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Am J Physiol Heart Circ Physiol 291: H2933-H2941, 2006. First published August 4, 2006; doi:10.1152/ajpheart.00514.2006
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Reduced susceptibility to ventricular tachyarrhythmias in rats selectively bred for high aerobic capacity

Heidi L. Lujan,1 Steven L. Britton,2 Lauren G. Koch,2 and Stephen E. DiCarlo1

1Department of Physiology, Wayne State University School of Medicine, Detroit; and 2Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, Michigan

Submitted 19 May 2006 ; accepted in final form 28 July 2006


   ABSTRACT
TOP
 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Reperfusion after a brief period of cardiac ischemia can lead to potentially lethal arrhythmias. Human epidemiological studies and experimental work with animals indicate that regular physical activity is associated with reductions in cardiovascular disease (CVD) risk factors and sudden cardiac death. Similarly, artificial selection of rats for high aerobic treadmill-running capacity (high-capacity runners; HCR) has been shown to reduce CVD risk factors relative to rats selected as low-capacity runners (LCR). Therefore, we tested the hypothesis that HCR, relative to LCR rats, would be less susceptible to ischemia-reperfusion-mediated ventricular tachyarrhythmias. To test this hypothesis, we measured the susceptibility to ventricular tachyarrhythmias produced by 3 min of occlusion and reperfusion of the left main coronary artery in conscious LCR and HCR rats. Results document a significantly lower incidence of ventricular tachyarrhythmias in HCR (3 of 11, 27.3%) relative to LCR (6 of 7, 85.6%) rats. The decreased susceptibility to tachyarrhythmias in HCR rats was associated with a reduced cardiac metabolic demand during ischemia (lower rate-pressure product and ST segment elevation) as well as a wider range for the autonomic control of heart rate. The HCR and LCR represent a unique substrate for evaluation of the mechanisms underlying ischemia-mediated cardiac arrhythmogenesis.

artificial selection; cardiovascular risks; arrhythmia; exercise

TEMPORARY OCCLUSION of the coronary arteries can lead to potentially lethal arrhythmias (66, 82). Coronary artery occlusion-induced arrhythmias are triggered by the ischemic insult directly or on relief of the ischemic insult during the reperfusion phase. The mechanisms underlying the ventricular arrhythmias during ischemia and reperfusion are related but distinct (5, 56, 75, 82). Although ischemia is a more common trigger of sudden death than is reperfusion, life-threatening reperfusion arrhythmias are observed during relief of coronary spasm, during angioplasty or thrombolysis, and after cardiac surgery with ischemic arrest (24).

It is clear from epidemiological studies that regular physical activity is protective against the morbidity and mortality associated with ischemic heart disease (4, 25, 26, 37, 46, 65, 70, 72–74, 79). Specifically, the incidence of sudden cardiac death is inversely related to the level of regular physical activity (3). Regular physical activity also reduces the incidence of cardiac arrhythmias in individuals with cardiac disorders (7, 38, 49, 55, 70, 71, 79). For example, regular physical activity improved cardiac function and reduced the arrhythmia frequency in individuals with congestive heart failure (27, 40). The frequency and severity of cardiac arrhythmias were also reduced after an exercise training program for individuals with myocardial infarction (33).

There is also experimental evidence documenting that daily exercise prevents arrhythmias induced by coronary artery occlusion in intact conscious dogs with myocardial infarction (8). Similarly, we recently documented that daily exercise decreased the susceptibility to ventricular arrhythmias, induced by acute coronary occlusion, in chronically instrumented, intact conscious hypertensive rats (21). However, with these exceptions (8, 21), there is limited experimental evidence documenting that regular physical activity reduces the susceptibility to cardiac arrhythmias in the intact conscious animal. Most of the experimental work examining the antiarrhythmic effects of regular exercise has used isolated rat hearts, anesthetized rats or isolated cells. For example, Opie and colleagues (69, 76) reported that exercise training increased the arrhythmia threshold during coronary artery occlusion in isolated rat hearts. Other investigators (13, 14, 35, 36, 39) using isolated rat heart preparations as well as cardiomyocytes have documented that exercise training improved cardiac and metabolic function after ischemia or anoxia. Exercise training also improved myocardial tolerance to ischemia in anesthetized rats (63, 77). It is important to note that, with few exceptions (69, 76), studies using isolated heart preparations or anesthetized rats do not document the incidence of arrhythmias despite prolonged periods of ischemia. This may be due to the fact that disturbances in cardiac autonomic balance play a critical role in triggering cardiac arrhythmias. Importantly, isolated hearts are devoid of cardiac autonomic innervation. Furthermore, anesthesia and acute surgical trauma significantly alter the autonomic nervous system and may alter the response to ischemia. Thus chronically instrumented, conscious models are critical for studying mechanisms of arrhythmia suppression by regular physical activity.

The mechanisms mediating the antiarrhythmic effects of regular exercise are largely unknown. Exercise capacity is a complex individual trait influenced by both genetic and environmental factors such as lifestyle, diet, and training status. For example, the genetic substrate of exercise capacity includes genes that determine the intrinsic exercise capacity of the untrained individual as well as genes that are responsible for regulating the adaptive responses to regular physical activity (9, 11, 12). It has been estimated that genes determining the intrinsic exercise capacity of the untrained individual account for up to 50% of the variations in individual exercise capacity (10). Previous studies comparing sedentary and exercise-trained animals have been unable to determine the relative contribution of genetic (intrinsic) and environmental (training status) influences mediating the mechanisms of arrhythmia suppression by regular physical activity.

In 1996, Koch and Britton (43) started a large-scale artificial selective breeding to develop rat strains that contrast for intrinsic (inborn, sedentary) aerobic treadmill running capacity. After 11 generations, rats bred as low-capacity runners (LCR) exhibited reduced cardiovascular capacity, features of the metabolic syndrome, and diminished mitochondrial function, relative to the high-capacity runners (HCR) (87). The HCR and LCR present a model in which intrinsic and environmental (training status) factors can be controlled because both the HCR and LCR remain sedentary throughout their lifetimes; thus differences between lines reflect differences in intrinsic exercise capacity. Here we utilize the LCR and HCR rat models that contrast for intrinsic aerobic capacity to test the hypothesis that the LCR would be more susceptible to ventricular tachyarrhythmia initiated by occlusion and reperfusion of the left main coronary artery compared with the HCR. Conscious, chronically instrumented rats were studied to negate the confounding effects of anesthetic agents and surgical trauma. Our data demonstrate that the LCR have greater susceptibility to ventricular tachyarrhythmia that is associated with an increased cardiac metabolic demand during ischemia (higher rate-pressure product and ST segment elevation) as well as a reduced autonomic control of heart rate (HR). These results support the contention that ventricular tachyarrhythmia is associated with low aerobic capacity and provide an animal model system to investigate a major cause of death in humans. The ultimate goal is to develop and utilize selectively bred strains to identify the genetic substrate that dictates the difference between low-endurance performance and high-endurance performance.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
All surgical procedures and experimental protocols were reviewed and approved by the Animal Care and Use Committee of Wayne State University and conformed to American Physiological Society guidelines and principles for research involving animals.

Experimental Subjects

The development of the LCR and HCR through generations 6 and 11 were described previously (43, 87). Briefly, artificial, two-way, selective breeding was used to create low and high strains for treadmill running capacity. The founder population was 80 male and 88 female genetically heterogeneous rats (N:NIH stock) obtained from a colony maintained at the National Institutes of Health (31). The protocol for estimation of endurance capacity required 2 wk and was started when the rats were 10 wk old (43). In the first week, rats were taught to run by placing them on the treadmill (model Exer-4, Columbus Instruments, Columbus, OH) for increasing duration each day, until the animals were able to run 5 min at 10 m/min on a 15° slope. During the second week, each rat underwent a daily endurance trial on five consecutive days at a constant slope of 15° and an initial velocity of 10 m/min. Treadmill velocity was increased by 1 m/min every 2 min until the third time a rat could no longer keep pace with the speed of the treadmill. For each of the five trials, the total distance run (in m) was used as the estimate of endurance capacity. The single best daily run of five trials for each rat was considered the trial most closely associated with the heritable component of exercise endurance. The 13 lowest- and 13 highest-capacity rats of each sex were selected from the founder population and randomly paired for mating. At each subsequent generation, within-family selection from 13 mating pairs was practiced because it decreases the rate of inbreeding to yield retention of genetic variation. Seven LCR and 11 HCR males derived from generations 15, 16, and 17 were used in the present study.

Surgical Procedures

Instrumentation. Rats were anesthetized with pentobarbital sodium (35 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. With the use of aseptic procedures, the hearts were approached via a left thoracotomy through the fourth intercostal space. Subsequently, a coronary artery occluder, made from 5.0-gauge atraumatic prolene suture (8720H, Ethicon), which passed through a PE-10 polyethylene guide tubing (Clay Adams), was passed around the left main coronary artery 2–3 mm from the origin by inserting the needle into the left ventricular wall under the overhanging left atrial appendage and bringing it out high on the pulmonary conus (20, 21, 51). 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 Vaseline and mineral oil to prevent a pneumothorax. At least 1 wk was allowed for recovery (45). During the recovery periods, the rats were handled, weighed daily, and acclimatized to the laboratory and investigators. Subsequently, the animals were anesthetized as described above, and three insulated stainless steel ECG electrodes were sutured subcutaneously on the ventral side of the thorax. The ECG leads were exteriorized at the back of the neck. In addition, a telemetry device (model PhysioTel PA-C40, Data Sciences International) was implanted as previously described (19, 78), and a catheter was placed in the intraperitoneal (IP) space for the infusion of drugs. The IP catheter was also exteriorized at the back of the neck. 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 via radio telemetry. Again, at least 1 wk was allowed for recovery (45). During the recovery periods, the rats were handled, weighed daily, and acclimatized to the laboratory and investigators. Two separate surgeries, separated by at least 1 wk, were performed because the animals recover significantly better than if two major surgeries are conducted during one session.

Experimental Procedures

Protocol I: susceptibility to ischemic-reperfusion-induced arrhythmias. 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 approximately 1 h to ensure stable hemodynamic conditions. Subsequently, the left main coronary artery was temporarily occluded for 3 min by use of the prolene suture. Specifically, acute coronary artery occlusion was performed by pulling up on the suture that was around the left main coronary artery and holding the occlusion for 3 min. A rapid change in the ECG (ST segment elevation) and a change in arterial pressure occur within seconds of pulling on the suture, documenting coronary artery occlusion. [Fig. 1A, (21)]. On release, the animals either experienced ventricular tachyarrhythmia or normal sinus rhythm (Fig. 1B). When ventricular tachyarrhythmia developed, normal sinus rhythm appeared by gently compressing the thorax. In the event when the animal did not resume normal sinus rhythm, cardioversion was achieved (after the rat lost consciousness) with the use of 1 shock (10 J) of direct current.


Figure 1
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  		Fig. 1. Analog recording of arterial pressure and the electrocardiogram (ECG) during occlusion of the left main coronary artery (A) and during reperfusion (release of the occluder; B) in an intact, conscious rat. Within seconds of the occlusion, there was a rapid change in the ECG (ST segment elevation) and change in arterial pressure, documenting occlusion of the left main coronary artery (A). Occlusion was maintained for 3 min and released. On release of the occluder, there was a gradual reduction of the ST elevation, followed by ventricular tachyarrhythmia (B). Ventricular tachyarrhythmia was associated with rapid, wide QRS complexes and decrease in arterial pressure. Results document a significantly lower incidence of ventricular tachyarrhythmias in rats with high aerobic capacity (3 of 11, 27.3%) vs. rats with low aerobic capacity (6 of 7, 85.6%).

 
Protocol 2: determination of sympathetic and parasympathetic tonus. Two trials were required to determine cardiac sympathetic and parasympathetic tonus. On day 1, the rats were studied in their home cage. The rats were allowed to adapt to the laboratory environment for 1 h so that baseline hemodynamic variables could be obtained. After the adaptation period, the HR, arterial pressure, and mean arterial pressure responses to cardiac autonomic sympathetic and parasympathetic blockade (beta1-adrenergic and muscarinic-cholinergic receptor blockade) were determined. Drug doses for the sympathetic and parasympathetic antagonists were calculated relative to the animal’s body weight on each experimental day. Cardiac muscarinic-cholinergic receptor blockade was achieved by infusion of the nonspecific muscarinic-cholinergic receptor antagonist atropine methyl bromide (3 mg/kg) through the IP catheter. Because the HR response to atropine methyl bromide reached its peak in 10–15 min, this time interval was standardized before the HR measurement. Cardiac beta1-adrenergic receptor blockade was achieved by infusion of the specific beta1-adrenergic receptor antagonist metoprolol (10 mg/kg) into the IP catheter. Metoprolol was infused 15 min after atropine methyl bromide, and again the HR response was measured after 10–15 min. The entire data collection took ~2 h. At the end of the experiment, the rats were returned to their housing facilities. On an alternate day (>48 h), trial 2 was conducted. Rats were treated identically as described in trial 1 except that the order of blockade was reversed. Intrinsic HR (HRi) was considered to be the HR after complete cardiac autonomic blockade (muscarinic-cholinergic and beta1-adrenergic receptor blockades). Sympathetic tonus was calculated as HRm – HRi and parasympathetic tonus as HRbeta – HRi, where HRm is the HR after muscarinic-cholinergic receptor blockade and HRbeta is the HR after beta1-adrenergic receptor blockade.

Determination of ischemic zone. Three days after the experiment, the rats were euthanized with an overdose of sodium pentobarbital. 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 around the left main coronary artery was tied. Evans Blue dye (100 µl, 0.5%) was perfused via the aorta causing the dye to infuse into the nonischemic area of the heart, leaving the ischemic regions unstained. The heart was trimmed leaving only the right and left ventricles, rinsed to remove the excess blue dye, and weighed. The heart was trimmed again leaving only the ischemic region. The weight of the ischemic zone was expressed as percentage of total heart weight (20–22, 85).

To determine whether the occlusion produced a myocardial infarction, the heart was sliced transversally into ~1.0 mm sections and incubated in a 1% solution of 2,3,5-triphenyltetrazolium chloride (TCC, 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 red brick stain. Necrotic tissue which has lost its dehydrogenase enzymes does not form a red stain and shows up as pale yellow. This stain has been shown to be a reliable indicator of myocardial infarction (28).

Data Analysis

All data were expressed as means ± SE. A {chi}2-test was used to compare the percentage of animals sustaining ventricular tachyarrhythmia in the LCR and HCR. A two-factor ANOVA with repeated measures on one factor with post hoc Student-Newman-Keuls method was used to compare mean arterial blood pressure and HR immediately before the occlusion (preocclusion) and immediately before the release of the occluder (prerelease) between the LCR and HCR. In addition, unpaired, one-tailed t-tests were used to compare sympathetic and parasympathetic tonus, rate-pressure product, and ST segment elevation as well as running capacity in the LCR and HCR. The rate-pressure product, an index of myocardial oxygen demand, was calculated as (systolic blood pressure x heart rate)/1,000 (41).


   RESULTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Initial phenotyping for intrinsic running capacity was performed at the University of Michigan. At 11 wk of age, the LCR ran to 243 ± 18 m (17 ± 1 min) and the HCR ran to 1,651 ± 37 m (64 ± 1 min) at exhaustion, representing a 579% difference in distance run. During the run (constant 15° grade), the LCR performed 19 ± 2 kg·m and the HCR performed 87 ± 4 kg·m of vertical work (P < 0.05). Maximal speed at the end of the run was 18 ± 1 m/min for the LCR and 42 ± 0.5 m/min for the HCR (P < 0.05). At 20 wk of age, the rats were shipped to Wayne State University for the rest of the measures.

Figure 2 presents the percentage of rats from the LCR and HCR that experienced ventricular tachyarrhythmia on release of the coronary artery occluder. Eighty-six percent (6 of 7) of the LCR and 27% (3 of 11) of the HCR experienced ventricular tachyarrhythmia on release of the coronary artery occluder. The {chi}2-test indicated that this difference was statistically significant at the P < 0.05 level.


Figure 2
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  		Fig. 2. Percentage of rats from the low-capacity runners (LCR) and high-capacity runners (HCR) that experienced ventricular tachyarrhythmia on release of the coronary artery occluder. Eighty-six percent (6 of 7) of the LCR and 27% (3 of 11) of the HCR experienced ventricular tachyarrhythmia on release of the coronary artery occluder. *P < 0.05, LCR vs. HCR.

 
Figure 3 presents the ST segment change and rate-pressure product immediately before release of the occluder (prerelease) from the LCR and HCR. The unpaired, one-tailed t-tests revealed a significantly higher rate-pressure product and ST segment elevation in the LCR.


Figure 3
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  		Fig. 3. ST segment elevation and rate-pressure product immediately before release of the occluder (prerelease) in LCR and HCR. HCR had a lower ST segment elevation and rate-pressure product. HR, heart rate; SBP, systolic blood pressure. *P < 0.05, LCR vs. HCR.

 
Table 1 presents resting mean arterial pressure and HR immediately before the occlusion (preocclusion) and immediately before the release of the occluder (prerelease) in the LCR and HCR. Preocclusion mean arterial pressure and HR were not different between the LCR and HCR. Although prerelease mean arterial pressure was not different between groups, prerelease HR was significantly higher in the LCR.


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  		Table 1. Mean arterial pressure and heart rate immediately before occlusion of the left main coronary artery (preocclusion) and immediately before the release of the occluder (prerelease) in low-capacity and high-capacity runners

 
Figure 4 presents resting cardiac sympathetic and parasympathetic tonus for the LCR and HCR. The unpaired, one-tailed t-tests revealed significantly higher sympathetic (100 ± 8 vs. 78 ± 6 beats/min) and parasympathetic (–26 ± 4 vs. –16 ± 4 beats/min) tonus for the HCR.


Figure 4
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  		Fig. 4. Resting cardiac sympathetic and parasympathetic tonus for the LCR and HCR. Sympathetic and parasympathetic tonus were higher in the HCR (100 ± 8 vs. 78 ± 6 and –26 ± 4 vs. –16 ± 4 beats/min, respectively). *P < 0.05, LCR vs. HCR.

 
Table 2 presents body weight, age, heart weight-to-body weight ratio, and ischemic zone for the LCR and HCR. Only body weight was different between groups, with the HCR weighing significantly less than the LCR. Finally, the ischemic zone averaged 48 ± 1 and 49 ± 1% of the total heart weight for the LCR and HCR, and there were no signs of myocardial infarction.


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  		Table 2. Body weight, age, heart weight-to-body weight ratio, and ischemic zone for the low-capacity runners and high-capacity runners

 

   DISCUSSION
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
In this study, we tested the hypothesis that artificial selection of rats for high intrinsic exercise capacity would reduce the susceptibility to ventricular tachyarrhythmia induced by myocardial ischemia and reperfusion. Specifically, we recorded the susceptibility to ventricular tachyarrhythmia induced by myocardial ischemia and reperfusion in conscious rats selectively bred for low or high aerobic capacity. Results document a significantly lower incidence of ventricular tachyarrhythmia in rats with high aerobic capacity (3 of 11, 27.3%; Fig. 2) vs. rats with low aerobic capacity (6 of 7, 85.6%). The reduced susceptibility to ventricular tachyarrhythmia was associated with a reduced cardiac metabolic demand during ischemia (lower rate-pressure product and ST segment elevation; Fig. 3) as well as a lower prerelease HR (Table 1) and enhanced cardiac autonomic control (Fig. 4). The HCR and LCR present a model in which intrinsic and environmental (training status) factors can be controlled because both the HCR and LCR remain sedentary throughout their lifetimes; thus differences between lines reflect differences in intrinsic exercise capacity.

One of the major manifestations of myocardial reperfusion after a brief period of ischemia is ventricular arrhythmias. These arrhythmias are observed clinically following relief of coronary artery spasm, angioplasty or thrombolysis, and cardiac surgery with ischemia arrest (56). The severity of reperfusion-induced arrhythmias may be related to the HR during the ischemic period (5). Specifically, pacing the heart at slower rates led to a frequency-dependent protective effect against reperfusion-induced arrhythmias. Furthermore, autonomic interventions have a HR-dependent effect on reperfusion arrhythmias. Specifically, when HR is held constant, neither beta-blockade nor vagus nerve stimulation protects against reperfusion arrhythmias (83). Taken together, these data suggest that the increased susceptibility to ventricular arrhythmias in the LCR may be due, in part, to the higher prerelease heart rates (Table 1) and is consistent with the reduced parasympathetic tonus in LCR (Fig. 4).

Human epidemiological studies indicate that regular physical activity is associated with cardiovascular benefits (65, 80). Furthermore, experimental studies have documented that both short- and long-term endurance exercise provides myocardial protection against ischemia-reperfusion injury in rats (6, 14, 23, 30, 53, 54, 77). Several factors, including an increase in calcium handling (14), endogenous antioxidants (50, 77), heat shock proteins (50, 81), and increased expression of myosin heavy chain-beta (34) as well as intrinsic metabolic factors and reduced content of the arrhythmogenic substance cyclic AMP, have been implicated as mechanisms responsible for the protective effects of exercise. For example, Posel et al. (76) documented a reduced accumulation of cyclic AMP in the ischemic left ventricular zone in hearts from trained rats. Similarly, Kleitke et al. (42) documented significantly lower cyclic AMP levels in response to acute global ischemia in hearts from swimming-trained rats.

Large-scale clinical investigations suggest an etiologic association of aerobic metabolism with a wide variety of complex diseases and clinical disorders. For example, Myers et al. (67) concluded that aerobic exercise capacity is a more powerful predictor of mortality than other currently established risk factors for cardiovascular disease. These investigators reported a 12% increase in survival for each 1-metabolic equivalent increase in aerobic exercise capacity. In accord with this view, the work of Akar et al. (1) suggests that ischemia-related electrophysiological alterations and arrhythmias in intact hearts are, at least in part, a consequence of the failure of the cellular mitochondrial network to maintain membrane electrical potential. They found that preventing membrane depolarization by blocking the mitochondrial benzodiazepine receptor stabilized the action potentials of metabolically stressed cardiomyocytes, blunted ischemia-induced action potential shortening, improved postischemic recovery of the action potential, and prevented the occurrence of spontaneous arrhythmias on reperfusion of the heart. In contrast, facilitating membrane depolarization with a mitochondrial benzodiazepine receptor agonist accelerated ischemia-induced changes in action potentials, created regions of conduction block, and promoted arrhythmias on reperfusion. These findings support the hypothesis that mitochondrial function is critical for normal cardiac electrical stability.

Considerable evidence documents that changes in the ST segment shift are a valid marker of changes in the severity of myocardial ischemia (47). For example, studies in patients document that the ST segment shift correlates with both metabolic and contractile parameters of myocardial ischemia (32, 48, 61, 62). Therefore, ST segment changes are widely used as an index of myocardial injury resulting from ischemia in experimental animals (52, 57–59, 64, 86). 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 (rate-pressure product; Fig. 3) as an index of the severity of myocardial ischemia. It can be seen in Fig. 3 that both indexes were significantly higher in LCR. Since the size of the ischemic zone was not different between the LCR and HCR, these results suggest a role for enhanced mitochondrial function mediating the cardioprotection (84).

Limitations

We documented a relationship between intrinsic aerobic capacity, the susceptibility to ventricular tachyarrhythmia, and cardiac autonomic control. Whereas these results suggest an underlying mechanism related to oxygen metabolism, a cause-and-effect linkage has not been determined. For example, the LCR are heavier than the HCR (Table 2), and body weight and its composition are known risk factors that could influence arrhythmogenesis via pathways independent of autonomic or aerobic metabolic influences. In addition, the production of cardiac ischemia via mechanical occlusion more accurately reflects the response to acute injury and not the progression of underlying vascular occlusive disease.

It is also important to note that the measures of sympathetic and parasympathetic tonus provide only an indirect indication of cardiac autonomic control. However, the role of the autonomic nervous system in regulating HR has been evaluated indirectly by using pharmacological cardiac autonomic blockade by a variety of investigators. Results obtained from these studies have been analyzed by a variety of approaches. For example, comparisons have been made among parasympathetic and sympathetic effects and parasympathetic and sympathetic tonus. A parasympathetic effect is defined as the tachycardic response after cardiac muscarinic cholinergic receptor blockade (difference between resting HR and maximal HR after muscarinic cholinergic receptor blockade). A sympathetic effect is defined as the bradycardic response after cardiac beta1-adrenergic receptor blockade (difference between resting HR and minimal HR after beta1-adrenergic receptor blockade). Unfortunately, these effects are difficult to interpret because it is difficult to distinguish the direct result of blockade from the indirect result. For example, the HR after muscarinic cholinergic receptor blockade (parasympathetic effect) is the result of the direct effect of removal of the parasympathetic influence on the heart as well as the indirect effect of the unopposed sympathetic influence on the heart in response to blockade of the parasympathetic limb. Another potential limitation when using the parasympathetic (or sympathetic) effect is that the change in HRi is not considered. Any change in HRi would affect the final HR.

In an attempt to reduce the influence of these two limitations, investigators have used parasympathetic and sympathetic tonus (15–18, 29, 44, 60, 68). Parasympathetic tonus is defined as the difference between HRi and the HR after beta1-adrenergic receptor blockade. Sympathetic tonus is defined as the difference between HRi and the HR after muscarinic cholinergic receptor blockade. Thus both parasympathetic and sympathetic tonus represents the effect of the parasympathetic and sympathetic nervous systems on the heart without the influence of the opposing limb of the autonomic nervous system. By using sympathetic and parasympathetic tonus, investigators are also able to account for the difference in HRi. Finally, the HR responses to autonomic blockers (using procedures identical to the procedures used in this study) are significantly associated with HR at rest, during exercise, and after exercise (15, 16).

Conclusion

This study documents that artificial selection of rats for low and high aerobic treadmill running capacity also selects for a differential in the susceptibility to ventricular arrhythmias. That is, LCR relative to HCR have an increased likelihood of ischemia-induced ventricular tachyarrhythmia that associates with an increased cardiac metabolic demand during ischemia (higher rate-pressure product and ST segment elevation) as well as a lower range for the autonomic control of HR. The HCR and LCR thus represent unique models for differences in vulnerability to cardiac ischemia-reperfusion that can be used to explore this trait at all levels of biological organization.


   GRANTS
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by National Institutes of Health Grants HL-67713 (to H. L. Lujan) and HL-64270 and RR-17718 (to S. L. Britton and L. G. Koch).


   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.


   REFERENCES
TOP
 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

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