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Am J Physiol Heart Circ Physiol 293: H2799-H2808, 2007. First published July 13, 2007; doi:10.1152/ajpheart.00596.2007
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Sex influences the susceptibility to reperfusion-induced sustained ventricular tachycardia and beta-adrenergic receptor blockade in conscious rats

Heidi L. Lujan, Victoria J. Kramer, and Stephen E. DiCarlo

Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan

Submitted 22 May 2007 ; accepted in final form 10 July 2007


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Reperfusion after a brief period of cardiac ischemia can lead to potentially lethal arrhythmias. Importantly, there are sex-related differences in cardiac physiology and in the types and severity of cardiac arrhythmias. Therefore, we tested the hypothesis that gonadal hormones influence the susceptibility to reperfusion-induced sustained ventricular tachycardia (VT), as well as the response to beta-adrenergic receptor blockade. Male and female intact and gonadectomized rats were instrumented, and arterial pressure, temperature, ECG, and cardiac output were recorded. In addition, a snare was placed around the left main coronary artery. Tension was applied to the snare for determination of susceptibility to sustained VT produced by 3 min of occlusion and reperfusion of the left main coronary artery in conscious rats. Reperfusion culminated in sustained VT in 77% (10 of 13 susceptible) of female rats and 56% (9 of 16 susceptible) of male rats (P > 0.05, male vs. female). beta-Adrenergic receptor blockade prevented sustained VT in females only [1 of 9 susceptible females (11%) vs. 6 of 9 susceptible males (67%), P < 0.05]. Ovariectomy did not significantly reduce the susceptibility to reperfusion arrhythmias [5 of 9 susceptible (56%)]. In sharp contrast, orchidectomy significantly increased the susceptibility to reperfusion arrhythmias [9 of 9 susceptible (100%)]. Finally, beta-adrenergic receptor blockade prevented sustained VT in ovariectomized females [0 of 4 susceptible (0%)] and orchidectomized males [0 of 7 susceptible (0%)], but the protective effect of beta-blockade was due to a reduction in heart rate in males only. Thus gonadal hormones influence the susceptibility to reperfusion-induced arrhythmias, as well as the effects and mechanisms of beta-adrenergic receptor blockade.

cardiovascular risks; arrhythmia; sex differences

REPERFUSION AFTER TEMPORARY (seconds or minutes) occlusion of the coronary arteries can lead to potentially lethal arrhythmias (39, 59). Although little tissue damage occurs during the ischemia, reperfusion precipitates deadly arrhythmias, which may account for some cases of sudden cardiac death (39, 59). Life-threatening reperfusion arrhythmias are observed during relief of coronary spasm, during angioplasty or thrombolysis, and after cardiac surgery with ischemic arrest (13).

Sudden cardiac death accounts for 300,000–400,000 deaths annually in the United States (42), and the incidence is much higher in men than in women. In fact, cardiovascular mortality due to the development of fatal arrhythmias is lower among premenopausal women than among similarly aged men (23). Furthermore, the loss of ovarian function parallels a dramatically increased risk of sudden cardiac death (12). Thus, although there is some controversy about their cardioprotective effects, ovarian hormones may protect against fatal arrhythmias. For example, estrogen therapy reduces ST segment depression, a marker of ischemia, in patients with exercise-induced angina (51).

Although men are more than three times as likely to develop ischemic heart disease as women, differences in female sex hormones may not explain the disparity. For example, estrogen replacement increased infarct size and failed to prevent left ventricular (LV) remodeling in ovariectomized rats (54). Similarly, Vaccarino and colleagues (58) concluded that younger women with myocardial infarction, but not older women, had higher rates of death during hospitalization than men of the same age, and Alexander et al. (1) reported that initiation of hormone replacement therapy after myocardial infarction is associated with more cardiac events during follow-up. Women taking oral contraceptives are at increased risk of ventricular ectopy, suggesting a proarrhythmic action of estrogen or progesterone (50). Furthermore, two large randomized controlled trials of female hormone replacement showed that female sex hormones are not cardioprotective (20).

Additionally, the presence of male hormones may not contribute to the excess male risk. Evidence is emerging that low serum testosterone levels are associated with many of the classic cardiovascular risk factors (53). Two large studies have found low testosterone to be associated with increased aortic and carotid atheroma (18). Furthermore, men with coronary disease have lower androgen concentrations than men with normal angiograms (14), and testosterone therapy has a beneficial anti-ischemic effect in men with coronary disease (15). Men also have lower mortality rates after myocardial infarction and display less diastolic heart failure than women (27). Other studies demonstrated greater systolic function in women than in men and reduced diastolic compliance in women compared with men (19).

Clearly, the importance of sex steroids on cardiac physiology is unclear and requires characterization in order to predict the functional outcomes of altered hormone levels during aging, therapeutic intervention, and hormone replacement therapy. Uncovering major differences between males and females in the function and pathophysiology of the cardiovascular system may result in sex-specific optimization of patient treatments (11).

In this context, a large release of endogenous catecholamines occurs during the early period of reperfusion, and a reduction of myocardial catecholamine reserves decreases reperfusion-induced arrhythmias (52, 56). These data suggest that blockade of beta-adrenergic receptors may reduce the susceptibility to reperfusion-induced arrhythmias. Furthermore, only beta-adrenergic receptor antagonists and amiodarone, a class III antiarrhythmia drug that also blocks beta-adrenergic receptors, have been shown to reduce sudden cardiac death (25, 61). However, the effect of beta-adrenergic receptor blockade on reperfusion-induced arrhythmias is controversial and, to our knowledge, has not been examined experimentally in conscious female animals.

Therefore, we tested the hypothesis that gonadal hormones influence the susceptibility to reperfusion-induced sustained VT, as well as the response to beta-adrenergic receptor blockade. Conscious, chronically instrumented rats were studied to negate the confounding effects of anesthetic agents and surgical trauma. The ability of anesthesia to influence the susceptibility to ventricular arrhythmias has been essentially ignored, and there are few studies of reperfusion-induced arrhythmias in conscious animals (28). Furthermore, use of conscious intact animals avoids the complications associated with isolated hearts, since isolation and denervation of the heart alter autonomic tone and the physiological responses to coronary occlusion.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Surgical Procedures

Experimental preparations and protocols were reviewed and approved by the Animal Care and Use Committee of Wayne State University. The studies conformed to American Physiological Society guidelines and principles for research involving animals.

Ovariectomy. All surgical procedures were performed using aseptic measures. Female rats were anesthetized with pentobarbital sodium (50 mg/kg ip), and supplemental doses (10 mg/kg ip) were administered if the rat regained the blink reflex or responded during the surgical procedures. Subsequently, a 10-mm dorsal abdominal incision centered between the dorsal hump and the base of the tail was made through the skin. The ovarian fat pad, visible under the muscle, was located, and the tip of a blunt hemostat was inserted through the muscle layer. The fat pad, with the ovary attached to the under side, was pulled through the opening with blunt forceps. Forceps were placed at the boundary between the oviduct and the uterus, and a 4-0 silk ligature was placed just below the hemostat. After removal of the ovary and oviduct with scissors, the hemostat was released, with care taken to ensure that no bleeding occurred. The uterine horn was returned to the dorsal abdominal cavity, and the dorsal abdominal wall and skin were closed. Subsequently, identical procedures were performed on the opposite side. The animals were allowed to recover for ≥4 wk to allow time for the clearance of the steroids.

Orchidectomy. Male rats were anesthetized as described above. A 1.0-cm medial incision was made through the skin at the tip of the scrotum, and the cremaster muscle was opened. The testicular fat pad was localized and pulled through the incision using blunt forceps. The cauda epididymis was exteriorized with the testis, then the caput epididymis, vas deferens, and testicular blood vessels were exteriorized. A single ligature (4-0 silk) was placed around the vas deferens and the blood vessels. The testis was removed with scissors and thoroughly checked for bleeding. This procedure was repeated for the other testis, and the remaining vas deferens, fat, and blood vessels were returned to the scrotal sac. The muscle layer and skin were closed, and the animals were allowed to recover for ≥4 wk to allow time for clearance of the steroids.

A telemetry device (PhysioTel C50-PXT, Data Sciences International) for measurement of pressure, temperature, and ECG was implanted at the time of the gonadectomy (GnX) procedures, as well as in intact male and female rats, as previously described (8, 49), and a catheter was placed in the intraperitoneal space for the infusion of fluids. The sensor of the telemetry device, located within the tip of a catheter, was inserted into the abdominal aorta for continuous, nontethered recording of pulsatile arterial blood pressure, temperature, and ECG via radio telemetry. During the recovery periods, the rats were handled, weighed daily, and acclimatized to the laboratory and the investigators.

After recovery, the animals were anesthetized as described above, and the hearts were approached via a left thoracotomy through the fourth intercostal space. A coronary artery occluder, made from an atraumatic needle holding 5.0-gauge prolene suture (8720H, Ethicon), which passed through a section of PE-10 guide tubing (Clay Adams), was routed around the left main coronary artery 2–3 mm from the origin by insertion of the needle into the LV wall under the overhanging left atrial appendage and exteriorized high on the pulmonary conus (9, 10). The guide tubing with the other end of the occluder was then exteriorized at the back of the neck. The tubing was filled with a mixture of petroleum jelly and mineral oil to prevent a pneumothorax. Teflon-coated silver wire electrodes were sutured 2–3 mm apart on the surface of the left atrial appendage, as previously described (49). In addition, a Doppler ultrasonic flow probe was positioned around the ascending aorta, as previously described (32). The electrodes and flow probe lines were tunneled beneath the skin and exteriorized at the back of the neck. At least 1 wk was allowed for recovery. During the recovery periods, the rats were handled, weighed daily, and acclimatized to the laboratory and investigators. Two separate surgeries (GnX + telemetry or telemetry alone, as well as thoracotomy) were performed, because recovery is significantly better than recovery from two major surgeries during one session.

Experimental Procedures

Susceptibility to reperfusion-induced sustained VT. Conscious, unrestrained rats were studied in their home cages (~13,350 cm3) for all experiments. Rats were allowed to adapt to the laboratory environment for ~1 h to ensure stable hemodynamic conditions. After the stabilization period, the left main coronary artery was temporarily occluded for 3 min by use of the prolene suture, as previously described (9, 10). Specifically, acute coronary artery occlusion was accomplished by pulling up on the suture around the left main coronary artery and holding the occlusion for 3 min. Rapid changes in the ECG (peak of the T wave followed by ST segment elevation), arterial pressure, and cardiac output occurred within seconds of pulling on the suture, documenting coronary artery occlusion (Fig. 1) (10). On release of the suture, the animals sustained VT or normal sinus rhythm (Fig. 1). VT was defined as sustained ventricular rate (absence of the P wave, wide bizarre QRS complex) >900 beats/min with a reduction in arterial pressure below 40 mmHg. When sustained VT developed, normal sinus rhythm could be restored by gentle compression of the thorax. Without compression of the thorax, the sustained VT progresses to ventricular fibrillation (VF). VF was defined as a ventricular rhythm without a recognizable QRS complex, in which signal morphology changed from cycle to cycle and for which it was impossible to estimate heart rate. In the event the animal did not resume normal sinus rhythm, cardioversion was achieved (after the rat lost consciousness) with the use of one shock (10 J) of direct current.


Figure 1
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  		Fig. 1. Analog recordings of arterial pressure, ECG, and cardiac output before left main coronary artery occlusion (control), at the onset of occlusion, during the 3rd min of occlusion (prerelease), and during reperfusion in an intact conscious male rat. Rapid changes in ECG (peak of T wave followed by ST segment elevation), arterial pressure, and cardiac output occurred within seconds of pulling on the suture, documenting coronary artery occlusion. Sustained ventricular tachycardia (VT) occurred during reperfusion.

 
On an alternate day (≥1 wk later), the protocol was repeated with cardiac beta1-adrenergic receptor blockade [10 mg/kg metoprolol (MT) (30)] or beta1-adrenergic receptor blockade with pacing to maintain heart rate at the nonblockade levels. Cardiac beta1-adrenergic receptor blockade was achieved by infusion of the specific beta1-adrenergic receptor antagonist MT into the intraperitoneal catheter. At 10 min after MT administration, coronary artery occlusion and reperfusion were performed as described above. For the pacing protocol, after MT administration, the heart was paced using the stimulating electrodes on the atrium [PowerLab programmable stimulator, 9 Hz, 1.0 V, 10 ms (48, 49)]. Coincident with the pacing, coronary artery occlusion and reperfusion were performed as described above. The order of the protocols, control and cardiac beta1-adrenergic receptor blockade, was randomized.

All recordings were sampled at 2 kHz, and the ECGs were analyzed offline to measure the QT interval (interval between the beginning of the Q wave and the end of the T wave) using ECG analysis software (Chart, ADInstruments). In an attempt to correct for heart rate dependence, QT was corrected for the R-R interval using several equations. Corrected and uncorrected QT intervals were plotted against R-R intervals. Regression lines and r2 were calculated to determine which method of QT correction produced the least dependence on R-R interval. Plotting the rate-corrected QT interval [QTc; QTc = QT/RR1/7, where RR is R-R interval] against R-R interval produced a regression line with a slope of zero, indicating that this correction removes the influence of heart rate. Therefore, all QT intervals were corrected according to this formula.

Determination of reproductive organ weight, body weight and ischemic zone. After the experiments, the rats were euthanized with an overdose of pentobarbital sodium, and the reproductive organs (seminal vesicle and prostate in males and uterus in females) were removed, rinsed clean, and weighed. To determine the size of the ischemic zone, the heart was excised with the occluder intact and perfused via the aorta with 30 ml of 0.9% saline to wash out the blood. Subsequently, the suture was tied to occlude the left main coronary artery. Evans blue dye (100 µl, 0.5%) was perfused via the aorta, allowing the dye to infuse into the nonischemic area of the heart and leaving the ischemic regions unstained. The heart was trimmed such that only only the right ventricle and LV remained, rinsed to remove the excess dye, and weighed. The heart was trimmed again such that only the ischemic region remained. The weight of the ischemic zone was expressed as a percentage of total ventricular weight (9, 10).

To determine whether the occlusion produced a myocardial infarction, the heart was sliced transversely into ~1.0-mm sections and incubated in a 1% 2,3,5-triphenyltetrazolium chloride (TCC) solution (Sigma) at 37°C for 20 min. The heart sections were placed between two glass slides and immersed in 10% formalin overnight to enhance the contrast of the stain. TCC staining differentiates viable tissue by reacting with myocardial dehydrogenase enzymes to form a brick-red stain. Necrotic tissue, which has lost its dehydrogenase enzymes, does not form a red stain and appears as pale yellow. This stain has been shown to be a reliable indicator of myocardial infarction (16).

Data Analysis

Values are means ± SE. Fisher's exact test was used to compare the percentage of animals sustaining VT in the control condition, during beta-adrenergic receptor blockade, and during beta-adrenergic receptor blockade with pacing conditions. A one-factor ANOVA with Fisher's post hoc least significant difference method was used to compare the time from the release of the occluder to sustained VT between the groups. A three-factor ANOVA with repeated measures on one factor with Fisher's post hoc least significant difference method was used to compare mean arterial blood pressure, heart rate, cardiac output, and vascular conductance immediately before the occlusion (preocclusion) and immediately before the release of the occluder (prerelease) in the three conditions. In addition, a two-factor ANOVA was used to compare ST segment elevation and rate-pressure product (RPP) in the control and beta-adrenergic receptor blockade conditions. RPP, an index of myocardial oxygen demand, was calculated as follows: (systolic blood pressure x heart rate) ÷ 1,000 (29). Unpaired t-tests were used to compare reproductive organ weights between intact and GnX males and females.


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Figure 2 presents the percent incidence of reperfusion-induced sustained VT in control and beta-adrenergic receptor blockade conditions for intact and GnX male and female rats. Reperfusion after a brief period of cardiac ischemia culminated in sustained VT in 77% (10 of 13 susceptible) of female rats and 56% (9 of 16 susceptible) of male rats (P > 0.05, male vs. female). Only data from the susceptible rats (i.e., those that experienced sustained VT in the control condition) were included in the beta-blockade analysis. beta-Adrenergic receptor blockade prevented sustained VT in females only: 11% (1 of 9 susceptible) of females vs. 67% (6 of 9 susceptible) of males (P < 0.05). Ovariectomy did not significantly reduce the susceptibility to reperfusion arrhythmias [56% (5 of 9 susceptible)]. In sharp contrast, orchidectomy significantly increased the susceptibility to reperfusion arrhythmias [100% (9 of 9 susceptible)]. Finally, beta-adrenergic receptor blockade prevented sustained VT in ovariectomized females [0% (0 of 4 susceptible)] and orchidectomized males [0% (0 of 7 susceptible)], but the protective effect of beta-blockade was due to a reduction in heart rate in males only (see GoGoFig. 5).


Figure 2
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  		Fig. 2. Incidence of reperfusion-induced sustained VT in control and beta-adrenergic receptor blockade conditions in intact and gonadectomized (GnX) male and female rats. Sustained VT occurred in 77% of female and 56% of male rats. beta-Adrenergic receptor blockade prevented sustained VT in females only. Ovariectomy did not significantly reduce susceptibility to reperfusion arrhythmias. Orchidectomy significantly increased susceptibility to reperfusion arrhythmias. beta-Adrenergic receptor blockade prevented sustained VT in ovariectomized females and orchidectomized males. Values within bars represent fraction of susceptible rats exhibiting VT. *P < 0.05, intact female vs. beta-blocked intact female. {dagger}P < 0.05, intact male vs. GnX male. {ddagger}P < 0.05, GnX male vs. beta-blocked GnX male.

 

Figure 3
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  		Fig. 3. Time from release of the occluder to onset of sustained VT in intact and GnX male and female rats. Time to sustained VT was greater in intact males than in intact females and GnX males. *P < 0.05, intact female vs. intact male. {dagger}P < 0.05, GnX male vs. intact male.

 

Figure 4
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  		Fig. 4. Analog recordings of arterial pressure (AP) and ECG during occlusion of the left main coronary artery and during reperfusion (release of the occluder) in an intact (A) and GnX (B) conscious male rat. On release of the occluder, there was a gradual reduction of ST segment elevation followed by sustained VT (VTach). Orchidectomy increased incidence of VT (Fig. 2) and decreased time from release of the occluder to sustained VT (Fig. 3).

 

Figure 5
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  		Fig. 5. Incidence of reperfusion-induced VT during beta-adrenergic receptor blockade with pacing for male and female rats. beta-Adrenergic receptor blockade prevented sustained VT, even when heart rate was paced at nonblockade levels in females only. Protective effect of beta-blockade was due to a reduction in heart rate in males (anti-ischemic effect); a different mechanism (antiarrhythmic effect) mediates this response for females. *P < 0.05, female vs. male.

 
Although there was no significant difference in the incidence of sustained VT between intact females and intact males (Fig. 2; 77 and 56%, respectively), the time from the release of the occluder to sustained VT was significantly longer in intact males than in intact females (Fig. 3; 30 ± 8 vs. 6 ± 2 s). Orchidectomy not only increased the incidence of VT (Fig. 2); it also decreased the time from the release of the occluder to sustained VT (Fig. 3; 30 ± 8 and 8 ± 2 s in intact males and GnX males, respectively; Fig. 4). Finally, ovariectomy did not alter the time to VT (Fig. 3; 6 ± 2 and 9 ± 3 s in intact females and GnX females, respectively).

Figure 5 presents the percent incidence of reperfusion-induced sustained VT in beta-adrenergic receptor blockade with pacing for male (1 intact and 4 GnX) and female (7 intact and 2 GnX) rats. Only data from the protected rats (i.e., those protected from VT in the beta-adrenergic receptor blockade condition) were included in the analysis. beta-Adrenergic receptor blockade prevented sustained VT, even when heart rate was paced at nonblockade levels in females only [1 of 9 susceptible females (11%), 1 intact female vs. 3 of 5 susceptible males (60%), 1 intact and 2 GnX males, P < 0.05]. These data document that the protective effect of beta-adrenergic receptor blockade was due to a reduction in heart rate in males (anti-ischemic effect); however, a different mechanism (antiarrhythmic effect) mediates this response in females.

Figure 6 presents the ST segment elevation and RPP immediately before release of the occluder in control and beta-adrenergic receptor blockade conditions for intact and GnX male and female rats. As expected, 3 min of coronary artery occlusion elevated the ST segment in all groups, and the elevation was reduced with beta-adrenergic receptor blockade (significant drug effect). ST segment elevation was greater in females (significant sex effect), and there was a significant sex x drug interaction. Specifically, ST segment elevation was higher in intact females than in intact males and GnX males, as well as in intact females than GnX females. For RPP, there was no sex effect or sex x drug interaction, but there was a significant drug effect (RPP was lower in all groups after beta-blockade).


Figure 6
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  		Fig. 6. ST segment change (A) and rate-pressure product (B) immediately before release of the occluder in intact and GnX male and female rats under control and beta-adrenergic receptor blockade conditions. Three minutes of coronary artery occlusion elevated the ST segment in all groups, and elevation was reduced with beta-adrenergic receptor blockade. ST segment elevation was higher in intact females than in intact males and GnX males as well as in intact females than in GnX females. Rate-pressure product was lower in all groups after beta-blockade. SBP, systolic blood pressure; HR, heart rate. *P < 0.05, intact female vs. GnX female. {dagger}P < 0.05, intact female vs. intact male and GnX male. {ddagger}P < 0.05, control vs. beta-blockade.

 
Table 1 presents resting mean arterial pressure, heart rate, cardiac output, and vascular conductance immediately before the occlusion (preocclusion) and immediately before the release of the occluder (prerelease) in male and female intact and GnX rats under control and beta-adrenergic receptor blockade conditions. Mean arterial pressures were not different between male and female intact and GnX rats (no sex effect). However, beta-blockade reduced mean arterial pressure (significant drug effect), and there was no drug x sex interaction. In contrast, heart rate was significantly lower in males under all conditions (significant sex effect), and beta-blockade reduced heart rate in all groups (significant drug effect); however, there was no drug x sex interaction. Interestingly, cardiac output was lower in males (significant sex effect) due to a lower cardiac output in the GnX male rats (P < 0.05). Furthermore, beta-blockade reduced cardiac output (significant drug effect with no drug x sex interaction). Results were similar for vascular conductance (significant sex and drug effects without a drug x sex interaction).


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  		Table 1. Resting hemodynamics immediately before occlusion, immediately before release of occluder (prerelease) in female and male intact and GnX rats under control and beta-adrenergic receptor blockade conditions

 
Table 2 presents body and reproductive organ weights, heart weight-to-body weight ratio, the extent of the ischemic zone (percentage of heart weight), and the QTc interval for male and female intact and GnX rats. As expected, GnX reduced reproductive organ weight in males and females; however, there were no differences in the heart weight-to-body weight ratio or the extent of the ischemic zone between groups. Reperfusion increased the QTc interval in all groups. In addition, the QTc interval was prolonged in GnX males compared with intact males. Finally, on the basis of TCC staining, no animal had an infarct.


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  		Table 2. Body and reproductive organ weights, heart weight-to-body weight ratio, extent of the ischemic zone, and QTc interval in female and male intact and GnX rats

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
In the present study, we tested the hypothesis that gonadal hormones influence the susceptibility to reperfusion-induced sustained VT, as well as the response to beta-adrenergic receptor blockade. Specifically, we recorded the susceptibility to sustained VT induced by myocardial ischemia and reperfusion in conscious male and female intact and GnX rats in the control and beta-adrenergic receptor blockade conditions. The major findings of this study are as follows: 1) There was no significant difference in the incidence of reperfusion-induced sustained VT between intact males and intact females (Fig. 2). However, the time from the release of the occluder to the onset of sustained VT was significantly longer in intact males (Fig. 3). 2) Female sex hormones did not alter the susceptibility to reperfusion-induced VT, the time to the onset of sustained VT, or the response to beta-adrenergic receptor blockade. 3) In sharp contrast, testosterone is cardioprotective. Specifically, the incidence of reperfusion-induced sustained VT was increased, and the time from the release of the occluder to the onset of sustained VT was significantly decreased in GnX males. 4) beta-Adrenergic receptor blockade protected intact females, GnX females, and GnX males, but not intact males. Thus testosterone blocks the protective effect of beta-adrenergic antagonism. 5) The cardioprotective effect of beta-adrenergic receptor blockade (in the susceptible rats) may be due to an antiarrhythmic mechanism in females and an anti-ischemic mechanism in males. Specifically, pacing the heart to nonblocked rates prevented the protection in males only. It is important to acknowledge that the results and conclusions of the present study would be strengthened if we had examined the effect of hormone replacement in the GnX animals. Specifically, future studies should examine females during the estrous cycle, after ovariectomy, after ovariectomy followed by estradiol replacement, and after ovariectomy followed by testosterone treatment. Similarly, intact males and males subjected to orchidectomy, orchidectomy + testosterone replacement, and orchidectomy + estradiol treatment should be studied in the future.

Reperfusion after coronary artery spasm, following cardiopulmonary bypass with ischemic cardiac arrest, during angioplastic or thrombolytic procedures to disrupt coronary occlusion, and after thrombotic episodes, may lead to lethal arrhythmias (23). Despite the clinical relevance of reperfusion-induced arrhythmias, very little information is available regarding sex-specific responses. In contrast, recent results suggest that hearts from females are more resistant to ischemia-reperfusion injury (improved functional recovery and reduced infarct size) (5, 22) and ischemia-induced arrhythmias (21, 37) than hearts from males.

For example, Humphreys and colleagues (21) documented a significantly reduced total number of ventricular ectopic beats (961 ± 170) and incidence of VF in anesthetized age-matched female rats (0%) compared with male rats (2,074 ± 206 and 40%) during 30 min of coronary artery occlusion. These investigators also demonstrated that the incidence of VT (81 vs. 25%) and the total number of ventricular ectopic beats (351 ± 73 vs. 81 ± 50) were significantly lower during ischemia in hearts isolated from weight-matched female than male rats. In contrast, McNulty and colleagues (41) failed to document a sex-specific difference in reperfusion-induced arrhythmias in pentobarbital-anesthetized open-chest rats. Kuhar and colleagues (31) also documented that supraphysiological (subtoxic) levels of estradiol and testosterone significantly decreased the incidence of arrhythmias in isolated rat hearts. Similarly, administration of 17beta-estradiol to males for 2 wk (26) or 15 min (57) before coronary occlusion reduced the incidence of reperfusion-induced ventricular arrhythmias in anesthetized open-chest dogs. These data contrast sharply with our findings that ovariectomy did not alter the susceptibility to VT, the time to the onset of sustained VT, or the response to beta-adrenergic receptor blockade.

It is also important to note that, with few exceptions (26, 57), the majority of studies documenting a cardioprotective effect of estrogen examined functional recovery and infarct size (5, 22), as well as ischemia-induced arrhythmias (37), but not reperfusion-induced arrhythmias (21). The mechanisms mediating the arrhythmias during ischemia and reperfusion are related but distinct (3, 39). Furthermore, there also appear to be separate mechanisms mediating infarct size and reperfusion-induced arrhythmias. Specifically, the infarct size-limiting effect of estrogen may be mediated by myocardial mitochondrial ATP-sensitive K+ (KATP) channels, whereas the antiarrhythmic effects may be mediated by myocardial sarcolemmal KATP channels (57). In this context, it is important to note that female guinea pig ventricular myocytes express more sarcolemmal KATP channels than males (45) and that 17beta-estradiol treatment of rat embryonic heart H9c2 cells upregulates these channels (44). In addition the density of current evoked by a KATP channel opener was significantly higher in estradiol-treated than in untreated cells, and the intracellular Ca2+ loading induced by hypoxia-reoxygenation was significantly decreased by treatment with estradiol. From these data, we would expect ovariectomy to increase the susceptibility to reperfusion-induced arrhythmias; however, this was not found. These discrepancies may stem from different species studied, the extent of collateral flow, different arrhythmic quantitative methods, and experimental procedures. For example, administration of 17beta-estradiol to males for 2 wk (26) or 15 min (57) before the occlusion may be significantly different from removal of the ovaries (loss of all ovarian hormones) from females for >4 wk. Thus, in a discussion of the cardioprotective role of estrogen, it is critical to emphasize the specific outcome variable as well as the species, model, and procedures.

The limited experimental evidence documenting sex-specific responses to reperfusion-induced arrhythmias may be due, in part, to the fact that the majority of studies using isolated heart preparations or anesthetized rats do not document the incidence of reperfusion-induced arrhythmias, despite prolonged periods of ischemia. Importantly, reductions in cardiac parasympathetic activity and increases in cardiac sympathetic activity play a critical role in triggering cardiac arrhythmias, and isolated hearts are devoid of cardiac autonomic innervation. Furthermore, anesthesia significantly alters the autonomic nervous system. In support of this concept, Kinoshita et al. (28) and Manning and colleagues (38) documented that the incidence of reperfusion-induced VF was significantly greater in conscious than in anesthetized rats after 3 min (67% vs. 20%) and 5 min (100% vs. 68%) of ischemia. Importantly, the limited number of clinically relevant animal models (4) has limited our understanding of cardiac arrhythmias, and treatment of cardiac arrhythmias remains a serious challenge. Until recently, most efforts to prevent and treat arrhythmias centered on pharmacological approaches (24). However, the pharmacological approach to antiarrhythmia therapy has encountered serious problems. Specifically, most antiarrhythmia drugs are less effective and far more dangerous than once believed. For example, the Cardiac Arrhythmia Suppression Trial demonstrated that antiarrhythmia drugs not only failed to prevent sudden cardiac death, but they actually increased overall mortality (6, 7). These findings have been confirmed in additional trials and have led to a shift away from antiarrhythmia drug therapy (24). The "proarrhythmic" effects of the most currently available antiarrhythmia drugs document the need for additional therapies as well as clinically relevant animal models in which cardiac arrhythmias can be induced. The conscious, chronically instrumented model negates the confounding effects of anesthetic agents and surgical trauma and can be used to study induction of reperfusion-induced cardiac arrhythmias.

The effects of beta-adrenergic receptor blockade on reperfusion-induced arrhythmias are controversial, and sex-specific responses have not been examined experimentally. Sommers and Jennings (55), in pentobarbital-anesthetized dogs, and Sheridan and colleagues (52), in chloralose-anesthetized cats, reported that beta-adrenergic receptor blockade did not prevent reperfusion arrhythmias. Similarly, beta-adrenergic receptor blockade in the isolated rat heart failed to prevent reperfusion-induced VF (47, 56). In contrast, Kinoshita and colleagues (28) reported that atenolol reduced the incidence of reperfusion-induced VF in conscious rats. In the present study, we documented that the cardioselective beta-adrenergic receptor antagonist MT reduced the incidence of reperfusion-induced sustained VT in intact females, GnX females, and GnX males, but not intact males. To our knowledge, this question had not been addressed in females. Importantly, when protection occurred, pacing the heart to rates achieved during occlusion in the control, non-beta-adrenergic receptor-blocked condition prevented the protection in males, but not females (Fig. 5). These data in males are consistent with previous results. Specifically, the severity of reperfusion-induced arrhythmias in males is related to the heart rate during the ischemic period (3). Pacing the heart at slower rates led to a frequency-dependent protective effect against reperfusion-induced arrhythmias. Furthermore, autonomic interventions have a heart rate-dependent effect on reperfusion arrhythmias in males. When heart rate is held constant, neither beta-blockade nor vagus nerve stimulation protects against reperfusion arrhythmias in males (60). In sharp contrast, females were protected from reperfusion-induced sustained VT, even without a reduction in heart rate. Thus MT has antiarrhythmic effects in females but anti-ischemic effects in males.

Sudden cardiac death is the unexpected natural death from a cardiac cause (often attributed to a ventricular arrhythmia) in a person without a prior condition that would appear fatal (42). The incidence of sudden cardiac death is much higher in men than women (75% of sudden cardiac deaths occur in men), reflecting sex differences in the incidence of coronary heart disease. The peak in the incidence of sudden cardiac death occurs between 45 and 75 yr of age. Most instances of sudden cardiac death are not associated with myocardial infarction (17, 35); however, it is unknown how often sudden cardiac death is associated with transient ischemic episodes from coronary artery spasm or acute coronary thrombosis. However, if transient ischemic episodes contribute significantly to sudden cardiac death, results from the present study may provide insights into potential mechanisms. Specifically, age-related hypogonadism may explain the higher incidence of sudden death in 45- to 75-yr-old men.

Considerable evidence documents that changes in the ST segment shift are a valid marker of changes in the severity of myocardial ischemia (33). For example, studies in patients document that the ST segment shift correlates with metabolic and contractile parameters of myocardial ischemia (34). Therefore, ST segment changes are widely used as an index of myocardial injury resulting from ischemia in experimental animals (40). Indirect indexes of myocardial oxygen consumption (tension-time index, double product, and triple product) are also used in clinical and experimental studies (2). These indirect indexes are highly correlated with direct measurements of myocardial oxygen consumption. We used ST segment shifts and double product (RPP; Fig. 6) as an index of the severity of myocardial ischemia. Although there was no sex effect, beta-blockade, as expected, reduced RPP in all groups. In contrast, ST segment elevation was significantly greater in intact females, further supporting a role for testosterone in arrhythmia protection.

It is well documented that resting heart rates are higher in women than in men and that QTc is longer in women (43). These sex differences are associated with the onset of puberty, which strongly implicates the sex hormones in the differences between men and women (46). Similar results are reported in the present study. Specifically, heart rate was significantly higher in females than in males. Excessive prolongation of ventricular repolarization (long QT interval) is thought to promote the generation of early afterdepolarizations and may lead to potentially lethal arrhythmias. Interestingly, the QTc interval was prolonged by reperfusion in the present study. Liu and colleagues (36) documented that testosterone confers a shorter QT interval and protects against QT prolongation through modulation of depolarizing K+ currents. Consistent with this idea, the QT interval in men gradually increases from puberty until it becomes similar to that in women by 50 yr of age. Importantly, orchidectomy increased the QTc interval before, as well as during, reperfusion in the present study. The following question arises: Can this account for the increased incidence of reperfusion-induced sustained VT in orchidectomized males, as well as the reduced time to reperfusion-induced sustained VT in intact females? In other words, is the testosterone-induced cardioprotection during reperfusion mediated by a reduction of the QT interval? This question merits further investigation.

Conclusion

Testosterone appears to provide protection from reperfusion-induced sustained VT, because GnX increased the incidence of reperfusion-induced VT and reduced the time from the release of the occluder to the onset of VT in males. Furthermore, intact males had a lower, although not statistically significant, incidence of reperfusion-induced tachyarrhythmia as well as a significantly longer time from the release of the occluder to the onset of reperfusion-induced sustained VT than intact females.

Testosterone appears to prevent the protection from beta-adrenergic receptor blockade. Specifically, beta-adrenergic receptor blockade protected intact females, GnX females, and GnX males, but not intact males. Thus testosterone blocks the protective effect of beta-adrenergic antagonism. The cardioprotective effect of beta-adrenergic receptor blockade (in the susceptible rats) may be due to an antiarrhythmic mechanism in females and an anti-ischemic mechanism in GnX males, because pacing the heart to rates achieved during occlusion in the control, non-beta-adrenergic receptor-blocked condition prevented the protection in males, but not females.

Clearly the importance of sex steroids in cardiac physiology is unclear, and characterization is required for prediction of the functional outcomes of altered hormone levels during aging, therapeutic intervention, and hormone replacement therapy. Uncovering major differences between males and females in the function and pathophysiology of the cardiovascular system may result in sex-specific optimization of patient treatments (11).


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This study was supported by National Heart, Lung, and Blood Institute Grants HL-67713 and HL-74122.


   FOOTNOTES
 

Address for reprint requests and other correspondence: H. L. Lujan, Wayne State Univ. School of Medicine, 540 E. Canfield Ave., Detroit, MI 48201 (e-mail: hlujan{at}med.wayne.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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H. L. Lujan and S. E. DiCarlo
Sex differences to myocardial ischemia and {beta}-adrenergic receptor blockade in conscious rats
Am J Physiol Heart Circ Physiol, April 1, 2008; 294(4): H1523 - H1529.
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