Regression of Left Ventricular Hypertrophy Prevents Ischemia-Induced Lethal Arrhythmias
Beneficial Effect of Angiotensin II Blockade
Abstract To evaluate the preventive effect of regression of left ventricular hypertrophy (LVH) on sudden cardiac death (SCD), the incidence of ventricular tachycardia or ventricular fibrillation (VT/Vf) after left coronary artery occlusion in Langendorff preparations was studied in the following five groups: (1) spontaneously hypertensive rats (SHR) without treatment (SHR-N), (2) SHR treated with captopril (SHR-C), (3) SHR treated with the angiotensin II receptor antagonist TCV-116 (SHR-A), (4) SHR treated with hydralazine (SHR-H), and (5) Wistar-Kyoto (WKY) rats. Although blood pressure was equally lowered in all treated groups, SHR-C and SHR-A but not SHR-H showed regression of LVH. The incidence of VT/Vf was 5% in WKY rats, 63% in SHR-N (P<.005 versus WKY rats), 0% in SHR-C, 10% in SHR-A, and 45% in SHR-H (P<.05 versus WKY rats). Further evaluation of the effect of TCV-116 revealed that SHR treated with a low dose of TCV-116 (1 mg/kg per day) showed a decrease in left ventricular mass with only a little decrease in blood pressure and that the incidence of VT/Vf was reduced in association with the degree of regression of LVH. Electrophysiological study using microelectrode techniques revealed that in the LVH groups (SHR-N and SHR-H), the action potential duration (APD) of the left ventricular papillary muscle was more prolonged than in WKY rats, whereas APD shortened to a greater extent during superfusion with a hypoxia/no-glucose solution. APD showed no difference in the regression groups (SHR-C and SHR-A) compared with the WKY group. Shortening of APD at 75% repolarization 30 minutes after exposure to the hypoxia/no-glucose solution was 34% in WKY rats, 53% in SHR-N (P<.05 versus WKY rats), 32% in SHR-C, 28% in SHR-A, and 47% in SHR-H (P<.05 versus WKY rats). These results suggest that LVH has a greater susceptibility to VT/Vf during acute myocardial ischemia because of greater APD dispersion between the normal and ischemic zones. The reduction of electrical inhomogeneity in regressed LVH may prevent SCD caused by ischemia-induced lethal arrhythmias. Effective regression of LVH by angiotensin II blockade may play a beneficial role in the prevention of SCD.
- regression of left ventricular hypertrophy
- sudden cardiac death
- ischemia-induced lethal arrhythmias
- dispersion of action potential durations
- angiotensin II blockade
Epidemiological studies have suggested that patients with left ventricular hypertrophy (LVH) secondary to systemic hypertension are at a significantly greater risk of sudden cardiac death (SCD).1 2 In general, SCD is considered to be caused by acute cardiac arrest secondary to lethal ventricular tachyarrhythmias such as ventricular tachycardia (VT) and ventricular fibrillation (Vf). Clinical experiences have shown that patients are most susceptible to lethal ventricular tachyarrhythmias in the acute phase of myocardial infarctions, particularly within 90 minutes from the onset.3 Thus, a possible cause of the high incidence of SCD in patients with LVH may be a greater susceptibility to VT/Vf during acute ischemia in addition to a high incidence of ischemic cardiac events. Experimental studies have revealed that the incidence of SCD in LVH dogs after coronary artery occlusion and the occurrence of Vf in Langendorff-perfused hypertrophied rat hearts after regional ischemia are significantly higher.4 5 Therefore, we can expect to reduce the incidence of SCD in patients with LVH if we prevent the occurrence of lethal ventricular tachyarrhythmias associated with acute myocardial infarction.
It has been reported that hypertensive LVH regresses after chronic treatment with antihypertensive agents such as angiotensin-converting enzyme (ACE) inhibitors, calcium antagonists, centrally acting sympathetic inhibitors, β-blockers, and α-blockers.6 7 However, it remains unknown whether a reduction of LVH will also reduce the excessive risk of SCD. In the present study, to test the hypothesis that regression of LVH prevents SCD, we examined the incidence of lethal ventricular tachyarrhythmias induced by acute ischemia in hypertrophied rat hearts and the effect of regression of LVH caused by chronic antihypertensive treatment on ischemia-induced lethal arrhythmias. In addition, we examined a possible mechanism underlying the enhanced arrhythmogenesis in hypertrophied hearts during acute ischemia by electrophysiological study using microelectrode techniques.
Materials and Methods
Twelve-week-old male spontaneously hypertensive rats (SHR), which were reported to show LVH,8 were chronically treated with antihypertensive agents for 6 weeks. These 18-week-old rats were then used for the experiments. In each treated group, drugs were withdrawn ≈24 hours before the experiments in order to eliminate their pharmacological actions. Hearts from age-matched SHR without treatment and Wistar-Kyoto (WKY) rats served as hypertensive hypertrophied hearts and normotensive hearts, respectively. Experimental animals were classified into the following five groups: (1) SHR without treatment (SHR-N), (2) SHR chronically treated with captopril (SHR-C), (3) SHR chronically treated with the angiotensin II receptor antagonist TCV-116 (SHR-A), (4) SHR chronically treated with hydralazine (SHR-H), and (5) WKY rats.
During the entire 6-week treatment period, SHR-C, SHR-H, and SHR-A received captopril (2 g/L), hydralazine (12 mg/kg per day) in drinking water, or TCV-116 (30 mg/kg per day) mixed with the chow, respectively. The doses of captopril and hydralazine were determined from previous reports.9 10 To examine the dose-dependent effect on both blood pressure and regression of LVH, in addition to SHR-A (receiving TCV-116 at 30 mg/kg per day), two additional SHR groups received antihypertensive treatment with TCV-116 at doses of 1 mg/kg per day (A1 group) and 10 mg/kg per day (A10 group). Moreover, another group of SHR received a 1-week treatment (from 12 to 13 weeks of age) with TCV-116 at a dose of 30 mg/kg per day to dissociate the antihypertensive effect from LVH regression; this short-term treatment group was classified as SHR-AS.
Measurement of Blood Pressure
At 12 (before treatment), 14, 16, and 18 weeks of age (during treatment), SHR blood pressure was measured at the same time of day by the tail-cuff method. WKY blood pressure was measured at 12 and 18 weeks of age, and that of SHR-AS was measured at 12 and 13 weeks of age.
Langendorff-Perfused Heart Studies
Animals 18 weeks old were weighed and anesthetized with diethyl ether. After thoracotomy, the hearts were quickly excised and placed in oxygenated Tyrode’s solution. Each heart was mounted on a Langendorff perfusion apparatus by cannulation of the aorta and retrogradely perfused with Tyrode’s solution from a reservoir at a constant pressure of 70 cm H2O in WKY rats and of 100 cm H2O in SHR-N because of differences in blood pressure. Since the blood pressures in the SHR-C, SHR-H, SHR-A, and SHR-AS treatment groups were all lowered to the normal (WKY) level, the perfusion pressure used in these groups was 70 cm H2O. The perfusion pressures used in the A1 and A10 groups were 100 and 85 cm H2O because the blood pressures in both groups were not sufficiently lowered to the normal level. In a part of the experiments, SHR-N hearts were perfused at 70 cm H2O and 130 cm H2O. Flow was measured by collecting the coronary efflux for 1 minute. Wet weight of the heart was measured after each experiment. The composition of Tyrode’s solution was (mmol/L) NaCl 129, KCl 4, MgCl2 0.5, NaH2PO4 1.8, CaCl2 2.7, NaHCO3 20, and glucose 5.5. The perfusate was equilibrated with 95% O2 and 5% CO2 (pH 7.30, 37°C).
An ECG was recorded with fine silver wire electrodes, one implanted in the right ventricle and the other fixed to the iron aortic cannula. The ECG was continuously monitored and recorded on a polygraph (model CM-616G, Nihon Kohden).
After a 30-minute equilibration period, regional ischemia was produced by ligation of the left anterior coronary artery; the subsequent study period was also 30 minutes. Spontaneous arrhythmias were recorded in 19 WKY rats, 19 SHR-N, 11 SHR-C, 11 SHR-H, 10 SHR-A, 9 A1, 10 A10, and 9 SHR-AS during sinus rhythm. Heart rate and arrhythmias were analyzed from the ECG recordings. Arrhythmias were defined as follows: Vf, rapid ventricular depolarizations with irregular and varying morphology that persisted for >5 seconds; VT, consecutive premature complexes lasting >10 seconds, whose morphology differed from that during sinus rhythm.
The risk area was measured in 11 WKY rats, 10 SHR-N, 8 SHR-C, 9 SHR-H, and 9 SHR-A. At the end of each experiment, Evans blue dye (Sigma Chemical Co) was added to the perfusate. After the removal of the atria and right ventricle, the left ventricle was cut transversely into four slices of approximately equal thickness. Each slice was photographed with magnification, and the perfused area and nonperfused area (risk area) were traced onto a transparent sheet and measured with computerized planimetry. The percentage of the risk area was then calculated.
Measurement of Action Potential
Conventional microelectrode techniques were used to record transmembrane action potentials in 10 WKY rats, 11 SHR-N, 10 SHR-C, 7 SHR-H, and 7 SHR-A. After anesthesia with diethyl ether, the hearts were quickly removed, and the papillary muscles of the left ventricle were carefully dissected. The preparation was transferred to a tissue chamber of 5-mL volume and superfused at a rate of 10 mL/min with a Krebs-Henseleit solution of the following composition (mmol/L): NaCl 119, KCl 4.8, CaCl2 2.5, MgSO4 1.2, KH2PO4 1.2, NaHCO3 24.9, and glucose 10.0. The solution was gassed with 95% O2 and 5% CO2 and kept at a temperature of 33±1.0°C. One end of the muscle was hooked to the lever arm, and the other end was pinned to the bottom of the tissue chamber. The muscle was maintained under a constant resting tension of 0.2 g. The preparations were stimulated at a rate of 0.5 Hz through platinum field electrodes. Stimuli were rectangular pulses of 1-millisecond duration at twice the diastolic threshold, delivered from an electronic stimulator (model SEN-6100, Nihon Kohden) through an isolation unit (model SS-302J, Nihon Kohden). Transmembrane potentials were recorded by using glass microelectrodes filled with 3 mol/L KCl (tip resistance, 10 to 30 MΩ). The microelectrode was coupled via a Ag/AgCl junction to a high-impedance-capacitance neutralizing amplifier (model MEZ8201, Nihon Kohden). An agar bridge containing 3 mol/L KCl was used as a reference electrode. An electronic differentiator whose output was linear from 50 to 800 V/s was used to measure the maximum rate of rise (V̇max) of action potentials. These amplified signals were displayed on an oscilloscope (model VC-9, Nihon Kohden), photographed on 35-mm film, and recorded on a chart recorder (model WR3101, Graphtec).
After an equilibration period of 90 to 120 minutes, control recordings of action potentials were made. Control measurements were obtained 30 minutes after stable recordings were achieved. The perfusate was then switched to a hypoxia/no-glucose solution (Krebs-Henseleit solution gassed with 95% N2 and 5% CO2 and containing no glucose). The Po2 of the hypoxia/no-glucose solution was 40 to 50 mm Hg compared with >500 mm Hg in the control solution. During superfusion with the hypoxia/no-glucose solution for 30 minutes, recordings of action potentials were made.
All data are expressed as mean±SEM. When multiple subgroups were present, the P value for comparisons was adjusted by the Bonferroni method. Differences between the mean values of multiple subgroups were evaluated by ANOVA, and intergroup comparisons were performed by the adjusted t test within ANOVA (Bonferroni method). The χ2 test was used to compare the difference in the incidence of arrhythmias. Significance was established at P<.05.
Antihypertensive Effects and Regression of LVH
Fig 1⇓ shows changes in systolic blood pressures (SBP) over 6 weeks in SHR with or without antihypertensive treatment. SBP in WKY rats was 102±3 mm Hg at 12 weeks of age and 114±4 mm Hg at 18 weeks of age. SBP in SHR-N 12 weeks old was 186±6 mm Hg and was higher than that in WKY rats (P<.005 versus WKY rats). SBP in SHR-N increased more thereafter and reached 205±4 mm Hg at 18 weeks of age. SBP values for SHR-C, SHR-A, and SHR-H were 186±4, 194±4, and 183±6 mm Hg at the age of 12 weeks (before drugs were given). SBP in each treated group was equally lowered 2 weeks after treatment and showed no differences between subgroups before and during treatment. At 18 weeks of age, SBP was 108±4 mm Hg in SHR-C, 117±3 mm Hg in SHR-A, and 111±3 mm Hg in SHR-H and did not significantly differ from 114±4 mm Hg in age-matched WKY rats (Fig 1⇓).
Table 1⇓ shows left ventricular weight (LVW), body weight (BW), and the ratio of LVW to BW (LVW/BW) in each group at 18 weeks of age. LVW and LVW/BW values for SHR-N and SHR-H were significantly higher than those for WKY rats (P<.005 versus WKY rats). These results indicate that hearts from SHR-N and SHR-H showed LVH and that treatment with hydralazine failed to cause LVH to regress sufficiently despite equally lowered blood pressure. LVW and LVW/BW values for SHR-C and SHR-A were lower than those for SHR-N (P<.005 versus SHR-N). Thus, SHR-C and SHR-A showed regression of LVH.
Ischemia-Induced Arrhythmias in Langendorff-Perfused Hearts
Ischemia-induced arrhythmias during the first 30 minutes after left coronary artery ligation are illustrated in Fig 2⇓, and the incidence of VT/Vf is summarized in Fig 3⇓. The number of occurrences of VT and Vf per 10 rats is also summarized in Table 2⇓. Most lethal arrhythmias in each group occurred 10 to 15 minutes after left coronary artery occlusion. Although premature complexes, bigeminy, or nonsustained VT sometimes occurred in WKY hearts, VT occurred in only 1 of 19 WKY hearts, and Vf never occurred. VT/Vf occurred frequently (63%) in SHR-N hearts with LVH. For SHR-N, the ratio of VT per 10 hearts was 5.3, and that of Vf per 10 hearts was 3.7. Since the performance of non–blood-perfused hearts may be highly dependent on coronary perfusion pressure, ischemia-induced arrhythmias in the SHR-N hearts were examined at two different coronary perfusion pressures of 70 cm H2O and 130 cm H2O in addition to coronary perfusion pressure of 100 cm H2O. VT/Vf occurred in 4 of 5 SHR-N hearts (80%) at a perfusion pressure of 130 cm H2O and in 4 of 4 SHR-N hearts (100%) at a perfusion pressure of 70 cm H2O. These results indicate that the SHR-N hearts are susceptible to ischemia-induced VT/Vf at various perfusion pressures in this non–blood-perfused preparation. In SHR-C and SHR-A hearts, which showed regression of LVH, arrhythmias (such as premature complexes, bigeminy, or nonsustained VT) sometimes occurred as in WKY hearts, but lethal arrhythmias such as VT/Vf rarely occurred. In SHR-H hearts, which did not show regression of LVH, the occurrence of lethal arrhythmias could not be prevented. The incidence of VT/Vf was high (45%) in SHR-H hearts (Fig 3⇓, Table 2⇓).
Heart rate and coronary efflux in each group showed no differences before coronary occlusion (Table 3⇓). Although heart rate and coronary efflux decreased after coronary occlusion, no differences in their extent were seen in the SHR groups. There was also no significant difference in risk area among groups, as shown in Table 3⇓.
Dose-Dependent Effect of Angiotensin II Receptor Antagonist
Since the antihypertensive treatment with captopril (SHR-C) and TCV-116 (SHR-A) equally caused LVH to regress and reduced the incidence of ischemia-induced VT/Vf, it was suggested that the common pathway of these agents, ie, blocking of the effect of angiotensin II (Ang II), may be very important. In addition, results from Table 1⇑ and Fig 3⇑ indicate that enhanced arrhythmogenesis during acute ischemia in SHR-N might be prevented not by lowering blood pressure but by regression of LVH. In other words, regression of LVH appears to be more important than normalization of blood pressure. To test this hypothesis, we examined the effect of lower doses of TCV-116 (A1 and A10, 1 and 10 mg/kg per day, respectively) and compared that with results from SHR-N and SHR-A (TCV-116, 30 mg/kg per day). Furthermore, SHR were treated for 1 week (from 12 to 13 weeks of age) with TCV-116 at a dose of 30 mg/kg per day (SHR-AS), which would be expected to cause reduction in blood pressure and little regression of LVH.
Fig 4⇓ shows changes in SBP in SHR treated with TCV-116 at doses of 1, 10, and 30 mg/kg per day (A1, A10, and SHR-A, respectively) and in SHR without treatment (SHR-N). During treatment for 6 weeks, SBP in A1 was only a little lower than that in SHR-N. SBP in A10 was significantly lower than that in SHR-N during the course of treatment, although the extent of decrease in A10 was not as great as in SHR-A. SBP in SHR-AS was 194±5 mm Hg at the age of 12 weeks (before the drug treatment) and was reduced to 119±5 mm Hg after 1 week of treatment. This value was almost the same as the SBP in SHR-A at the age of 14 to 18 weeks.
LVW/BW in each group at 18 weeks of age and in SHR-AS at 13 weeks of age is shown in Fig 5A⇓. As shown in Fig 5A⇓, TCV-116 caused LVH to regress in a dose-dependent manner. The incidence of VT/Vf (Fig 5B⇓) and the occurrence ratios per 10 hearts for VT/Vf (Table 2⇑) during the first 30 minutes after left coronary artery ligation in SHR treated with TCV-116 were parallel with the degree of LVH regression. Treatment with TCV-116 reduced the incidence of VT/Vf in a dose-dependent manner. However, in SHR-AS with short-term treatment, little regression of LVH and a high incidence of VT/Vf were observed. LVW/BW in SHR-AS was 3.04±0.05 mg/g (n=9) and was not significantly different from 3.06±0.08 mg/g in SHR without treatment at 13 weeks of age (n=6).
Again, there were no significant differences in heart rate before coronary occlusion and coronary efflux before and after coronary occlusion among the subgroups.
Action Potential Duration in Normal and Ischemia-Simulating Conditions
Original chart recordings of action potential and action potential duration (APD) at −50 mV (APD−50 mV) during 30 minutes of superfusion with hypoxia/no-glucose solution in the left ventricular papillary muscle of SHR-N are shown in Fig 6A⇓. Resting membrane potential (RMP), action potential amplitude (APA), and APD began to decrease within a few minutes after exposure to the hypoxia/no-glucose solution.
The actual recordings of the action potentials recorded before and 30 minutes after exposure to the hypoxia/no-glucose solution are shown in Fig 6B⇑. Table 4⇓ summarizes the action potential characteristics before and after exposure to the hypoxia/no-glucose solution. In the control condition, APDs in SHR-N were significantly longer than those in WKY rats, although there were no significant changes in other action potential parameters among subgroups. APDs in SHR-H, which failed to show regression of LVH, were as long as those in SHR-N. However, APDs in the LVH regression groups (SHR-C and SHR-A) showed no differences from those in the WKY group.
After exposure to the hypoxia/no-glucose solution, APDs in each group shortened almost to the same level, and there were no significant differences in absolute values of APDs at 20% and 75% repolarization (APD20 and APD75, respectively) among the subgroups (Table 4⇑). In other words, the extent of APD shortening during superfusion with the hypoxia/no-glucose solution in the LVH groups was significantly greater than that in the WKY group, as shown in Fig 7⇓. Shortening for both APD20 and APD75 was greater in the LVH groups than in the WKY group during superfusion of the hypoxia/no-glucose solution from 5 to 30 minutes, whereas shortening in the regression groups was almost the same as that in the WKY group during superfusion of the hypoxia/no-glucose solution.
There were no differences in changes of other action potential parameters including RMP, APA, and V̇max during superfusion of the hypoxia/no-glucose solution among subgroups (Table 4⇑).
The present study in the rat heart model demonstrates the following: (1) Hypertrophied hearts show a greater susceptibility to VT/Vf during acute myocardial ischemia because of greater APD dispersion between the normal and ischemic zones. (2) The reduction of electrical inhomogeneity in regressed hypertrophied hearts may prevent lethal ventricular tachyarrhythmias. (3) Blockade of the effect of Ang II plays an important role not only in the regression of LVH but also in the prevention of SCD. We should extrapolate these findings to the clinical setting with great caution, because there are the species differences in cardiac electrophysiological properties. However, our data lead us to suggest that regression of LVH can reverse enhanced arrhythmogenesis in LVH during acute myocardial ischemia and that chronic inhibition of the effect of Ang II in patients with LVH may prevent SCD caused by ischemia-induced lethal tachyarrhythmias.
The susceptibility to ischemia-induced lethal ventricular tachyarrhythmias in SHR with LVH is consistent with the previous studies of hypertrophied rat hearts induced by pressure overload.5 These experimental studies indicate that in hypertensive LVH the risk of SCD caused by VT/Vf during the acute phase of myocardial infarction is very high. The findings are consistent with epidemiological data1 2 showing that the incidence of SCD in hypertensive patients with LVH is significantly higher than in those without LVH.
Chronic treatment with captopril and the Ang II receptor antagonist TCV-116 caused LVH to regress in SHR and prevented ischemia-induced VT/Vf, although hydralazine failed to reduce the incidence of VT/Vf because LVH remained, despite equal reduction of blood pressure. These results support the idea that regression of LVH is very important in preventing lethal tachyarrhythmias during the acute phase of myocardial infarction and that it is necessary to use drugs with a highly potent effect on regression of LVH in treating hypertensive patients with LVH.
Despite the equally lowered blood pressure, there was a difference in regressive effects achieved by captopril, TCV-116, and hydralazine. This means that in addition to blood pressure, other important factors may be involved in cardiac hypertrophy11 and its regression. It was recently shown that cardiac hypertrophy of aortic-constricted rats might be related to increased activity of the renin-angiotensin system and that the direct cardiac actions of Ang II included acceleration of protein synthesis that resulted in cardiac hypertrophy.12 13 These previous reports strongly suggest that Ang II plays an important role in cardiac hypertrophy. In addition, there is increasing evidence indicating the existence of the tissue (local) renin-angiotensin system in several organs, including the heart,14 15 and molecular biological measurements suggest that Ang II, particularly mediated by the type-1 Ang II (AT1) receptor, causes hypertrophy of cardiac myocytes.16 It was reported that due to chronic aortic banding, LVH rats showed regression of LVH with a nonantihypertensive low dose of the ACE inhibitor ramipril but did not show any significant decrease in left ventricular mass with the calcium antagonist nifedipine and the arterial vasodilator hydralazine, despite effective reduction in blood pressure.17 Dzau18 also suggests that ACE inhibitors have a potent effect on the decrease in left ventricular mass in hypertensive LVH. In the present study, to evaluate the effect of Ang II blockade on regression of LVH and prevention of SCD, we used captopril, an ACE inhibitor, and TCV-116, an AT1 receptor–specific antagonist. These two drugs effectively caused LVH to regress and reduced the incidence of VT/Vf during acute ischemia. Moreover, low doses of TCV-116 (1 mg/kg per day) inhibited the progression of LVH with only a slight antihypertensive effect. On the other hand, treatment with hydralazine failed to cause LVH to regress sufficiently, possibly because of augmented sympathetic nerve activity and sodium retention.19 Thus, blocking the effect of Ang II may play a beneficial role not only in the regression of LVH but also in the prevention of SCD.
The main electrophysiological feature of experimental LVH induced by aortic banding or renal hypertension in rats is prolongation of APD at the plateau level.5 20 Ventricular myocytes from felines with right ventricular hypertrophy induced by pulmonary artery binding showed that the time course of inactivation of the Ca2+ current was delayed and that the magnitude of the delayed rectifier K+ current was reduced with slower activation and enhanced deactivation.21 22 In feline left ventricular myocytes with hypertrophy induced by long-lasting pressure overload, the newly expressed T-type Ca2+ current23 and the long-lasting opening of the L-type Ca2+ channels24 have been described. These reports explain the prolongation of APD in felines with ventricular hypertrophy. However, we cannot simply extrapolate these ionic mechanisms to APD prolongation in hypertrophied rat hearts because there are some differences of the membrane current system between rat and feline heart cells. The transient outward current (Ito) plays an important role in the repolarization of rat ventricular cells.25 In rats with LVH, diminished Ito due to reduced functional channel density, which may result in the prolongation of APD, has been reported.26 27 However, it has also been suggested that the functional expression of Ito is enhanced in hypertrophied feline right ventricular myocytes.28 The L-type Ca2+ current density in hypertrophied rat left ventricular myocytes has been reported to be unchanged29 or increased.30 Further studies are needed to determine electrophysiological alterations in the hypertrophied rat heart.
Mechanical overload and humoral factors associated with cardiac hypertrophy were reported to promote protein synthesis not only quantitatively but also qualitatively, as an adaptive response.31 Rat cardiac muscles in the neonatal phase, when the thickness of the ventricular wall increases prominently, showed prolongation of APD.32 Thus, the ion channels or their modulatory mechanisms may be changed in cardiac myocytes in both hypertrophied hearts and neonatal hearts as a kind of adaptive response.
Treatment with hydralazine did not cause LVH to regress sufficiently, and prolongation of APD remained. However, treatment with captopril or TCV-116 reversed LVH, and APD in these regression groups was not prolonged and did not differ from that in the WKY group. These results suggest that prolongation of APD was normalized by removal of both the mechanical overload and humoral factors, such as Ang II, and that a close relation exists between hypertrophied cardiac myocytes and prolongation of APD.
The mechanism of lethal ventricular tachyarrhythmias during the acute phase of myocardial infarction is considered to be reentry, although abnormal automaticity arising from depolarized Purkinje fibers may be included.33 34 In an inhomogeneous tissue affected by acute ischemia, in which the conduction velocity and duration of refractoriness greatly differ in various areas of myocardium, reentry can easily occur.35
In LVH groups such as SHR without treatment or those treated with hydralazine, APD was more prolonged than in WKY rats in the control condition and showed a greater shortening during superfusion of the hypoxia/no-glucose solution. These results indicate greater APD dispersion between the normal and ischemic zones in the hypertrophied myocardium. Greater APD dispersion may reflect enhanced dispersion of refractoriness and then cause an augmented injury current not only between the normal and ischemic zones but also among myocardial cells within the risk area because of the wave-front phenomenon.36 The previous report comparing SHR and WKY rats described that the action potential changes and the alterations of conduction and refractoriness were more prominent in hypertrophied than in normal endocardial tissue during simulated ischemia.37 These results also agree with our data showing the enhanced shortening of APD during ischemia in hypertrophied myocardium. Therefore, reentrant arrhythmias might occur easily in hypertrophied hearts.
In regression groups such as SHR chronically treated with captopril or TCV-116, APD values varied little from those found in the WKY group and shortened slightly during superfusion with the hypoxia/no-glucose solution. At the same time, the incidence of VT/Vf was significantly reduced. It is suggested that the electrical inhomogeneity and enhanced arrhythmogenesis in LVH was reversed by the regression of LVH. The reduction of electrical inhomogeneity during acute ischemia in regressed LVH may lessen the likelihood of SCD resulting from ischemia-induced lethal arrhythmias.
The enhanced shortening of APD during ischemia in hypertrophied hearts may be attributed to greater changes of the membrane currents responsible for ischemia-induced APD shortening. Experiments in hypertrophied feline left ventricular myocytes using the patch-clamp method revealed that the open-state probability of the ATP-sensitive K+ channel was significantly higher at various pH levels and depleted ATP conditions38 39 and that the magnitude of the Ca2+ current was significantly reduced during metabolic inhibition induced by CN+.40 Therefore, depletion of intracellular ATP in hypertrophied myocytes might induce greater activation of ATP-sensitive K+ current at any given level of ATP and greater inhibition of the Ca2+ current. These results may partly explain the enhanced shortening of APD during ischemia in hypertrophied cardiac cells. However, the ischemia-induced changes in other membrane currents in hypertrophied myocytes still remain unclarified. Further study to determine the ischemia-induced changes in membrane currents in hypertrophied hearts may help to prevent ischemia-induced lethal arrhythmias.
- Received September 20, 1993.
- Accepted February 13, 1995.
- © 1995 American Heart Association, Inc.
Kannel WB. Prevalence and natural history of electrocardiographic left ventricular hypertrophy. Am J Med. 1983;75(suppl 3A):4-11.
Koyanagi S, Eastham C, Marcus ML. Effects of chronic hypertension and left ventricular hypertrophy on the incidence of sudden cardiac death after coronary artery occlusion in conscious dogs. Circulation. 1982;65:1192-1197.
Messerli FH, Oren S, Grossman E. Left ventricular hypertrophy and antihypertensive therapy. Drugs. 1988;35(suppl 5):27-33.
Massie BM, Tubau JF, Szlachcic J, O’Kelly BF. Hypertensive heart disease: the critical role of left ventricular hypertrophy. J Cardiovasc Pharmacol. 1989;13(suppl 1):S18-S24.
Sen S, Tarazi RC, Bumps FM. Effect of converting enzyme inhibitor (SQ14,225) on myocardial hypertrophy in spontaneously hypertensive rats. Hypertension. 1980;2:169-176.
Pfeffer JM, Pfeffer MA, Mirsky I, Braunwald E. Regression of left ventricular hypertrophy and prevention of left ventricular dysfunction by captopril in the spontaneously hypertensive rat. Proc Natl Acad Sci U S A. 1982;79:3310-3314.
Sen S, Tarazi RC, Khairallah PA, Bumpus FM. Cardiac hypertrophy in spontaneously hypertensive rats. Circ Res. 1974;35:775-781.
Morgan HE, Baker KM. Cardiac hypertrophy: mechanical, neural and endocrine dependence. Circulation. 1991;83:13-25.
Baker KM, Chernin MI, Wixson SK, Aceto JF. Renin-angiotensin system involvement in pressure-overload cardiac hypertrophy in rats. Am J Physiol. 1990;259:H324-H332.
Aceto JF, Baker KM. [Sar1] angiotensin II receptor-mediated stimulation of protein synthesis in chick heart cells. Am J Physiol. 1990;258:H806-H813.
Dzau VJ. Circulating versus local renin-angiotensin system in cardiovascular homeostasis. Circulation. 1988;77(suppl I):I-4-I-13.
Lee MA, Boehm M, Paul M, Ganten D. Tissue renin-angiotensin systems: their role in cardiovascular disease. Circulation. 1993;87(suppl IV):IV-7-IV-13.
Sadoshima J, Izumo S. Molecular characterization of angiotensin II–induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts: critical role of the AT1 receptor subtype. Circ Res. 1993;73:413-423.
Linz W, Schoelkens BA, Garten D. Converting enzyme inhibition specifically prevents the development and induces regression of cardiac hypertrophy in rats. Clin Exp Hypertens. 1989;A11:1325-1350.
Dzau VJ. Angiotensin converting enzyme inhibitors and the cardiovascular system. J Hypertens. 1992;10(suppl 3):S3-S10.
Aronson RS. Characteristics of action potentials of hypertrophied myocardium from rats with renal hypertension. Circ Res. 1980;47:443-454.
Kleiman RB, Houser SR. Calcium currents in normal and hypertrophied isolated feline ventricular myocytes. Am J Physiol. 1988;255:H1434-H1442.
Kleiman RB, Houser SR. Outward currents in normal and hypertrophied feline ventricular myocytes. Am J Physiol. 1989;256:H1450-H1461.
Nuss HB, Houser SR. T-type Ca2+ current is expressed in hypertrophied adult feline left ventricular myocytes. Circ Res. 1993;73:777-782.
Kimura S, Bassett AL, Xi H, Tomita F, Myerburg RJ. Single Ca2+ channel properties in hypertrophied feline ventricular myocytes. Circulation. 1993;88(suppl I):I278. Abstract.
Josephson IR, Sanchez-Chapula J, Brown AM. Early outward current in rat single ventricular cells. Circ Res. 1984;54:157-162.
Tomita F, Bassett AL, Myerburg RJ, Kimura S. Diminished transient outward currents in rat hypertrophied ventricular myocytes. Circ Res. 1994;75:296-303.
Ten Eick RE, Zhang K, Harvey RD, Bassett AL. Enhanced functional expression of transient outward current in hypertrophied feline myocytes. Cardiovasc Drugs Ther. 1993;7(suppl 3):611-619.
Scamps F, Mayoux E, Charlemagne D, Vassort G. Calcium current in single cells isolated from normal and hypertrophied rat heart: effects of β-adrenergic stimulation. Circ Res. 1990;67:199-208.
Keung EC. Calcium current is increased in isolated adult myocytes from hypertrophied rat myocardium. Circ Res. 1989;64:753-763.
Couch JR, West TC, Hoff HE. Development of the action potential of the prenatal rat heart. Circ Res. 1969;24:19-31.
Wit AL, Bigger JT. Possible electrophysiological mechanisms for lethal arrhythmias accompanying myocardial ischemia and infarction. Circulation. 1975;51(suppl III):III-96-III-115.
Janse MJ, van Capelle FJL, Morsink H, Kleber AG, Wilms-Schopman F, Cardinal R, d’Alnoncourt CN, Durrer D. Flow of injury current and patterns of excitation during early ventricular arrhythmias in acute regional myocardial ischemia in isolated porcine and canine hearts: evidence for two different arrhythmogenic mechanisms. Circ Res. 1980;47:151-165.
Surawicz B. Ventricular fibrillation. J Am Coll Cardiol. 1985;5:43B-54B.
Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. The wavefront phenomenon of ischemic cell death, 1: myocardial infarct size vs duration of coronary occlusion in dogs. Circulation. 1977;56:786-794.
Belichard P, Pruneau D, Rouet R, Salzmann JL. Electrophysiological responses of hypertrophied rat myocardium to combined hypoxia, hyperkalemia, and acidosis. J Cardiovasc Pharmacol. 1991;17(suppl 2):S141-S145.
Cameron JS, Kimura S, Jackson-Burns DA, Smith DB, Bassett AL. ATP-sensitive K channels are altered in hypertrophied ventricular myocytes. Am J Physiol. 1988;255:H1254-H1258.
Kimura S, Bassett AL, Xi H, Tomita F, Myerburg RJ. Characteristics of ATP-sensitive K+ channels in hypertrophied cells: effect of pH. Circulation. 1992;86(suppl I):I-92. Abstract.
Furukawa T, Myerburg RJ, Furukawa N, Kimura S, Bassett AL. Metabolic inhibition of ICa,L and IK differs in feline left ventricular hypertrophy. Am J Physiol. 1994;266:H1121-H1131.