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Cardiovascular Research 2001 49(1):110-117; doi:10.1016/S0008-6363(00)00227-3
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Copyright © 2000, European Society of Cardiology

Significance of timing of angiotensin AT1 receptor blockade in rats with myocardial infarction-induced heart failure

Qin-Gui Xia, Oliver Chung, Heidi Spitznagel, Sascha Illner, Gunnar Jänichen, Birthe Rossius, Peter Gohlke and Thomas Unger*

Institute of Pharmacology, Christian-Albrechts-University of Kiel, Hospitalstrasse 4, 24105 Kiel, Germany

* Corresponding author. Tel.: +49-431-597-3500; fax: +49-431-597-3522 th.unger{at}pharmakologie.uni-kiel.de

Received 25 May 2000; accepted 11 September 2000


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Limitations of the...
 6 Conclusion
 References
 
Objective: Blockade of angiotensin AT1 receptors has been shown to prevent cardiac remodeling and improve left ventricular function and survival after myocardial infarction (MI). However, the timing of initiation of treatment has not been fully elucidated. Therefore, the purpose of the present study was to compare the effects of very early (30 min after MI), early (3 and 24 h after MI) and delayed (7 days after MI) treatments with the angiotensin AT1 receptor antagonist fonsartan (HR 720) on cardiac morphological and hemodynamic parameters in a rat model of MI-induced heart failure and to establish the therapeutic window for the start of treatment. Methods: Male Wistar rats underwent coronary ligation and were randomized fonsartan (HR720) treatment starting 30 min, 3 h, 24 h and 7 days after MI or no treatment. Treatment was continued up to 6 weeks post MI. Results: Fonsartan (HR720) treatment attenuated cardiac hypertrophy when treatment started 30 min or later after MI, limited infarct size when treatment initiated 3 and 24 h after MI, decreased left ventricular end-diastolic pressure when treatment started 3 h to 7 days after MI, and improved dP/dtmax when treatment commenced 24 h and 7 days after MI compared to untreated infarct group. Conclusion: Our results show that angiotensin AT1 receptor blockade with fonsartan (HR720) produced the best cardioprotective effects when treatment was started 3 to 24 h after MI although a start of treatment 7 days following MI still could improve functional parameters. These results suggest an optimal time window for the start of treatment with angiotensin AT1 receptor antagonists seems to be between 3 and 24 h post MI.

KEYWORDS Heart failure; Infarction; Renin angiotensin system; Remodeling; Ventricular function; Angiotensin; Receptors


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 5 Limitations of the...
 6 Conclusion
 References
 
The renin–angiotensin system through its primary effector peptide angiotensin II, exerts a variety of effects, including blood pressure regulation and maintenance of water and electrolyte balances. However, angiotensin II has also been recognized as a pathological factor in the pathophysiology of cardiac hypertrophy and failure. Therefore, inhibition of the renin–angiotensin system has been considered a powerful therapeutic approach in the treatment of hypertension and other cardiovascular disorders [1]. Angiotensin-converting enzyme inhibitors are now first-line drugs in treating myocardial infarction-induced heart failure. Angiotensin AT1 receptor blockers have been recently introduced into therapy for hypertension and congestive heart failure. Results from clinical studies have shown that the angiotensin AT1 receptor blockade is beneficial in patients with symptomatic heart failure [2–4].

Myocardial infarction (MI) is a common cause of heart failure. Several experimental studies have investigated the effects of angiotensin AT1 receptor antagonists on MI-induced heart failure. Schieffer et al. [5] reported that the losartan treatment effectively prevented ventricular remodeling when initiated 7 days after MI in rats. This result was supported by Richer et al. [6], demonstrating that the treatment with irbesartan dose-dependently increased survival, normalised left ventricular dP/dt and cardiac index values, improved left and right ventricular regional blood flows, and decreased myocardial hypertrophy when started 7 days after MI. However, Ambrose et al. [7] found that the irbesartan did not decrease left ventricular end-diastolic pressure and improve dP/dtmax when treatment was started 24 h before MI. Hu et al. [8] reported that the treatment with losartan reduced left ventricular end-diastolic pressure only in rats with large myocardial infarction but failed to improve cardiac performance and reduce cardiac weight when started 30 min after MI. In a previous study [9], we demonstrated that the angiotensin AT1 receptor blocker, fonsartan (2-butyl-4-(methylthio-)-1-[[2'-[[[(propylamino) carbonyl]amino] sulfonyl] (1,1'-biphenyl)-4-yl]methyl]-1H-imidazole-5-carboxylate, HR720), attenuated cardiac hypertrophy and improved left ventricular function when treatment was initiated 24 h post MI. However, in all these studies, only one time point for therapy initiation was investigated. In the present study, therefore, we extended our previous study to assess the relative effectiveness of very early (30 min after MI), early (3 and 24 h after MI) and delayed (7 days after MI) treatments with fonsartan (HR720) on left ventricular dysfunction and cardiac structural remodeling in rat model of MI-induced heart failure in order to provide information about an optimal time window for the initiation of therapy with angiotensin AT1 receptor antagonists after MI.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 5 Limitations of the...
 6 Conclusion
 References
 
2.1 Animals and model of myocardial infarction
Male normotensive Wistar rats weighing 250–280 g were obtained from Charles River Inc. (Sulzfeld, Germany). Before operation, the rats were housed in our animal facility for at least 5 days under controlled conditions of constant temperature and humidity and exposed to a 12-h light/dark cycle. The rats had free access to a standard rat chow (Ssniff Spezialdiäten GmbH, Soest, Germany). Drinking water was provided ab libitum. The investigation conforms with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996) and was performed in accordance with the German law on animal protection as released in the new version in 1993.

The ligation of the left descending coronary artery and sham operations were performed as previously described [9,10]. Briefly, animals were anesthetized with ether and an i.v. injection of methohexital-sodium (initially 10 mg/kg). The trachea was intubated and the animals were artificially ventilated with room air under positive pressure (50 hubs/min, 200 mmH2O, 1.5 ml/hub) by using a small-animal ventilator (Model 4600, Rhema-Labortechnik GmbH, Germany). After left thoracotamy, the heart was exposed, the pericardium was opened, and left descending coronary artery was then ligated with a sterile 6.0 silk suture (Ethibond, Ethicon, Norderstedt, Germany) under a stereomicroscope. Successful ligation of the coronary artery was confirmed by the occurrence of arrhythmias in electrocardiogram (ECG) and visually, by observing blanching of the ischemic area. Sham-operated rats were subjected to the same protocol, except that the ligation was placed beside the coronary artery. The muscle and skin were sutured and the thorax was closed in layers. At the end of the operation procedure, analgesia was induced by a subcutaneous injection of buprenorphin-HCl (0.2 mg/kg). After recovery of spontaneous respiratory efforts, each animal was extubated and warmed in the individual cage. With this method, about 40% of infarcted rats die within the first 24 h.

2.2 Experimental protocol
Rats were divided randomly into six groups (the number of rats actually included in the final analysis/ the number of rats allocated to groups) and treated according to the following protocol: group 1 (sham-operated group, n = 11/13): no treatment. group 2 (untreated infarct group, n = 13/36): no treatment. group 3 (30 min post MI group, n = 10/25): fonsartan (HR720), 3 mg/kg/day, s.c.; treatment was started 30 min after MI. group 4 (3 h post MI group, n = 10/22): fonsartan (HR720), 3 mg/kg/day, s.c.; treatment was started 3 h after MI. group 5 (24 h post MI group, n = 8/18): fonsartan (HR720), 3 mg/kg/day, s.c.; treatment was started 24 h after MI. group 6 (7 days post MI group, n = 9/21): fonsartan (HR720), 3 mg/kg/day, s.c.; treatment was started 7 days after MI (Fig. 1).


Figure 1
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  		Fig. 1 Time table of experimental protocol (study design).

 
Fonsartan (HR720) was kindly provided by Aventis Pharma Deutschland GmbH (Frankfurt/Main, Germany). HR720 was dissolved in isotonic saline and loaded into osmotic minipumps (Alzet Model 2002; Alza Corporation, Palo Alto, CA, USA). The osmotic minipump filled with fonsartan (HR720) was implanted subcutaneously between the shoulder blades, all minipumps were replaced under light ether anaesthesia at intervals of 2 weeks, and the treatment was continued for 6 weeks post MI. At the end of the treatment period, arterial, venous and left ventricular catheters were chronically implanted. Twenty-four hours later, hemodynamic signals were recorded in conscious rats. At the end of the recording, rats were sacrificed and hearts were taken out for morphological examinations.

2.3 Hemodynamic studies
Under chloral hydrate (400 mg/kg, i.p.) anaesthesia, polypropylene tubes (Portex, London, UK) were inserted into the right femoral artery and vein and a specially constructed pig-tail catheter consisting of a PP 10 and PP 50 polypropylene tubes via the right carotid artery was introduced in the left ventricle. Then the catheters were exteriorized and anchored at the posterior neck region. Blood pressure, heart rate and left ventricular pressure were recorded 24 h after catheterization in conscious rats. The arterial and left ventricular catheters were connected to pressure transducers (PVB medizintechnik GmbH & Co KG, Kirchseeon, Germany), and all hemodynamic signals were processed by two pressure processors (Gould, Valley View, OH, USA). The output signals (mean arterial blood pressure, heart rate and left ventricular pressure) from these pressure processors were recorded on a pen recorder (Gould Series 2000, Gould) and analysed by a computer-based recording and analysing system (MEGA) [11]. Left ventricular end-diastolic pressure and maximum rate of rise of left ventricular pressure (dP/dtmax) were calculated offline from the left ventricular pressure signal by MEGA program. Mean arterial blood pressure, heart rate, left ventricular end-diastolic pressure and dP/dtmax were averaged over 5-min periods to be used in the statistical analysis. Rats were allowed to get acquainted with the recording circumstances for 30 min before the hemodynamic measurements.

2.4 Cardiac morphological examinations
After recording of the hemodynamic signals, rats were anaesthetized with ether and the hearts were arrested in diastole by an intravenous injection of KCl solution. The hearts were excised and the atria and large vessels removed. The hearts were cleaned and weighed, then placed in 4% phosphate-buffered formalin in 0.15 M NaCl for at least 24 h, and cut transversely into five sections of approximately identical thickness from the apex to the base. These sections were transferred into 10% phosphate-buffered formalin and were kept overnight. After dehydration, the sections were embedded in paraffin, and cut in serial 4-µm-thick slices. The slices were mounted onto glass slides and were stained with haematoxylin-eosin or Goldner, respectively.

The histology of haematoxylin-eosin transections showed transmural myocardial infarctions, the Goldner transections of the midsagittal level with the largest left ventricular circumference were used for further morphometric analysis. Measured morphological parameters were: total heart weight, infarct size, septal thickness, left ventricular circumference and inner diameter. For these measurements, a computerised morphometric system (Quantimet 570, Leica, Cambridge, UK) was used as described previously by Sandmann et al. [10].

2.5 Statistical analysis
All values are expressed as mean±S.E.M. Differences between sham-operated and untreated infarct groups were evaluated by uncorrected Student's t-test. Statistical analysis of obtained morphological and hemodynamic data for each time point was performed using one-way ANOVA. If the ANOVA revealed significance, differences between individual group means were evaluated using the post-hoc Student's t-test. Differences were considered to be statistically significant at the level of P<0.05.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 5 Limitations of the...
 6 Conclusion
 References
 
3.1 Characteristics of untreated infarct rats
In rats randomized to the untreated infarct group, myocardial infarction resulted in a significant increase in heart weight and heart weight to body weight ratio compared with sham-operated rats. This was accompanied by a significant increase of left ventricular circumference and left ventricular inner diameter and a reduction of septal thickness, indicating a development of an eccentric cardiac hypertrophy. In these animals, there was also a significant decrease of mean arterial blood pressure and myocardial contractility (dP/dtmax), whereas left ventricular end-diastolic pressure was markedly elevated (Table 1). These characteristics are consistent with many previous studies from our laboratory and others using this rat model of myocardial infarction-induced heart failure [5,6,10,12–16].


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  		Table 1 Characteristics of untreated MI rats compared to sham-operated ratsa

 
3.2 Survival rate
In the present study, the coronary ligation resulted in a total mortality of 55.5%. In all infarcted groups, the highest mortality occurred within 24 h after surgery. Six weeks after induction of MI, the survival rate was 36.6% in untreated infarct group, 40.0% in 30 min group, 45.5% in 3 h group, 44.3% in 24 h group and 42.9% in 7 days group. Since the number of rats in each group was too small no statistical analysis of survival rate was performed. More animals were required in the untreated infarct group and 30 min group in order to obtain an adequate number of animals surviving the protocol.

3.3 Cardiac morphology
After MI, food and water intake was markedly reduced in all animals followed by a decrease of body weight (data not shown). One week post infarct, the food and water intake was normalised and was not different from sham-operated animals any more. At the end of the experiment, no significant difference in body weight was found between the groups.

Cardiac hypertrophy was evaluated by comparing heart weight and heart weight to body weight ratio. Six weeks after MI, heart weight and heart weight to body weight ratio were significantly increased in untreated infarct animals compared to the sham-operated group (both P<0.05).

Fonsartan (HR720) treatment started 30 min or later after induction of MI normalised both parameters with respect to the sham-operated group (all P>0.05) (Table 2).


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  		Table 2 Effects of fonsartan (HR720) treatments on cardiac morphological parametersa

 
The left ventricular circumference and the left ventricular inner diameter were used to determine left ventricular dilatation. Myocardial infarction resulted in a marked increase of left ventricular circumference and left ventricular inner diameter. Both parameters were practically not modified by fonsartan (HR720) regardless of the time of initiation compared to the untreated infarct group.

Septal thickness was reduced in the untreated infarct group. This parameter was slightly but not significantly increased in fonsartan (HR720)-treated groups. Infarct size was measured at the end of the experiment in all animals. None of the sham-operated rats had evidence of myocardial infarction, while the coronary ligation animals had microscopic evidence of transmural infarction. Compared to the untreated infarct group, infarct size tended to decrease when fonsartan (HR720) treatment was started 30 min after MI and was significantly reduced in animals in which fonsartan (HR720) treatments were initiated 3 h and 24 h post MI (both P<0.05). When treatment was started 7 days after induction of infarct, no difference in infarct size was detected compared to the untreated infarct group (Table 2).

3.4 Hemodynamic parameters
Mean arterial blood pressure was decreased in untreated infarct animals compared with sham-operated rats (Table 3). Fonsartan (HR720) treatment initiated 3 h after MI further decreased this parameter compared to untreated infarct rats. A more pronounced blood pressure lowering effect was observed when fonsartan (HR720) treatment was started 30 min after induction of MI compared to the untreated infarct group (Table 3).


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  		Table 3 Effects of fonsartan (HR720) treatments on hemodynamic parametersa

 
There were no effects of infarction or treatment on heart rate, nor were there any statistically significant differences in heart rate among all groups (Table 3).

Left ventricular end-diastolic pressure (LVEDP) was markedly increased in untreated infarct rats; fonsartan (HR720) treatment commencing 3 h, 24 h and 7 days after MI reduced left ventricular end-diastolic pressure compared to the untreated infarct group, but LVEDP was still significantly elevated compared to sham-operated control (Table 3). In contrast, when treatment with fonsartan (HR720) was begun 30 min after induction of MI, LVEDP was not significantly reduced compared to the untreated infarct group.

Myocardial contractility (dP/dtmax) was severely impaired in untreated infarct rats; fonsartan (HR720) treatment starting 24 h and 7 days after myocardial infarction significantly improved left ventricular dP/dtmax compared to the untreated infarct group (Table 3). Fonsartan (HR720) treatment commenced 30 min and 3 h after myocardial infarction slightly but not significantly improved this parameter (Table 3).


   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
5 Limitations of the...
 6 Conclusion
 References
 
Previous studies have demonstrated that angiotensin AT1 receptor antagonists are effective in the therapy of myocardial infarction-induced heart failure. Moreover, the effects of AT1 receptor blockers on mortality and clinical events after acute MI are being studied in two large scale clinical trials: OPTIMAAL with the use of losartan, and VALIANT with the use of valsartan, to test the hypothesis that interruption of the renin-angiotensin system at the AT1 receptor level will be more effective in saving lives than ACE inhibitors [17,18]. However, the optimal timing of initiation of AT1 receptor blockade has not yet been studied. Therefore, in the present study, we compared the effects of different time points of initiation of treatment on cardiac morphological parameters and hemodynamics. The results indicate that the efficacy of fonsartan (HR720) treatment was most pronounced when initiated 3–24 h after induction of MI. The present study also provides evidence that the effect of angiotensin AT1 receptor antagonists on MI-induced heart failure might be influenced by the pathophysiological status present at the onset of treatment. Many experimental studies [5,13,14,19,20] have compared the effects of angiotensin-converting enzyme inhibitors and angiotensin AT1 receptor blockers in the rat model of myocardial infarction-induced heart failure and demonstrated that the two classes of drugs caused similar cardioprotective effects. However, results from clinical trials suggest that the efficacy of angiotensin-converting enzyme inhibitors in congestive heart failure could be affected by the pathophysiological status present at the onset of treatment [21,22]. Whether the effects of angiotensin AT1 receptor antagonists on myocardial infarction-induced heart failure are also influenced by the time-point of initiation of treatment is unknown. Wound healing following coronary ligation is a complex process in which at least the following phases can be distinguished: the early phases of acute myocardial ischemia, necrosis and inflammation, and the late phases of fibrous tissue replacement and histological healing [23]. In addition, several investigations have demonstrated that scar formation was almost complete and moderate cardiac remodeling and left ventricular dysfunction were present at day 7 after coronary ligation [12,15]. Accordingly, in the present study we chose four different time periods (30 min, 3 h, 24 h and 7 days after coronary ligation) to compare the relative effectiveness of fonsartan (HR720) treatments initiated at different pathophysiological periods after MI.

Fonsartan (HR720) is a non-peptide angiotensin AT1 receptor antagonist. The drug is ten times more potent than losartan in decreasing angiotensin II mediated catecholamine release in pithed spontaneously hypertensive rats [24]. HR720 is equivalent to EX3174 (2-n-butyl-4-chloro-1-[(2,-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic acid), the active metabolite of losartan, in inhibiting angiotensin II-induced trophic effects on rat vascular smooth muscle cells [25]. In a previous study [9], we have demonstrated that fonsartan (HR720) could attenuate cardiac hypertrophy and improve left ventricular dysfunction in rat model of myocardial infarction-induced heart failure.

The present study demonstrated the most pronounced beneficial effects of angiotensin AT1 receptor antagonist therapy initiated during 3 to 24 h after MI. Our findings are supported by previous studies investigating infarct expansion and neurohormonal activation at early phase post MI. Hochman and Bulkey [26] reported in rats that the cardiac expansion (regional dilatation and thinning) of acute myocardial infarction was present in 61% at 1–2 days after transmural infarction, in 65% at 3–4 days and in 80% at 5–7 days in rats, and the percentage with severe expansion increased markedly over this period, from 0% at 1–2 days to 23% at 3–4 days to 65% at 5–7 days. Zardini and colleagues [27] observed that the cardiac expansion develops within the first few hours following MI. These investigations suggest that the infarct expansion begins in the early phase of MI and the period within 1 day following infarct appears to be most critical. Pfeffer et al. [28] found that early infarct expansion is associated not only with immediate but also with continued (late) ventricular remodeling. Preventing infarct expansion can preserve left ventricular geometry and function [29], because both, degree of infarct expansion and left ventricular dilation depend on infarct size [23,26]. Thus, limiting the infarct size by prompt therapeutic interventions within the first few hours might be the most effective way to prevent or minimize the infarct expansion and secondary ventricular dilation after MI. In the present study, fonsartan (HR720) treatment started 3 and 24 h post MI limited infarct size, which may be an important mechanism for early fonsartan (HR720) treatment to exert maximum benefit. In addition, neurohormonal activation occurs very early almost immediately after MI [30]. Activation of the sympathetic nervous system is believed to be of importance in the progressive nature of heart failure. Losartan has been shown to improve baroreflex control of sympathetic outflow in rabbits [31]. Angiotensin AT1 receptor antagonists may pass the blood–brain barrier more easily than angiotensin-converting enzyme inhibitors [32], thus, angiotensin AT1 receptor antagonists may also directly influence central sympathetic tone [33]. Furthermore, Spinale and colleagues [34] reported that angiotensin

AT1 receptor blockade increases cardiac output, decreases systemic and pulmonary vascular resistance as well as plasma catecholamines levels in pigs with heart failure. Therefore, either less infarct expansion and left ventricular enlargement or a prompter improvement of hemodynamics and inhibition of neurohormonal activations may explain in part the beneficial effects of early fonsartan (HR720) treatment.

In addition, Bolognese et al. [35] found that the degree of left ventricular dilation following MI is reversely related to the extent of residual myocardial viability in infarct zone, the presence of a relative large amount of viable myocardium in the infarct zone strongly contributes to maintenance of left ventricular wall shape and size by preventing infarct expansion. Recent studies have suggested that the loss of cardiomyocytes after MI can also be caused by apoptosis. Kajstura [36] reported that apoptosis is the major form of myocardial damage after coronary ligation in rats. Myocardial infarction has been demonstrated to activate the renin–angiotensin system, and lead to an increase of angiotensin II concentrations and expression of AT1 and AT2 receptors in myocardium. Angiotensin II is known to have cardiotoxic effects, and induces myocyte apoptosis [37]. Several studies have demonstrated that angiotensin II-induced apoptosis of ventricular myocytes was inhibited by angiotensin AT1 receptor antagonist losartan [37,38]. Thus, contributory mechanisms for early fonsartan (HR720) treatment exerting the best cardioprotective effects most likely included a prompt inhibition in myocyte apoptosis and an increase in the amount of viable myocytes in infarct zone.

However, in the present study we observed that very early fonsartan (HR720) treatment initiated 30 min after coronary ligation did not improve left ventricular dysfunction. These results suggest that therapy with angiotensin AT1 receptor antagonists should not be started very early after MI. It appears that very early treatment with angiotensin AT1 receptor antagonists could compromise the potential beneficial effects that these drugs may have when used long term in this model of heart failure. This is in agreement with previous investigations [7,8] although the exact mechanism is poorly understood. In the present study, fonsartan (HR720) treatment initiated 30 min after coronary ligation markedly decreased mean arterial blood pressure compared to untreated infarct animals. This hypotensive reaction may reduce coronary blood flow and increase heart rate through the baroreceptor reflex, and thus may induce harmful effects on the heart during the very early phase after myocardial infarction. Whether the used high dose of fonsartan (HR720) rather than fonsartan (HR720) itself is the reason for the poor outcome in the 30 min group. In pilot experiments, we chose a dose of fonsartan (HR720) 3 mg/kg/day, that had a sufficient efficacy over 24 h (i.e., 70–80% cardiovascular effects of angiotensin II 100 ng i.v. was blocked by fonsartan over 24 h), but did not change blood pressure on healthy Wistar rats. A recent study from Linz et al. [39] reported that the antihypertensive dose of fonsartan (HR720) is 10 mg/kg/day in stroke-prone spontaneously hypertensive rats (SHR-SP). Thus, the dose of fonsartan (HR720) 3 mg/kg/day in present study might be appropriate.


   5 Limitations of the study
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Limitations of the...
6 Conclusion
 References
 
Although the rat model of coronary artery ligation is a well-established model of heart failure, it must be recognized that any animal model will not fully represent the complex clinical situation of cardiac failure. Thus, the results of the present study should be further evaluated in clinical trials. In addition, fonsartan (HR720) treatment starting 3 and 24 h after MI limited infarct size and reduced LVEDP, a decrease in infarct size and LVEDP should be associated to a reduction of LV dilation, which was not observed in the present study. Also, measurements of LV length may be helpful, this variable would allow to calculate LV volume, a better estimation of LV remodeling than the diameter and circumference.


   6 Conclusion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Limitations of the...
 6 Conclusion
References
 
This study performed in a rat model of myocardial infarction-induced heart failure shows that the treatment with an angiotensin AT1 receptor blocker fonsartan (HR720) starting 3 to 24 h after MI exerts the best cardioprotective effects. Thus, we suggest that the therapy with angiotensin AT1 receptor antagonists should be commenced within 1 day of acute myocardial infarction.

Time for primary review 21 days.


   References
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
 5 Limitations of the...
 6 Conclusion
 References
 

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