonism in patients with heart failure is associated with a significant improvement in plasma fibrinolytic parameters. Moreover, this improvement was greater than with ACE inhibition, which suggests that these effects are mediated directly through suppression of angiotensin II.
Previous studies have shown the beneficial effects of ACE inhibition on fibrinolytic parameters in patients after an acute myocardial infarction.7 8 In the present study, we assessed the acute effects in patients with heart failure, and our results are consistent with these post–myocardial infarction studies. This suggests that the benefits of ACE inhibition are not limited to the immediate postinfarction period but may also be achieved in patients with heart failure. Additionally, we have directly assessed t-PA activity and have confirmed that the changes in basal t-PA and PAI-1 antigen concentrations are associated with an increase in t-PA activity.
It has been suggested that the changes in fibrinolytic parameters seen with ACE inhibitors may be mediated through augmentation of bradykinin, because t-PA release is induced by bradykinin infusions during systemic ACE inhibition.6 However, the present study would suggest that bradykinin is not involved in basal t-PA release because of the similar effects of AT1 receptor antagonism on the profile of plasma t-PA and PAI-1 concentrations. Moreover, given the greater efficacy of AT1 receptor antagonism, particularly on PAI-1 concentrations, it would appear that angiotensin II is the principal mediator of this effect. This is consistent with the in vitro13 and in vivo5 release of PAI-1 with angiotensin II administration. Furthermore, these observations may provide one potential explanation for the findings of the ELITE [Evaluation of Losartan in The Elderly] study, in which AT1 receptor antagonism was associated with reduced mortality compared with ACE inhibition in patients with heart failure.14
Plasma t-PA and PAI-1 concentrations undergo diurnal variations, which have a complementary and inverse sinusoidal relationship.15 Such diurnal variation may contribute in part to the observed changes in fibrinolytic parameters, although this does not explain the differential effects of ACE inhibition and AT1 receptor antagonism, especially on PAI-1. In addition, the doses of losartan14 and enalapril16 were chosen on the basis of the major published heart failure trials, and the observed differences are unlikely to reflect a dose effect because the resultant hemodynamic effects were similar.
In conclusion, the present study suggests that in patients with heart failure, acute angiotensin II inhibition with AT1 receptor antagonism produces a marked improvement in basal fibrinolytic balance through a reduction in PAI-1.
This work was supported by a grant from the British Heart Foundation (PG/97197). Dr Newby was the recipient of a British Heart Foundation Junior Research Fellowship (FS/95009). We would like to thank Pamela Dawson and Dr J.J. Morton for performing the assays.
Dr Goodfield is currently at the Department of Cardiology, Stobhill Hospital, Glasgow, UK.
- Received November 9, 1998.
- Revision received April 7, 1999.
- Accepted April 15, 1999.
- Copyright © 1999 by American Heart Association
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The CONSENSUS trial study group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316:1429–1432.Twenty patients with moderate chronic heart failure received enalapril 10 mg and losartan 50 mg on 2 separate occasions in a single-blind, randomized, crossover design. Acute administration of losartan but not of enalapril reduced plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) antigen concentrations, which was associated with an increase in t-PA and decrease in PAI-1 activity. Reductions in plasma PAI-1 antigen concentrations were significantly greater than with enalapril. Acute AT1 antagonism in patients with heart failure is associated with a significant improvement in plasma fibrinolytic parameters that is greater than during ACE inhibition.