Effects of pre-, peri-, and postmyocardial infarction treatment with losartan in rats: effect of dose on survival, ventricular arrhythmias, function, and remodeling

Losartan treatment, pre- peri- and post-MI 1

Effects of pre, peri and postmyocardial infarction treatment with Losartan in

rats: effect of dose on survival, ventricular arrhythmias, function and

remodeling

Ali Pourdjabbar 1; Thomas G. Parker 1; Quang Trinh Nguyen 2; Jean-Francois Desjardins 1; Nathalie Lapointe 2; James N. Tsoporis 1; Jean-Lucien Rouleau 3

1 Division of Cardiology and Department of Medicine, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, M5B 1W8; 2 Division of Cardiology, University Health Network, Toronto, Ontario, M5G 2C4; and 3 Department of Medicine, Montreal Heart Institute, Montreal, Quebec, H1T 1C8.

Running head: Losartan treatment pre-, peri- and post-MI

Address correspondence and reprint requests to Dr. Thomas G. Parker, M.D. Division of Cardiology, St. Michael’s Hospital, Room 6-044 Queen Wing, 30 Bond Street, Toronto, Ontario; M5B 1W8, Canada. Tel: 416-864-5271; Fax: 416-864-6189; E-mail: [email protected]

Articles in PresS. Am J Physiol Heart Circ Physiol (November 11, 2004). doi:10.1152/ajpheart.00671.2004

Copyright © 2004 by the American Physiological Society.


Abstract

Angiotensin receptor blockers (ARBs) reduce post-MI adverse left ventricular (LV) remodeling, improve

LV function and survival when started post-myocardial infarction (MI). ARBs also reduce ventricular

arrhythmias during ischemia-reperfusion injury when started pre-MI. No information exists regarding

their efficacy and safety when started pre-MI and continued peri- and post-MI. We evaluated whether the

ARB, Losartan improves outcome when started pre-MI, and continued peri- and post-MI. Male Wistar

rats (n=502) were treated for 7 days pre-MI with Losartan high-dose, 30 mg/kg/day, or progressively

increasing dose, 3mg/kg/day (increased to 10mg/kg/day 10 days and 30mg/kg/day 20 days post-MI) or

no-treatment. Ambulatory systolic blood pressure and Holter monitoring were performed for 24-hours

post-MI. Echocardiography was done 30-days post-MI, and LV remodeling, cardiac hemodynamics and

fetal gene expression were assessed 38-days post-MI. High-dose Losartan reduced 24-hour post-MI

survival compared to progressive dose and control (21.9% vs. 36.6%, 38.1%, p=0.033 and p=0.009

respectively). This was associated with greater hypotension in high dose, and no change in ventricular

arrhythmias in all groups. In 24-hour post-MI survivors, the progressive dose group had reduced mortality

from 24hour to 38-days (8.5% vs. 28.6% for control vs. 38.9% for high dose, p=0.032 and p=0.01

respectively). Survivors of both Losartan groups demonstrated improved LV remodeling, cardiac

hemodynamics, preserved GLUT-4 and reduced cardiac fetal-gene expression. Pre-treatment with ARBs

does not reduce 24-hour post-MI ventricular arrhythmias or survival, and high doses increase mortality by

causing excessive hypotension. In 24-hour post-MI survivors, progressively increasing doses of Losartan

have multiple beneficial effects, including improved survival.

Keywords: Angiotensin II receptor blockers, Heart Failure, Infarction, Remodeling, Hypotension


Introduction

During the acute phase of a myocardial infarction (MI), ventricular arrhythmias are the principle cause of

death. Indeed, nearly 70% of patients dying of an acute MI die suddenly prior to arriving to hospital (10).

Safe and effective reduction in peri-MI arrhythmias is thus an essential strategy in improving peri-MI

survival. Once a patient reaches hospital, a major goal of therapy is re-establishing cardiac perfusion in

order to limit MI size. Once the MI is well established and the damage irreversible, it is important to limit

adverse left ventricular (LV) remodeling in order to reduce the risk of heart failure (HF). Indeed, the

extent of LV dilation is the most powerful predictor of long-term prognosis post-MI (22).

The acute phase of the MI is characterized by neurohumoral activation, a process that lasts for days then

generally subsides over days to weeks, unless HF develops, in which case there is chronic progressive

neurohumoral activation. The renin-angiotensin system, particularly angiotensin II (Ang II), is up-

regulated peri- and post-MI. Angiotensin receptor blockers (ARBs) have been shown to improve

outcome when started early post-MI (21). One of the proposed mechanisms for these beneficial effects is

improved LV remodeling (24), but other mechanisms are also possible (15) but not well worked out. It

is uncertain as to what effect the presence (pre-treatment) of an ARB would have in the setting of an acute

MI. One possibility is that it would exert a beneficial effect. In favor of this is a report of the ARB

Losartan decreasing peri-MI arrhythmias during cardiac ischemia-reperfusion (28). However, it is also

possible that they induce adverse effects due to excessive hypotension, as has been shown to occur with

the ACEi Enalapril (26).

In the two studies that compared ARBs to ACEi therapy, drugs were initiated in small doses in order to

avoid the adverse effects of excessive hypotension observed in the CONSENSUS II trial (26). The dose

was then progressively increased. In the OPTIMAAL trial, the ARB did not perform as well as the ACEi

(7). One proposed hypothesis is that the dose of the ARB was inadequate (6). Consistent with this

hypothesis, a larger dose of an ARB was found to be equivalent to an ACEi in the VALIANT trial (21).


Thus, avoiding excessively high doses of an ARB early post-MI and assuring the use of higher doses later

post-MI may be important in order to obtain the optimal effects of ARBs post-MI.

Thus, in the present study, we chose to mimic the proposed optimal clinical use of ARBs post-MI that is,

starting with smaller known effective doses and progressively increasing to a high dose of the ARB

losartan. We compared these effects to early and sustained high doses of losartan and to no treatment at

all. We compared early (24 hour) post-MI ventricular arrhythmias, systemic blood pressure and survival,

and late post-MI LV remodeling, function, MI size and fetal gene expression. We hypothesized that

progressive doses of losartan would exert beneficial effects that would be superior both control and early

a large doses of Losartan.

Materials and Methods

Animals and Drug-Regimen

Male Wistar rats (Charles River, St-Constant, Quebec, Canada) weighing 160-200 g were assigned to one

of three groups: Losartan (Merck Frosst, Montreal, Qc) at 30mg/kg/day (High-dose) or 3mg/kg/day with

an increase to 10mg/kg/day on day 10 post-MI, and to 30mg/kg/day on day 20 post-MI (progressive-

dose) or control. The low and high doses of Losartan were chosen based on a previous report

demonstrating cardio-protective effects in rats following a MI (5,24). The increasing dose of Losartan

over time post-MI was chosen to simulate the clinical situation where Losartan is started low and

increased post-large-MI. Losartan was administered in drinking water starting 7 days prior to MI surgery.

In order to assure adequate levels of Losartan peri and early post-MI, it was administered by oral gavage,

in high dose 15mg/kg (0.25ml) or low dose 1.5mg/kg (0.25ml) of Losartan or vehicle (0.9% saline) the

evening after the MI and again twice the next day, after which the medication was once again

administered in drinking water and continued for the duration of the specific protocol. All of the animal

experiments followed the guidelines of the Canadian Council on Animal Care and were approved by the

Animal Care Committee of the University Health Network (Toronto, ON).


Experimental Myocardial infarction

Rats were anaesthetized with an intra-muscular injection of a mixture of ketamine 50mg/kg (Rogar/STB,

Montreal, Qc), and xylazine 10 mg/kg (Bayer Canada, Etobicoke, ON). MI was induced by ligation of

the left anterior descending coronary artery as described previously by Nguyen et al. (19). Sham

operated rats underwent a similar procedure except the silk suture was not tied. Once awakened

following surgery, the rats were injected with buprenorphine HCl 0.01 mg/kg as described previously.

Twenty-Four Hour Protocol:

Ambulatory Electrocardiogram (ECG) and Blood Pressure Monitoring

Ten days prior to the MI, under ketamine and xylazine anesthesia, rats (n=48) had a transmitter

implanted in the peritoneal cavity and anchored to the abdominal musculature. The implants had a pair

of flexible stainless steel wires/leads (Data Sciences International, St-Paul, MN) implanted

subcutaneoulsy for continuous ECG monitoring, and a blood pressure catheter, which was inserted into

the descending aorta, as previously described (14). The body of the implant that contains the electronics

for signal handling and radio-transmission was placed in the peritoneal cavity. Rats were then housed in

an individual cage placed on a receiver that continuously captures the radio-frequency signal from the

transmitter and converts it into a serial bit stream (Dataquest A.R.T.2.2, DSI, St-Paul, Mn.). Ambient

barometric pressure was also measured and subtracted from the telemetered pressure by data collection

software to compensate for changes in atmospheric pressure.

Arrhythmia Analysis: Monitoring started 6-hours prior to MI until the time of death or 24-hours post-MI.

The observer classified all arrhythmic events on ambulatory electrocardiographic recordings according to

the guidelines provided by The Lambeth Conventions and Curtis and Walker (4) with minor

modifications as previously described by Lapointe et al (14). The average arrhythmia score was

calculated 6 h before MI, and for 4 post-MI time periods, 0-1 h, 1-6 h, 6-12 h, and 12-24 h.

Assessment of MI Size


Rats dying <4 hours post-MI were considered to have had a large-MI. Rats dying between 4 and 24-

hours or surviving 24-hours post-MI had their hearts removed for determination of infarct size by

triphenyl tetrazolium chloride (TTC). The LV was hand-cut into four slices before staining with TTC.

Tissue slices were stained by incubation in 1% TTC for 10 to 15 minutes at 37°C and pH 7.8. The tissue

was then bathed for 15 minutes in a 10% formalin phosphate buffer to enhance color contrast. For each

slice, the scarred area was photographed under a Leica M26 (Leica Microsystems Inc., Quebec, CA) and

its surface was determined by planimetry (Labtronics Inc., Guelph, ON). Sections were traced on a

calibrated digitizing tablet and morphologic variables calculated directly by computerized-planimetry

with the Sigma Scan Pro software (Labtronics Inc., Guelph, Ontario, Canada).

Thirty-Eight Day Protocol:

454 male Wistar rats were randomly assigned into 3 groups: Losartan High-dose (30mg/kg/day) (n=103),

Losartan Low-dose (3mg/kg/day increasing gradually to 30mg/kg/day) (n=161) or control (n=190),

administered as described above (Figure 1).

To verify if the low dose of Losartan chosen blocked the Angiotensin (Ang) II signaling pathway, a dose-

response curve to AngII 6.5ng/kg to 650ng/kg (Sigma, Lot# 31K51142) was constructed in 16 rats treated

with 3mg/kg/day of Losartan. The presser response to AngII was significantly attenuated for all doses of

Ang II as compared with control (results not shown).

Echocardiographic measurements:

Thirty days post-MI, cardiac function and geometry were evaluated with an echocardiographic system

equipped with a 15-MHz linear transducer (Acuson c256, Osiris Medical Inc., Toronto, ON). All studies

were performed with rats anaesthetized with 2% halothane (Halocarbon Laboratories, Riveredge, NJ)

using a vaporizer for halothane (Harvard Apparatus, Quebec, CA) and 0.2 l/min of oxygen. A

comprehensive 2-dimensional study was performed for the measurement of the LV circumference and

areas in both, systole and diastole. LV systolic diameter (LVSD), LV diastolic diameter (LVDD) were

measured in the short-axis M-mode as previously described (14).

Cardiac hemodynamic measurements


Thirty-eight days post-MI, rat were anesthetized with an intramuscular injection of ketamine (50 mg/kg),

and xylazine (10 mg/kg) mixture. The LV and right ventricular (RV) pressures were measured by a

Millar micro-tip catheter transducer, inserted into the right jugular vein and carotid artery and advanced to

the RV and LV, respectively. Systolic and diastolic arterial pressures were measured in the aorta before

being advanced to the LV. The maximum rate of pressure rise (+dP/dt) and decline (-dP/dt) were also

measured. The pressures were recorded on a Gould 2600S recorder (Gould, Cleveland, OH). Once the

hemodynamic measurements completed, rat were sacrificed and either used for assessment of LV

remodeling by passive pressure-volume relationship, or morphologic assessment of cardiac hypertrophy.

Morphological Assessment of Cardiac Hypertrophy

In rats surviving to 38-days, the heart was removed, rapidly rinsed in saline solution, and dissected into

atria, RV, LV, septum and scar. All portions of the heart, as well as the lungs, were then weighed

individually and frozen at -80ºC. MI size was assessed by measuring the surface area of the scar. Prior to

weighing, the scar was pinned on paper and its surface area measured by planimetry (Labtronics Inc.,

Guelph, ON). A large-MI was defined as an infarct size ≥ 0.8 cm2, a moderate MI was defined as an

infarct size < 0.8 cm2 and sham as no scar. A scar area of ≥ 0.8 cm2 is equivalent to an MI of ≥ 35% of

LV circumference in our experience (19). Rats dying later than 24-hours post-MI but prior to

hemodynamic monitoring had morphologic assessment for classification of MI size by assessing % of LV

circumference infracted, as previously described (3), but were not used for other measurements, except

for survival.

Passive Pressure-Volume Relationship and Ventricular Remodeling

Because the number of rats surviving the 38-days protocol in the high dose ARB group was low, only

control and low-dose Losartan groups were used for this protocol. Hearts were removed after cardiac

hemodynamic measurements, rinsed in a saline solution and then arrested in a supersaturated solution of

KCL, after which passive pressure volume was assessed as previously described (3). After the

assessment of the pressure-volume relationship, the hearts were filled with saline to a pressure of 15mm


Hg, sealed and fixed in 10% formalin phosphate solution for 24-hours. The heart was then cut halfway

between the base and apex, and 2 slices were obtained 1 mm above and below the middle cut and stained

with hematoxylin-phloxine saffron for assessment of MI size as previously described (3). Using this

method, a large-MI was defined as those having a LV scar of ≥35% of the ventricular cross-sectional

circumference, a moderate MI as having an LV scar<35%, and sham having no scar.

RNA Isolation and Purification

Total RNA was isolated from treated and untreated tissues from the septum of hearts, using TRIZOL

method. RNA samples were further subjected to RNase-free DNase I treatment at 37 °C for 30 min, then

purified with phenol chloroform and isoamyl alcohol, re-precipitated, and dissolved in nuclease-free

water. RNA was quantified with GeneQuant spectrophotometer (Amersham Pharmacia Biotech,

Piscataway, NJ) and RNA integrity was confirmed by running it on a formaldehyde gel. The isolated

total RNA was used in real-time quantitative RT-PCR experiments.

Real-Time Quantitative RT-PCR

Thermoscript one-step quantitative RT-PCR with platinum Taq kit was used in order to synthesize cDNA

and subsequent real-time quantitative RT-PCR (Applied Biosystems, Foster City, CA). The gene specific

sequences of oligonucleotide primers (100 nM final concentration of forward and reverse primers) were

used to check the expression of respective genes with a 1× final concentration of SYBR Green PCR

master mix (SYBR Green I Dye, AmpliTaq Gold DNA polymerase, dNTPs with UTP, passive reference,

and optimized buffer components), 0.25 U/mL multiscribe reverse transcriptase, 0.4 U/mL of RNase

inhibitor, and 10 ng of tissue RNA in a 50 µl PCR mixture according to the manufacturer’s protocol

(Applied Biosystems, Foster City, CA). The temperature profile included an initial 30 min, at 48 °C (for

cDNA synthesis), then denaturation at 95 °C for 10 min, in order to deactivate the RT and activate the

thermoscript taq polymerase. This was immediately followed by 40 cycles of denaturation at 95 °C for

15 s, 60 s at 60 °C annealing and elongation with optics on for fluorescence monitoring. The specificity

and purity of the amplification reaction was determined by performing a melting curve analysis. The


relative quantification of gene expression by real-time RT-PCR in a sample was determined by comparing

the target-amplified product against GAPDH (internal standard) within the same sample. GAPDH

mRNA expression was not significantly different among the various groups. Treated/control ratios were

tested for deviation from unity by calculation of confidence limits.

Statistical Analysis

All values were expressed as mean ± SEM. Results in figures 3 and 4 were analyzed by a

repeated- measures ANOVA across time post-MI and time prior to death and planned pairwise

comparisons (comparing 30mg dose to other conditions). A one-way ANOVA and Dunnett’s

Test were also used in figure 4A to compare mean arterial pressure prior to treatment and MI

procedure. Figure 5 was analyzed by a 2-way repeated measures ANOVA across volume by

dosage and condition (Large MI vs. sham). Lastly results within a given MI group and across

treatment groups in figure 6, and tables 1, 2 and 3 were analyzed by a one-way ANOVA and

Dunnett’s Test. Probability values of p< 0.05 were accepted as statistically significant. Kaplan-

Meier survival curves over the follow-up period were constructed and analyzed by the

generalized savage (Mantel-Cox) test.

Results

Survival

In the control group (n=190), 91 of 147 rats with a large-MI died within the first 24-hours (38.1%

survival), and 16 died over the following 37 days, leaving 40 survivors (27.2%) at the end of the 38-day

protocol. Of the rats receiving Losartan at 3mg/kg/day (n=161), 78 of 123 with a large-MI died within

the first 24-hours (36.6% survival) and 4 died over the following 37 days, leaving 41 survivors (33.3%).

Of the rats receiving Losartan at 30mg/kg/day (n=103), 64 of 82 with a large-MI died within 24-hours

(21.9% survival, p<0.01 vs. control and p<0.04 vs. Losartan low-dose). Of the remaining 18 rats, 7 died


over the following 38-days, leaving only 11 survivors (13.4%, p<0.0001 vs. control and p<0.0001 vs.

Losartan low-dose) (figure 2A).

If one considers only rats with a large-MI that survived the first 24 h post-MI, over the following 37 days,

the group receiving low-dose Losartan with a gradual increase in dose had the best survival, 91.5% as

compared with 71.4% in the control group and 61.1% in Losartan high-dose (p<0.02 and p<0.01

respectively) (figure 2B).

24-Hour Protocol:

Incidence and Duration of Ventricular Arrhythmias: (figure 3)

No VT or VF was recorded during the 6-hour baseline recording prior to coronary artery occlusion.

There was no difference in average ventricular arrhythmia score between large-MI control rats and large-

MI rats receiving high-dose or low-dose Losartan.

Ambulatory Blood Pressure (figure 4A):

Mean arterial pressure (MAP) did not differ amongst the 3 treatment groups prior to Losartan

administration, but it was significantly lower after 7 days of Losartan treatment in the 30mg/kg/day

group. MAP decreased as a result of a large-MI in all 3 groups. Over the 24 hours post-MI period, MAP

differed significantly across treatment groups. Planned pairwise comparisons revealed that following a

large-MI, high dose treated animals had a lower MAP as compared to control and low-dose groups,

p=0.05 and 0.02, respectively. Following a large-MI the MAP of rats receiving Losartan 3mg/kg/day did

not significantly differ from those of control rats.

In high-dose Losartan rats with a large-MI that died in the first 24-hours post-MI, MAP was extremely

low prior to death. As compared with controls and low-dose rats with equivalent MI size, MAP was lower

over the 60-5 minutes time interval prior to death (both p<0.05), (figure 4B) suggesting that hypotension

played a role in the death.

38-Day Protocol:


Echocardiographic Measurements (Table 1)

In the sham-operated groups, Losartan in low or high-dose did not have a discernable effect on

echocardiographic measurements. In control large-MI, there was significant LV dilatation with LV

circumference and area in systole and diastole all increasing as compared to sham controls. There was

also significant thinning of both the anterior and posterior walls, an increase in LV diastolic and systolic

dimensions (LVDD and LVSD respectively), and impaired LV function as reflected by decreased LV

shortening fraction (LVSF) and LV ejection fraction (LVEF).

Losartan high and low-doses had similar effects. Following a large-MI, they attenuated LV dilatation and

helped preserve LV function as compared with control large-MI.

Hemodynamic Effects of Chronic Losartan Treatment (Table 2)

Thirty-eight days post-MI, in sham operated rats, in both Losartan groups (both were receiving 30

mg/kg/day at sacrifice) systolic and diastolic blood pressures were lower.

As compared with their sham counterparts, control large-MI rats had a decrease in LV systolic pressure

(LVSP), an increase in LV end diastolic pressure (LVEDP) and a decrease in all measured indices of

contractility and relaxation. These changes were accompanied by an increase in RV systolic pressure

(RVSP) and RV end diastolic pressure (RVEDP).

Both groups of Losartan large-MI rats had similar hemodynamic changes. Systemic arterial pressure as

well as LVSP decreased as compared with control animals with a large-MI. LVEDP, RVSP, and RVEDP

all increased less suggesting improved LV function. LV +dP/dt when corrected for LVSP also improved

as compared with control large-MI.

Morphological Measurements (Table 3)

In sham-operated rats, Losartan treatment had little effect, the only change being a reduction in LV mass

in the high-dose Losartan group. As compared with their sham counterparts, control large-MI rats had a

significant increase in RV, atrial and lung weights. In the two large-MI Losartan groups, the increase in

RV, septal, atrial and lung weights were less marked than in control large-MI.


Passive LV Pressure-Volume Relationship

Losartan treatment exerted a significant effect on the passive pressure-volume relationship (p<0.02). In

sham- operated rats, Losartan caused a slight leftward shift in the passive pressure-volume relationship.

A rightward shift in the passive pressure-volume relationships of all large-MI groups was observed,

however the rightward shift was less in the Losartan treated rats (Figure 5)

MI Size

Animals with a large infarct surviving the 38-day protocol used for real-time PCR had similar infarct

surface area, in the high dose group 1.05 ± 0.06 cm2 (n= 11) as compared to 1.21 ± 0.04 cm2 (n=31) and

1.24 ± 0.05 cm2 (n=14) in non-treated and low-dose treated animals respectively (p >0.05). No difference

in MI-size was also observed in animals who underwent passive LV pressure-volume assessment and had

their MI size calculated via HPS staining and computer planimetry in the non-treated (n= 9) and low-dose

treated (n=27) groups, 45.1 ± 1.8% vs. 41.6 ± 1.4% of the LV wall circumference, respectively, p=0.2.

Real-time PCR (Figure 6)

Losartan had no effect on LV target mRNA expression in sham-operated rats. In control-large-MI, there

was a significant reduction in GLUT-4 mRNA expression, and an increase in fetal gene expression

(SKACT, ANF, and β-MHC mRNA) as compared to sham-operated rats. Both Losartan large-MI groups

had significantly higher levels of GLUT-4 mRNA expression as compared to control large-MI, and LV

SKACT, ANF, and β-MHC mRNA expression were significantly less elevated than control large-MI.

Discussion:

The main findings of this study are 1) that the administration of the ARB Losartan in the pre- peri- and

post-large-MI period does not result in improved 38-day post-MI survival, and that the administration of

high-doses in the peri-MI period actually increases mortality due to excessive hypotension; 2) that

Losartan also does not reduce peri-MI (24 hours) arrhythmias in a meaningful way; 3) that Losartan has

beneficial effects on LV function remodeling and fetal gene expression, and that this results in improved


survival starting 24-hours post-MI. Thus, during the peri-MI period, as has been found with ACEi in the

clinical setting, large doses of ARBs should be avoided. Rather, ARBs should be given at lower doses

early post-MI and increased progressively over time. A similar progressive dosing schedule of ARBs in

the peri- and early post-MI settings should form the basis of the administration of ARBs in further

experimental studies in the field.

Peri-MI effects of Losartan: concerns regarding hypotension:

In animals with a large-MI, higher dose of Losartan given peri-MI resulted in an increase in 24-hour post-

MI mortality. Careful analysis of MAP in rats dying during the first 24-hours post-MI, revealed that rats

receiving the higher dose of Losartan more frequently had marked hypotension the hour prior to death

suggesting that hypotension contributed to their death. In these rats, MAP within 1-hour of dying ranged

between 50 and 60 mmHg, much lower than the 75-90 mmHg in rats dying in the control and lower dose

Losartan groups, suggesting a possible relationship between the hypotension caused by Losartan and

increased mortality. Persistent hypotension post-MI is a serious concern since it has been linked to the

occurrence of tachy-arrhythmias and ventricular fibrillation leading to sudden death (8). It must

nevertheless be noted that the lower dose of Losartan used in this study resulted in partial AT1 receptor

blockade as reflected by the rightward shift in Ang-II dose-response curve that it caused. In the

CONSENSUS II trial, a high dose of the ACEi, Enalapril, started within the first 24-hours following an

acute-MI resulted in a significantly higher incidence of hypotension and a trend towards increased

mortality within 6 months following the initial infarction (26). Worrisome hypotension has also been

reported in other clinical trials were ACE inhibition was initiated within the first day of a MI (1,2).

The idea of delaying therapy in order to reduce the onset of hypotension is a controversial one given that

infarct expansion and remodeling is initiated within hours of a MI. In favor of an early aggressive

approach is the HEART study by Pfeffer et al., where patients were randomized to early (within 24 hours)

low dose Ramipril, early higher dose (progressive dose increase), and delayed Ramipril use. The low

dose of Ramipril chosen for this study did not normally have hemodynamic effects, but did have mild

hemodynamic effects in the acute MI setting (20). Of the three treatment groups, the early high dose


group had the best effects on LV remodeling suggesting that adequate doses of an ACEi early post MI is

important. In the present study, the initial dose of losartan used, 3 mg/kg/day was proportionately greater

than the dose used in the HEART study. In pilot studies we showed this dose to cause a significant

rightward shift of the Ang-II dose-response relationship, and in a previous study, this dose that has been

shown to have significant beneficial effects in the post-MI setting (4). The dose was then rapidly

increased to 10 mg/kg/day, a larger dose also shown to be useful post-MI (12), and finally to 20 then 30

mg/kg/day. The results of the present study thus support the early use of lower doses of an ARB post-MI

with up-titration to full doses early, as the HEART study did in with ACEi.

The findings of this study, contrast previous reports that have demonstrated beneficial outcomes with the

use of ARBs administered pre- or early post-MI at doses similar to or higher than the 30mg/kg/day, used

in this study. In a study by Zhu et al., the authors reported that pre-treatment with Losartan at

40mg/kg/day for 10 weeks followed by 17-minutes of ischemia and two hours of reperfusion (IR),

resulted in decreased ventricular arrhythmias, decreased MI size, and decreased 2 hour post-MI mortality

(28). Surprisingly, the authors failed to show any hemodynamic modification with this high dose of

Losartan. The explanation for these differences is not clear, but may have resulted from a combination of

the experimental protocol (IR), the short follow-up period, and the anesthesia used in their study, our rats

were awake and mobile most of the 24hour follow-up period. In another study, Ruzicka et al., who

started Losartan treatment (15mg/kg/day) 3 days prior to MI and continued for 4 weeks post-MI, also did

not report any early detrimental effects, but also did not report mortality following LAD ligation (23).

Effects of Losartan on Ventricular Arrhythmias:

Losartan was not found to modify ventricular arrhythmias during the first 24-hours post-MI in either low

or high doses. In IR, results from Zhu et al would suggest that pre-treatment with Losartan at

40mg/kg/day, decreases ventricular arrhythmias in a rat model of IR (28). In another paper, the same

group found that longer duration of pre-treatment (i.e. 4 weeks) was more cardio-protective than shorter

periods (i.e. one week and one day) of pre-treatment prior to IR in rats (27), suggesting that longer pre-


treatment in our study may have resulted in different findings. Alternatively, it may be that Losartan

affects the arrhythmic properties in IR differently than it does in trans-mural MI, the mechanisms

involved in both being quite different (17). It may also be that the lack of hypotension associated with IR

combined with high doses of Losartan is both necessary for its anti-arrhythmic effects to occur. In the

study by Zhu et al, despite large doses, Losartan did not modify systolic blood pressure throughout the

study (28), while in ours, the hypotension associated with the MI and high dose Losartan may have

negated its anti-arrhythmic effects.

Beneficial post-MI effects of Losartan:

Losartan treatment in rats surviving the acute (24-hours) MI period with a low-dose, followed by timed,

gradual increase in the dosing regimen resulted in dramatic improvement in survival over the next 37-

days of the protocol. This improvement in survival was accompanied by an improvement in LV

remodeling and function, a finding compatible with previous experimental post-MI studies using ARBs in

rats (5,13,16,24,25), and more importantly, compatible with the results of the VALIANT study that found

the ARB Valsartan to be as effective as the ACEi Captopril post large-MI (21). Animals in both high and

progressive dose groups that survived the 38-day protocol, also presented similar improvements in LV

remodeling and function reported by others, suggesting that in survivors both dosing regimens are equally

cardio-protective. Our findings are supported by a previous study by Nakamura et al. who demonstrated

that chronic low and high dose ARB treatment following a MI in rats are equally beneficial in terms of

LV remodeling and function (18). In our study, the observed improvement in LV remodeling and

function was accompanied by attenuation in fetal gene re-expression, and in preservation of the cardiac

expression of the glucose transporters, GLUT-4. Our study confirms the results of Hanatani et al that

have previously reported attenuation of fetal gene expression in a shorter post-MI study with another

ARB in the post-MI setting (9). This is, however the first report of preservation of the glucose transporter

GLUT-4 in the post-MI setting. Greater expression of GLUT-4 could result in improved glucose

utilization in the failing heart, and thus improved cardiac energetics.


We also documented a significant improvement in right ventricular function as well as a reduction in

pulmonary congestion. Zornoff et al. have reported that RV dysfunction is a very important predictor of

survival (29). Thus, Losartan’s beneficial effects on RV hypertrophy, pressure and function could at least

partially be responsible for the observed improvement in survival in our study.

Despite these improvements we were unable to show a reduction in infarct size with Losartan pre- and

post-MI treatment, which has been previously reported by (25). Once again our findings contrasts with

the findings of Zhu et al. demonstrating that pre-treatment with 40mg/kg/day of Losartan decreased MI

size, but again the results of Zhu et al were in the setting of 17 minutes of ischemia then 2 hours of

reperfusion, a setting in which they found no reduction in systolic blood pressure with losartan (28).

This is the first time that the pre-, peri-MI effects of Losartan have been combined with their long-term

post-MI effects. Why the combined peri-and post-MI use of Losartan did not result in improved survival

is not clear, but an early detrimental effect of Losartan, even in the smaller dose, cannot be excluded.

Alternatively, because no early harm could be documented acutely (<24-hours) with the lower dose, this

lack of overall benefit may have resulted from inadequate sample size and power to detect a difference.

A study by Hu et al. has also reported that Losartan, at 10mg/kg/day; started early post-MI did not

attenuate structural dilatation following coronary occlusion in rats (11). At this time, no other study

evaluating the peri-MI effects of an ARB exists to evaluate consistency with our results.

Limitations:

Animals were anesthetized at the time of surgery. This may have influenced arrhythmias and survival in

the first two hours post-MI. Thereafter rats were awake and unrestrained for the next twenty-two hours of

monitoring. A number of rats died during the study, which may have influenced hemodynamic

measurements at the end of the study. In order to minimize problems related to loss of rats during the

study, we classified rats according to MI size. Finally, because we did not include a low dose group

without progressive up-titration, it is possible that it was unnecessary to progressively increase the dose.

This does not, however, change the clinical implications of our findings, that high doses of an ARB


should be avoided early post-MI because they result in excessive hypotension and death. The combined

results of the OPTIMAAL and VALIANT studies have established the need to up-titrate post-MI.

Conclusions:

This study indicates that pre- and peri- MI treatment with the ARB Losartan exerts no beneficial effect on

survival and ventricular arrhythmias in the acute period post-MI, and high doses may even be detrimental

due to excessive hypotension. Losartan does not have early anti-arrhythmic properties, but, when given in

progressively increasing doses, results in improved LV remodeling and function, which in 24-hour post-

MI survivors, results in improved survival, reduced fetal gene expression, and preserved cardiac GLUT-4

expression despite no difference in infarct size.

Acknowledgement

The assistance of Aurora Mendelsohn on the statistical analysis of this study is gratefully acknowledged.

Ali Pourdjabbar is a recipient of The Government of Ontario/ Heart and Stroke Foundation of Ontario

Graduate Scholarship. This work was supported by the Canadian Institute of Health Research and Merck

Frosst Canada.

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Legends for Figures

Figure 1: Flow diagram of the various groups of rats according to treatment and the experimental design.

Figure 2A: Comparison of the 38-day survival of rats with a large-myocardial infarction (MI), in the

various treatment groups.

Figure 2B: Comparison of survival between day 1 and day 38 in rats with a large-myocardial infarction

(MI), in the various treatment groups.

Figure 3: Average arrhythmia score of rats with a large-myocardial infarction (MI), 24-hours following

the MI. Cont. = Control, L30 = Losartan at 30mg/kg/day, L3 = Losartan at 3mg/kg/day

Figure 4A: Continuously monitored mean arterial blood pressure of rats with a large myocardial

infarction (MI) starting post treatment, prior to the MI and 24-hours following the MI. ‡p<0.05 vs.

3mg/kg/day, † p=0.05 vs. control.


Figure 4B: The monitored mean arterial blood pressure of rats with large-myocardial infarction (MI) that

died during the first 24-hours post-MI. Cont = Control, L30 = Losartan at 30mg/kg/day, L3= Losartan at

3mg/kg/day. *p<0.05 vs. Control, ‡p<0.05 vs. 3mg/kg/day.

Figure 5: Passive left ventricular (LV) pressure-volume relations of rats 38-days following a sham

operation or a large-myocardial infarction (MI) according to treatment groups.

Figure 6(A-D): The relative mRNA expression of GLUT-4, Sk. α actin, ANF and β-MHC, after

adjusted to sham control 38-days post-MI. * = P<0.05 vs. Sham, # = P<0.05 vs. control LMI. LV = left

ventricle, Sk. α actin = skeletal α actin, ANF = atrial natriuretic factor, MHC = myosin heavy chain,

Losartan HD = Losartan at high dose (30mg/kg/day), Losartan LD = Losartan at progressive dose starting

at 3mg/kg/day.


Figure 1

Wistar Rats (n=455)

Losartan 30mg/kg/day ( n=103) Losartan 3mg/kg/day

( n=161)

Control ( n=191)

MI

Echocardiography

Hemodynamics Hemodynamics Pressure-Volume Hemodynamics

Day -7

Day 0

Day 30

Day 38

Losartan 10mg/kg/day

Losartan 30mg/kg/day Day 20

Day 10

71 Deaths 82 Deaths 103 Deaths

Wistar Rats (n=455)


( n=161)

Control ( n=191)

MI

Echocardiography


Day -7

Day 0

Day 30

Day 38



Day 10

Wistar Rats (n=454)


( n=161)

Control ( n=190)

MI

Echocardiography


Day -7

Day 0

Day 30

Day 38



Day 10

71 Deaths 82 Deaths 103 Deaths


Figure 2A

0 10 20 30 400

50

100Control (n=147)

Losartan (30mg/kg/day) (n=82)

Losartan (Progressive Dose) (n=123)

Time (Days)

Surv

ival

%

*

*

* P < 0.05 vs. 30mg/kg/day


Figure 2B

0 10 20 30 4050

75

100 Control (n=56)

Losartan 30mg/kg/d (n=18)

Losartan Progressive Dose (n=45)

Time (Days)

Surv

ival

%

*

*

* P<0.05 vs. Progressive dose Group


Figure 3

1-6 6-120

2

4

6 Cont n=20

L3 n=11

L30 n=17

Arr

hyth

mia

Sco

re

Hours Post-MI 0-1 12-24


Figure 4A

0 5 10 15 20 2540

50

60

70

80

90

100

110

Control (n=15)Losartan 30mg/kg/day (n=11) Losartan 3mg/kg/day (n=10)

Hours Post-MI

Mea

n A

rter

ial P

ress

ure

(m

mH

g)

‡ †


Figure 4B

45

50

55

60

65

70

75

80

85

90

95

Mea

n A

rter

ial P

ress

ure

(mm

Hg)

Time Prior to Death (minutes)

Control (n=9) Losartan 3mg/kg/day (n=6) Losartan 30mg/kg/day (n=9)

-60 -15 -5

* ‡


Figure 5

0

10

20

30

40

50

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3

Large MI+Losartan 3mg/kg/day (n=27)

Large MI+Control (n=9) SHAM+Losartan

3mg/kg/day (n=9) SHAM+Control (n=9)

Pas

sive

Dia

stol

ic P

ress

ure

(mm

Hg)

Volume (ml)


Figure 6

0.0

0.5

1.0

1.5 ControlLosartan LDLosartan HD

Rel

ativ

e m

RN

Aex

pres

sion

0

1

2

3

4ControlLosartan LDLosartan HD

Rel

ativ

e m

RN

Aex

pres

sion

0.0

2.5

5.0

7.5

10.0 ControlLosartan LDLosartan HD

Rel

ativ

e m

RN

Aex

pres

sion

0

1

2

3 ControlLosartan LDLosartan HD

Rel

ativ

e m

RN

Aex

pres

sion

LV Glut4 mRNA ExpressionLV Glut4 mRNA ExpressionFigure 6AFigure 6A

Sham LMISham LMI

Figure 6BFigure 6B

Sham LMISham LMI

Figure 6CFigure 6C

Sham LMISham LMI

Figure 6DFigure 6D

Sham LMISham LMI

LV SKLV SK--αα actin mRNA Expressionactin mRNA Expression

LV ANF mRNA ExpressionLV ANF mRNA Expression LV LV ββ−−MHC mRNA ExpressionMHC mRNA Expression

*

#

#

##

####

*

*

*

Ant W. (cm)

LVDD(cm)

Pos W.(cm)

LVSD(cm)

LVSF(%)

LVEF(%)

SHAM (n=20) 0.2±0.02 0.8±0.02 0.2±0.01 0.6±0.04 31±2 46±4SHAM + Losartan (30mg/kg/day) (n=10) 0.2±0.01 0.8±0.04 0.1±0.01 0.6±0.05 29±3 39±4SHAM + Losartan (3mg/kg/day) (n=16) 0.14±0.01 0.8±0.03 0.2±0.01 0.6±0.04 29±3 41±4

LMI (n=40) 0.1±0.01* 1.14±0.01* 0.1±0.0* 1.1±0.01* 8.1±0.6* 16±1.*LMI + Losartan (30mg/kg/day) (n=11) 0.1±0.01* 1.09±0.01*† 0.14±0.01* 0.95±0.03*† 12.4±2*† 21±3*LMI + Losartan (3mg/kg/day) (n=41) 0.1±0.01* 1.11±0.01* 0.12±0.01* 0.99±0.01*† 11±0.7*† 20±1*†

LMI = Large myocardial infarction; Ant W. = anterior wall thickness; LVDD = left ventricular diastolic dimension; Pos W. = posterior wall thickness; LVSD left ventricular systolic dimension in short axis, just below plane of mitral valve; LV SF = left ventricular shortening fraction; LV EF = left ventricular ejection fraction

Values are given as mean ± SEM. *P < 0.05, vs sham; †P < 0.05, vs control Large MI.

Table 1: Echocardiographic Measurements at 30 Days Post MI


SBP DBP HR RVSP RVEDP DP/DT(+)/RVSP LVSP LVEDP DP/DT(+)/LVSP(mmHg) (mmHg) (BPM) (mmHg) (mmHg) (mmHg) (mmHg)

SHAMControl n=15 123±4 92±2 274±14 28±1 2±0.5 69±3 120±5 4±1 70±3Losartan (30mg/kg/day) n=9 104±4† 78±4† 303±25 26±1 1±1 80±6 101±3† 3±0.5 73±4Losartan (3mg/kg/day) n=16 101±3† 75±3† 284±10 26±1 1±0.5 69±2 99±3† 6±1 73±2

Large MIControl n=37 102±3* 81±2* 289±8 43±2* 5±1 53±2* 97±3* 15±1* 57±1*Losartan (30mg/kg/day) n=11 96±4 73±3 273±7 32±4† 2±0.5† 63±3*† 93±4 10±2* 56±2*Losartan (3mg/kg/day) n=41 89±3*† 69±2† 301±13 31±1*† 2±0.3† 63±2*† 83±3*† 10±1*† 59±2

SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = heart rate; RVSP = right ventricular systolic pressure; RVEDP = right ventricular end diastolic pressure; LVSP = left ventricular systolic pressure; LVEDP = left ventricular end diastolic pressure.

Values are given as mean ± SEM. *P < 0.05, vs sham; †P < 0.05, vs control Large MI.

Table 2: Hemodynamic Measurements at 38 Days Post MI


BW LV Total Septum RV Scar Atria Lungs(g) (g) (g) (g) (g) (g) (g)

SHAMControl n=10 430±9 0.83±0.03 0.27±0.02 0.25±0.01 0.1±0.01 1.6±0.05Losartan (30mg/kg/day) n=9 420±10 0.70±0.03† 0.24±0.02 0.22±0.01 0.07±0.003 1.6±0.04Losartan (Progressive) n=6 448±10 0.77±0.04 0.22±0.02 0.25±0.02 0.08±0.01 1.9±0.17

Large MIControl n=32 422±8 0.67±0.02 0.31±0.01 0.42±0.02* 0.1±0.01 0.20±0.01* 2.8±0.12*Losartan (30mg/kg/day) n=11 411±12 0.65±0.02 0.28±0.01 0.29±0.03*† 0.1±0.01 0.12±0.01*† 2.0±0.24†Losartan (Progressive) n=14 441±7 0.64±0.03 0.26±0.01† 0.32±0.03† 0.1±0.01 0.16±0.01*† 2.2±0.11†

BW = body weight; LV = left ventricle; RV = right ventricle; LV total = LV + septum

Values are given as mean ± SEM. *P < 0.05, vs sham; †P < 0.05, vs control Large MI

Table 3: Morphological Measurements at 38 Days Post MI

Documents

Effects of pre-, peri-, and postmyocardial infarction treatment with losartan in rats: effect of dose on survival, ventricular arrhythmias, function, and remodeling