Fig. 1. A flow chart illustrating the classification of animals that have been studied using a canine model of sudden cardiac death. VF = ventricular fibrillation, defib = defibrillation.

Fig. 2. The time course for the animals that died acutely following myocardial infarction. The majority of the dogs died either during the surgery (n = 90) or within the first 24 hr following the (n = 52, 15 died within the first 6 hr) myocardial infarction.

Fig. 3. Representative recordings from 1 susceptible and 1 resistant animal. The exercise plus ischemia test induced ventricular flutter (that rapidly progresses to ventricular fibrillation) in the susceptible animal. Note the smaller heart rate increase in response to the coronary occlusion in the resistant animal. LVP = left ventricular pressure, CBF = coronary blood flow, HR = heart rate (beats per min).

Fig. 4. The hemodynamic response to submaximal exercise in dogs susceptible (n = 59, solid line/filled circles) and resistant (n = 55, dashed line/open circles) to ventricular fibrillation. Note that exercise elicited larger increases in heart rate and left ventricular diastolic pressure in the susceptible compared to the resistant animals. Exercise levels: level 1 = control 1 min before the onset of exercise; level 2 = 4.8 kph/0% grade; level 3 = 6.4 kph/0% grade; level 4 = 6.4 kph/4% grade; level 5 = 6.4 kph/8% grade; level 6 = 6.4 kph/12% grade; and level 7 = 6.4 kph/16% grade. P < .01 susceptible versus resistant, LVP = left ventricular pressure.

Fig. 5. The hemodynamic response to left circumflex coronary occlusion at rest submaximal exercise in dogs susceptible (n = 59, solid line/filled circles) and resistant (n = 55, dashed line/open circles) to ventricular fibrillation. Note that exercise elicited larger increases in heart rate in the susceptible compared to the resistant animals. P < .01 susceptible versus resistant dogs, Pre = control 1 min before the occlusion, Post = 3 min after the occlusion release. Time indicated is seconds.

Fig. 6. The hemodynamic response to the exercise plus ischemia test. The coronary artery occlusion provoked significant reductions in left ventricular systolic pressure and left ventricular dP/dt maximum for the both the resistant (n = 55) and susceptible (n = 59) dogs. Note further that the coronary artery occlusion provoked larger increases in heart rate and left ventricular diastolic pressure in the susceptible animals. P < .01 exercise versus occlusion (60 sec or last 5 sec before ventricular fibrillation) resistant dogs, ^#P < .01 susceptible versus resistant dogs, LVP = left ventricular pressure.

Fig. 7. A comparison of the hemodynamic response to the first and second exercise plus ischemia test in dogs susceptible (n = 21) to ventricular fibrillation. Note that coronary artery occlusion elicited similar changes in both the first and second occlusions. P < .01 occlusion versus exercise. LVP = left ventricular pressure.

Fig. 8. The effect of gender on myocardial infarction in animals susceptible (n = 93) or resistant (n = 50) to ventricular fibrillation. Note that the myocardial infarction was larger in susceptible (male n = 34, female n = 59) animals of either gender as compared to resistant (male n = 30, female n = 25) dogs. P < .01 susceptible versus resistant dogs.

Fig. 9. The effects of the exercise plus ischemia test on electrocardiographic parameters in dogs susceptible (n = 45) or resistant to ventricular fibrillation (n = 31). The coronary occlusion provoked similar reductions in P–R interval in both groups of dogs. In contrast, the coronary occlusion provoked larger increases in both heart rate and Q–T interval corrected for heart rate (QTc). P < .01 susceptible versus resistant dogs.

Fig. 10. A comparison of baroreceptor reflex sensitivity in dogs susceptible (n = 40) or resistant (n = 27) to ventricular fibrillation. The data are plotted either as changes in R–R interval versus systolic arterial pressure (top panel) or changes in heart rate versus systolic arterial pressure (bottom panel). P < .01 susceptible versus resistant dogs.

Fig. 11. The heart rate and heart variability response to submaximal exercise in susceptible (n = 69, solid line/filled circles) and resistant (n = 42, dashed line/open circles) animals. Note the higher heart rate and greater reductions in all 3 indices of cardiac parasympathetic activity in response to the exercise for the susceptible animals. P < .01, Exercise levels: level 1 = control 1 min before the onset of exercise; level 2 = 4.8 kph/0% grade; level 3 = 6.4 kph/0% grade; level 4 = 6.4 kph/4% grade; level 5 = 6.4 kph/8% grade; level 6 = 6.4 kph/12% grade; and level 7 = 6.4 kph/16% grade.

Fig. 12. The effect of the beta-adrenoceptor antagonist (propranolol HCl 1.0 mg/kg, i.v.) on the heart rate and heart variability response to submaximal exercise in susceptible (n = 41, solid line/filled circles) and resistant (n = 26, dashed line/open circles) animals. Note the higher heart rate and greater reductions in all 3 indices of cardiac parasympathetic activity in response to the exercise (lower levels of exercise) for the susceptible animals. P < .01, Exercise levels: level 1 = control 1 min before the onset of exercise; level 2 = 4.8 kph/0% grade; level 3 = 6.4 kph/0% grade; level 4 = 6.4 kph/4% grade; level 5 = 6.4 kph/8% grade; level 6 = 6.4 kph/12% grade; and level 7 = 6.4 kph/16% grade.

Fig. 13. The effect of gender on the heart rate and heart variability response to submaximal exercise in susceptible animals. There were no differences between male (n = 23) or female (n = 46) dogs. Exercise levels: level 1 = control 1 minute before the onset of exercise; level 2 = 4.8 kph/0% grade; level 3 = 6.4 kph/0% grade; level 4 = 6.4 kph/4% grade; level 5 = 6.4 kph/8% grade; level 6 = 6.4 kph/12% grade; and level 7 = 6.4 kph/16% grade.

Fig. 14. The heart rate and heart variability response to left circumflex coronary artery occlusion at rest in susceptible (n = 83, solid line/filled circles) and resistant (n = 48, dashed line/open circles) animals. Note the higher heart rate and greater reductions in all 3 indices of cardiac parasympathetic activity in response to myocardial ischemia in the susceptible animals. P < 0.01, Pre = control 1 min before the occlusion, Post = 3 min after the occlusion release. Time indicated is seconds.

Fig. 15. The effect of the beta-adrenoceptor antagonist (propranolol HCl, 1.0 mg/kg, i.v.) on the heart rate and heart variability response to left circumflex coronary artery occlusion at rest in susceptible (n = 44, solid line/filled circles) and resistant (n = 32, dashed line/open circles) animals. Note the higher heart rate and greater reductions in all 3 indices of cardiac parasympathetic activity in response to myocardial ischemia in the susceptible animals. P < .01, Pre = control 1 min before the occlusion, Post = 3 min after the occlusion release. Time indicated is seconds.

Fig. 16. The effect of gender on the heart rate and heart variability response to left circumflex coronary artery occlusion at rest in susceptible (male n = 29, female n = 54) animals. There were no effects of gender on the response to the coronary artery occlusion. Pre = control 1 min before the occlusion, Post = 3 min after the occlusion release. Time indicated is seconds.

Fig. 17. Wavelet transform analysis of the heart rate variability during the exercise plus ischemia test in animals susceptible (n = 6) or resistant (n = 6) to ventricular fibrillation. Note the greater variability in the resistant animals.

Fig. 18. Representative recordings obtained from the same susceptible animal before and after treatment with 8-bromo cyclic GMP (long acting analog of cyclic GMP, parasympathetic intracellular 2nd messenger). Note the absence of ventricular arrhythmias during the 8-bromo cyclic GMP treatment. 8-Bromo cyclic GMP prevented ventricular fibrillation in 8 of 9 susceptible animals, dibutyryl cyclic GMP protected 5 of 5 susceptible animals. Thus, cyclic GMP protected 13 of 14 animals tested. LVP = left ventricular pressure, CBF = coronary blood flow, HR = heart rate (beats per min). (Reprinted with permission from Billman, 2005.)

Fig. 19. Representative recordings obtained from the same susceptible animal before and after removal of the left stellate ganglion (LSGX). Note that despite the large ischemic ECG changes, the removal of the left stellate ganglion prevented ventricular fibrillation during the second exercise plus ischemia test. LSGX protected 11 of 11 susceptible animals tested. LVP = left ventricular pressure, HR = heart rate (beats per min). (Reprinted with permission from Billman, 2005.)

Fig. 20. Effects of selective β-adrenoceptor antagonists on the maximum isoproterenol induced Vcf responses in dogs susceptible (n = 12) or resistant (n = 15) to ventricular fibrillation. Isoproterenol elicited a greater increase in the susceptible compared to the resistant dogs. The β₂-adrenoceptor antagonist ICI 118,551 (0.2 mg/kg, i.v.) elicited a significantly greater reduction in the isoproterenol response in the susceptible compared to the resistant animals. β₁-adrenoceptor antagonist = bisoprolol (0.6 mg/kg, i.v.), isoproterenol = 0.5 μg/kg/min. P < .01 susceptible versus the corresponding drug treatment for the resistant dogs.

Fig. 21. Representative recordings of calcium transients recorded in ventricular myocytes obtained from 1 susceptible dog in which β-adrenoceptor agonist isoproterenol (ISO, 100 nmol/L) induced aftertransients. Treatment with the β₂-adrenoceptor antagonist ICI 118,551 (ICI, 100 nmol/L) but not β₁-adrenoceptor antagonist CGP-20712A (CGP, 300 nmol/L). Completely suppressed these after transients. (Reprinted with permission from Billman et al., 1997b.)

Fig. 22. Representative recording from 1 resistant dog with and without pretreatment with cocaine (1.0 mg/kg, i.v., given 3 min before the coronary artery occlusion).

Fig. 23. The effect of the 10-week exercise training (n = 9) or 10-week sedentary (n = 7) period on the heart rate and the heart rate variability responses to a 2 min coronary occlusion in animals susceptible to ventricular fibrillation. The coronary occlusion elicited significantly smaller increase in heart rate and smaller reductions in the various indices of cardiac vagal regulation in the exercise-trained dogs as compared to animals that received a similar sedentary period. The post-training response in the susceptible exercise trained animals was no longer different from that noted for the resistant (either exercise trained or sedentary) dogs. P < 0.01 exercise-trained versus sedentary. Pre = last 30 sec before the coronary occlusion, Post = 1 min following coronary occlusion release (i.e., average over 30–60 sec post release). (Reprinted with permission from Billman & Kukielka, in press.)

Fig. 24. The effect of the 10-week exercise training (n = 9) or 10-week sedentary period (n = 7) on the heart rate and the heart rate variability responses to submaximal exercise in animals susceptible ventricular fibrillation. Exercise elicited significantly smaller increase in heart rate and smaller reductions in the various indices of cardiac vagal activity in the exercise-trained dogs as compared to animals that received a similar sedentary period. The post-training response in the susceptible exercise-trained dogs was no longer different from that noted for the resistant (exercise trained or sedentary) dogs. P < 0.01 exercise-trained versus sedentary, Exercise levels: 1 = 0 kph/0% grade, 2 = 4.8 kph/0% grade, 3 = 6.4 kph/0% grade, 4 = 6.4 kph/4% grade, 5 = 6.4 kph/8% grade, 6 = 6.4 kph 12% grade, 7 = 6.4 kph/16% grade. (Reprinted with permission from Billman & Kukielka, in press.)

Fig. 25. Representative ECG recordings from 2 different susceptible dogs, 1 before after completion of a 10-week endurance exercise program and 1 before and after an equivalent 10-week sedentary period. Note arrhythmias were no longer induced by the exercise plus ischemia test in the exercise-trained animal. The arrow indicates the time at which the treadmill was stopped. (Reprinted with permission from Billman et al., in press.)

Fig. 26. Effects of selective β-adrenoceptor antagonists on the maximum isoproterenol induced Vcf response in susceptible animals before (control n = 18) and after either exercise training (n = 8) or a sedentary (n = 10) time period. The β₂-adrenoceptor antagonist ICI 118,551 (0.2 mg/kg, i.v.) elicited a significantly greater reduction in the isoproterenol response in the sedentary animals. In contrast, the β₂-adrenoceptor response was significantly reduced in the exercise-trained animals. β₁-adrenoceptor antagonist = bisoprolol (0.6 mg/kg, i.v.), isoproterenol = 0.5 μg/kg/min. P < 0.01 control drug treatment response compared to the corresponding drug treatment response for either the 10-week exercise-trained or the 10-week sedentary group. (Reprinted with permission from Billman et al., in press.)

Fig. 27. The effect of exercise training on the single-cell shortening (% change from control) response to the selective β-adrenoceptor agonist (zinterol, 100 nM). The responses were compared between ventricular myocytes (up to 15 cells per dog, averaged such that only value was reported for a given animal) obtained from susceptible (sedentary n = 7, exercise training n = 8) and resistant (sedentary n = 5, exercise training n = 6) animals. Note the much larger response in the sedentary susceptible animals. P < .01 sedentary versus exercise training. (Reprinted permission from Billman et al., in press.)

Fig. 28. Representative recordings of 1 susceptible dog before and after pretreatment with the omega-3 fatty acid, eicosapentaenoic acid (1 g in 100 mL infused over 1 hr). Note the absence of arrhythmias after treatment with the omega-3 fatty acid. This treatment prevented ventricular fibrillation in 5 of 7 susceptible dogs.

Fig. 29. Summary of the results of some of the interventions tested in dogs susceptible to ventricular fibrillation. 1st and 2nd control (no drug treatment) n = 257; BB = β-adrenoceptor blockade (propranolol HCl., 1.0 mg/kg, i.v., n = 38); B2 = β₂-adrenoceptor blockade (ICI 118,551; 0.2 mg/kg, i.v., n = 11); Ca = calcium channel antagonists (average 90.5%, range 76.5–100% depending on agent used, see text for details); K(ATP) = ATP-sensitive potassium channel antagonist (HMR 1883/1098 and HMR 1402, n = 28); IKs = slow component of the delayed rectifier current (L-768,673, 0.03 mg/kg, i.v., n = 6); IKr = rapid component of the delayed rectifier current (d-sotalol, 2.0 to 8.0 mg/kg, i.v., n = 18); n-3 = omega-3 fatty acids (n = 21); LSGx = left stellate ganglionectomy (n = 11); Ex = endurance exercise training (n = 24).

Fig. 30. Summary of results some of the interventions tested in dogs resistant to ventricular fibrillation. 1st (n = 209) and 2nd (n = 133) = control no drug occlusions (n = 209); Bay K = the calcium channel agonist Bay K 8644 (30 μg/kg, i.v., 3 min before the coronary occlusion, n = 14); cocaine (1.0 mg/kg, i.v., 3 min before the occlusion, n = 55); Atropine (50 μg/kg, i.v., n = 66), PE = phenylephrine, 10 μg/kg/min 2 min before occlusion onset, n = 17) IKr = rapid component of the delayed rectifier current (d-sotalol 2.0 mg/kg, i.v., induction of arrhythmias in 2 of 3 dogs tested).