Cardiovascular Drugs and Therapy 1992;6:7-10 © Kluwer Academic Publishers, Boston. Printed in U.S.A.
Pharmacotherapy of Dilated Cardiomyopathy: Current Status and Future Directions Chuichi Kawai Department of Internal Medicine, Kyoto University Hospital, Kyoto, Japan
Summary. The current status and future directions of the pharmacotherapy of dilated cardiomyopathy are reviewed. The Japanese multicenter study on the effect of [5-blockers revealed significant improvement of NYHA functional classification, LV end-diastolic dimension, ejection fraction, and exercise tolerance time in patients with dilated cardiomyopathy. From our study using normal rabbits, metoproiol augmented adenylate cyclase activity without upregulation of the [5-adrenergic receptor number. Carteolol, a {5-adrenergic blocker with intrinsic sympathomimetic action, prevented the development of dilatation and hypertrophy of the heart in the chronic stage following murine encephalomyocarditis (EMC) viral myocarditis. Metoprolol exerted no such effect. Animal experiments indicated that immunosuppressive treatment for inflammatory myocarditis may aggravate the clinical course of the disease. However, immunosuppressive treatment in acute myocarditis should be reevaluated with the use of newly developed antiviral agents. A new synthetic immunoactive peptide FK 565, given before or simultaneously with viral inoculation, proved effective in inhibiting myocardial virus replication and myocardial damage in murine EMC viral myocarditis. Beneficial effects of captopril on survival rate and myocardial injury were demonstrated dose dependently in murine EMC viral myocarditis, even when the treatment was started around the peak of virus replication, namely, on day 4-14 after inoculation. Captopril may be promising for the treatment of acute myocarditis, and hopefully for prevention of the progression from myocarditis to dilated cardiomyopathy. Cardiovasc Drugs Ther 1992;6:7-10 Key Words. dilated cardiomyopathy, beta-adrenergic blockers, immunosuppressive drugs, antiviral agents, immunoactive peptide, captopril, murine viral myocarditis
Epidemiology of Dilated Cardiomyopathy in Japan Based on 1255 cases of cardiomyopathy collected from 17 institutions throughout Japan, a cumulative survival rate was calculated in 786 patients with hypertrophic and 469 patients with dilated cardiomyopathy. Five- and 10-year survival rates were 54% and 36% in dilated cardiomyopathy, respectively, while in hypertrophic cardiomyopathy, including obstructive and nonobstructive, they were approximately 92% and 80%, respectively.
It is obvious that the prognosis of dilated cardiomyopathy is very poor, and it is the patient with dilated cardiomyopathy who most needs effective treatment for dilated cardiomyopathy. The treatments for dilated cardiomyopathy that are currently available are summarized in Table 1. Some of the pharmacotherapies that are included in these treatments will be selected and discussed in this review.
Beta-Adrenergic Blockers in the Treatment of Dilated Cardiomyopathy: Mode of Action and Multicenter Study in Japan Waagstein et al [1] first reported in 1975 that ~-adrenergic blockers can provide beneficial effects on patients with congestive cardiomyopathy. They attributed the favorable effects of ~-adrenergic blockers in congestive cardiomyopathy to the blockage of the adrenergic ~1 receptors of the myocardium. ReCently, upregulation of ~-adrenergic receptors, allowing restoration of catecholamine responsiveness in the myocardium, has been claimed to be a beneficial effect of ~-adrenergic blocker treatment in dilated cardiomyopathy. In our laboratory, we continuously intravenously infused 8 mg/kg of metoprolol into normal rabbits for 14 days. The adenylate cyclase activity stimulated by isoproterenol, Gpp(NH)p, NaF, and forskolin was significantly higher in the metoprolol group than in the controls. There was no significant difference in Bmax in the rabbit heart. The Gs protein showed no significant changes in either number or activity between the two groups. We concluded that metoprolol augments adenylate cyclase activity without upregulation of ~-adrenergic receptor number in the normal rabbit heart. We are now trying to elucidate the mechanism of action of ~-adrenergic blockers
State-of-the-Art-Lecture, Fourth International Symposium on Cardiovascular Pharmacotherapy, Geneva, Switzerland, April 1991. Address for correspondence and reprint requests: Third Division, Department of Internal Medicine, Kyoto University Hospital, 54 Kawaracho Shogoin, Sakyoku, Kyoto 606, Japan.
8
Kawai
Table 1. Treat~r;entof dilatedcardio~Tyopathy • • • • • • • • • •
To remove cause, if present Rest and restriction of salt intake Diuretics, digitalis [3-adrenergicagonists (dopamine, dobutamine, denopamine, etc) Vasodilating agents Antiarrhytbmic agents, pacemaker Anticoagulants, antiplatelets [3-adrenergicblocking agents Immunosuppressive agents Cardiac transplantation
in the treatment of dilated cardiomyopathy using the cardiomyopathic hamster, Bio 53.58. A multicenter study on the effect of 13-blockers was carried out in Japan in 95 patients with dilated cardiomyopathy and suspected postmyocarditis collected from 23 institutions throughout the country. Metoprolol was given to more than 80% of patients given [3-blockers. There were 18 patients who improved from NYHA functional class III to class II, six patients from class II to class I, three patients from class III to class I, and one patient from class IV to class III. Only four patients worsened. The heart rate decreased from 83 to 70 beasts/min, and the LV enddiastolic dimension decreased from 66 to 62 mm. The E F increased from 27.8 to 35.6 The exercise tolerance time examined by the treadmill test also increased significantly from 7.6 to 9.5 min. The increase in the exercise tolerance was more prominent in class III patients than in class II patients.
Beta-Adrenergic Blocker with or without Intrinsic Sympathomimetic Action: Choice a n d Selection Recently, 13-adrenergic blockers with intrinsic sympathomimetic action (ISA), such as pindolol, have been reported to favor the upregulation of [3-adrenergic receptors in the failing heart [2]. Previous studies indicated no beneficial effects of I3-adrenergic blockers with ISA on dilated cardiomyopathy for short-term use. Carteolol, a I3-adrenergic blocker with ISA, has a vasodilating action that is mediated in part by 13adrenoceptor stimulation. We evaluated long-term therapy of carteolol in 16 patients with dilated cardiomyopathy. Although the number of patients is still limited, all patients who received carteolol either improved or were unchanged when evaluated in terms of NYHA functional class after 3-month treatment. Pulse rate decreased significantly, cardiothoracic ratio tended to be decreased, and ejection fraction increased significantly.
In order to assess the possible superiority of carteolol to metoprolol in the treatment of dilated cardiomyopathy, we gave oral daily doses of 1 mg/kg and 10 mg/kg of carteolol and 30 mg/kg of metoprolol, starting on day 14 after infection, to DBA/2 mice inoculated with the encephalomyocarditis (EMC) virus. Such mice are known to develop pathologic changes similar to dilated cardiomyopathy in humans approximately 3 months after inoculation. The administration of carteolol or metoprolol was continued until day 104 after infection, when the mice were sacrificed. The heart weight and heart weight/body weight (HW/ BW) ratio of mice given 1 and 10 mg/kg/day of carteolol were significantly lower than those of the infected control group. The HW of mice given 10 mg/kg/day of carteolol and the HW/BW ratio of mice given 1 and 10 mg/kg/day were also significantly lower than those of mice given metoprolol. On the other hand, the HW and HW/BW ratio of mice given metoprolol showed no significant changes from the infected control group. There were no significant changes in the body weight among these four groups. Dilatation and hypertrophy of the heart were less severe in mice given 10 mg/kg/day of carteolol (center, Figure 1) than in mice of the infected control group (left, Figure 1) and in mice given 30 mg/kg/day of metoprolol (right, Figure 1). We conclude from our murine study that carteolol prevents the development of myocardial lesions similar to dilated cardiomyopathy in the chronic stage following myocarditis [3]. 131selective blocking agents, such as metoprolol, exert no such effect.
Immunosuppressive Drugs and Antiviral Agents in the Treatment o f Murine Viral Myocarditis Our group has aimed, clinically as well as experimentally, to prove the direct link between acute myocarditis and dilated cardiomyopathy, with the hope of achieving benefits in the treatment of myocarditis, resulting in the prevention of progress to dilated cardiomyopathy. Since our study demonstrated the presence of a crucial role for immune mechanisms in the pathogenesis of viral myocarditis, we investigated the effect of some of the immunosuppressive agents on our murine viral myocarditis model. The effect of prednisolone on viral myocarditis was studied in BALB/c mice, 4-5 weeks old, inoculated with EMC virus (0.1 ml of suspension containing 102.5 TCD 50, i.p.). There were two types of experiments: In experimerit 1, prednisolone was given intramuscularly, 10 mg/kg once a day, on days 4-13; and in experiment 2, on days 8-17. The control mice in each experiment were given intramuscular injections of 0.1 ml of distilled water. Each group in experiment 1 comprised 20 mice.
Pharmacotherapy of Dilated Cardiomyopathy
9
Fig. 1. Effect of carteolol and metoprolol o~ the heart of DBA/2 mice inoculated with EMC virus. Left: infected control mouse; center: mouse given 10 mg/kg/day of carteolol; ~ght: mouse given 30 mg/kg/day of metoprolol.
The survival rate of the prednisolone group was lower (p < 0.05) than that of the control group on days 21-23. Why did this happen? Viral titers in the myocardium were maximal on day 4 in the control group. In the prednisolone group in experiment 1, viral titers were almost identical to those of the control group on day 8, but remained elevated on day 10 (p < 0.01), at which time only 1 of 5 control mice had a demonstrable but very low viral titer. Viruses were not isolated on day 14 in either group, both in experiment 1 and in experiment 2. In the control group, almost no neutralizing antibodies were detected on day 4. The average neutralizing antibody titers were elevated on days 8 and 10, and reached maximum levels on day 14. On the other hand, the average titers in the prednisolone group in experiment 1 were lower than those of the control group on days 8 and 10 (p < 0.01 for each). However, they increased to the same level as those of the control group on day 14. In experiment 2, where prednisolone was started after day 8 when the neutralizing antibody titers were already elevated, the average neutralizing antibody titers in the prednisolone group were elevated to the same level as the control group on day 14. As a result, the survival rate of the prednisolone group in experiment 2 showed no significant difference from that of the control group throughout the experiment until day 27 [4]. Similar results were obtained with cyclosporine. These animal experiments indicated that the use of steroids or other immunosuppressive agents in the treatment of viral myocarditis was associated with greater mortality if administered early in the illness, when neutralizing antibody titers are still low. AIthough the extrapolation of the results from animal studies to humans should be made with caution, one should be fully aware of the fact that immunosuppressive treatment for inflammatory myocarditis due to viral infection may aggravate the clinical course of the disease [5].
Currently, antiviral agents have become available for clinical use. It has been demonstrated by our group that the nucleoside analogue ribavirin and recombinant interferon effectively inhibit myocardial virus replication and reduce the inflammatory response and myocardial damage in EMC virus murine myocarditis. Recently, we found a synergistic effect from the combined use of ribavirin and a-interferon on the inhibition of myocardial viral replication. When 1000 U/g of a-interferon and O. 1 mg/g of ribavirin, each dose having no suppressive effect on the viral replication in a single use, were given in the combined use, they significantly suppressed the virus titer in the myocardium. With the use of these antiviral agents, immunosuppressive treatment in acute myocarditis should be reevaluated, as it may become more promising and hopefully be able to prevent the development of dilated cardiomyopathy.
Immunoactive
Peptide in the
Treatment of Murine Myocarditis
Viral
FK565 is a new synthetic immunoactive peptide composed of hepatanoic acid and three amino acids. Recent studies demonstrated that FK565 mainly activates macrophages and produces interleukin 1 (IL-1), thus enhancing the host defense ability of mice. We administered FK565 to 4-week-old male BALB/c mice inoculated intraperitoneally with EMC virus. The survival rate on day 14 was 80% in mice treated intraperitoneally with 0.01 mg/kg/day of FK565, 70% in mice treated with 1 mg/kg/day, both starting 1 day prior to infection, and 60% in mice treated with 1 mg/kg/day starting on the same day as virus inoculation. The survival rate was only 30% in mice treated with 1 mg/kg/day of FK565 1 day after infection and 20% in the control infection group treated with phosphate-buffered saline solution. Initi-
10
Kawai
ation of treatment with FK565 either before or on the same day of virus inoculation improved the survival rate as compared with control group (p < 0.01) Administration of FK565 starting before or simultaneously with virus inoculation also proved effective in the inhibition of myocardial virus replication and reduced inflammatory responses and myocardial damage as compared with control mice.
Beneficial Effects o f Captopril in M u r i n e Viral Myocarditis Captopril has been proved to be effective for the treatment of congestive heart failure, mainly due to reduction of afterload and preload via its vasodilating effect [6]. It has also been reported that captopril may alleviate reperfusion-induced myocardial dysfunction through its free-radical scavenger action, which is probably related to the presence of a sulfhydryl moiety [7]. We gave captopril orally in daily doses of 10, 30, and 100 mg/kg to 4-week-old BALB/c mice inoculated with EMC virus starting on days 4-14 after infection. The survival rate of infected mice treated with captopril improved dose dependently on days 12-14; mice treated with 100 mg/kg of captopril showed a significantly higher survival rate than those in the placebo group. Likewise, histologic changes were less prominent in the treated groups in a dose-dependent manner. Thus, captopril improved virus-induced myocardial injury and congestive heart failure in mice in a dose-dependent manner. More important to note is that captopril had bene-
ficial effects, even when the treatment was started around the peak of virus replication.
Acknowledgments This work was supported in part by a research grant from the Ministry of Health and Welfare, a grant-in-aid for General Scientific Research from the Ministry of Education, Scienceand Culture, Japan, and the Kanazawa Research Fund.
References
1. Waagstein F, Hjahmarson A, Vernauskas E, Wallentin I. Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy. Br Heart J 1975;37:1022-1036 2. Golf S, Hansson V. Effects of beta blocking agents on the density of beta adrenoceptors and adenylate cyclase response in human myocardium: Intrinsic sympathomimetic activity favours receptor upregulation. Cardiovasc Res 1986;20: 637-644. 3. Tominaga M, Matsumori A, Okada I, et al. ~-blocker treatment of dilated cardiomyopathy. Beneficial effect of carteolol in mice. Circulation 1991;83:2021-2028. 4. Tomioka N, Kishimoto C, Matsumori A, Kawai C. Effects of prednisolone on acute viral myocarditis in mice. J Am Coll Cardiol 1986;7:868-872. 5. Kawai C, Takatsu T. Clinical and experimental studies on cardiomyopathy. N Eugl J Med 1975;293:592-597. 6. Suzuki H, Matsumori A. Myocardial injury due to viral myocarditis improved by captopril in mice (abstract). Circulation 1990;82(Suppl III):674. 7. Westlin W, Mullane K. Does captopril attenuate reperfusion-induced myocardial dysfunction by scavenging free radicals? Circulation 1988;77(Suppl I):30-39.
Pharmacotherapy of Dilated Cardiomyopathy: Current Status and Future Directions Chuichi Kawai Department of Internal Medicine, Kyoto University Hospital, Kyoto, Japan
Summary. The current status and future directions of the pharmacotherapy of dilated cardiomyopathy are reviewed. The Japanese multicenter study on the effect of [5-blockers revealed significant improvement of NYHA functional classification, LV end-diastolic dimension, ejection fraction, and exercise tolerance time in patients with dilated cardiomyopathy. From our study using normal rabbits, metoproiol augmented adenylate cyclase activity without upregulation of the [5-adrenergic receptor number. Carteolol, a {5-adrenergic blocker with intrinsic sympathomimetic action, prevented the development of dilatation and hypertrophy of the heart in the chronic stage following murine encephalomyocarditis (EMC) viral myocarditis. Metoprolol exerted no such effect. Animal experiments indicated that immunosuppressive treatment for inflammatory myocarditis may aggravate the clinical course of the disease. However, immunosuppressive treatment in acute myocarditis should be reevaluated with the use of newly developed antiviral agents. A new synthetic immunoactive peptide FK 565, given before or simultaneously with viral inoculation, proved effective in inhibiting myocardial virus replication and myocardial damage in murine EMC viral myocarditis. Beneficial effects of captopril on survival rate and myocardial injury were demonstrated dose dependently in murine EMC viral myocarditis, even when the treatment was started around the peak of virus replication, namely, on day 4-14 after inoculation. Captopril may be promising for the treatment of acute myocarditis, and hopefully for prevention of the progression from myocarditis to dilated cardiomyopathy. Cardiovasc Drugs Ther 1992;6:7-10 Key Words. dilated cardiomyopathy, beta-adrenergic blockers, immunosuppressive drugs, antiviral agents, immunoactive peptide, captopril, murine viral myocarditis
Epidemiology of Dilated Cardiomyopathy in Japan Based on 1255 cases of cardiomyopathy collected from 17 institutions throughout Japan, a cumulative survival rate was calculated in 786 patients with hypertrophic and 469 patients with dilated cardiomyopathy. Five- and 10-year survival rates were 54% and 36% in dilated cardiomyopathy, respectively, while in hypertrophic cardiomyopathy, including obstructive and nonobstructive, they were approximately 92% and 80%, respectively.
It is obvious that the prognosis of dilated cardiomyopathy is very poor, and it is the patient with dilated cardiomyopathy who most needs effective treatment for dilated cardiomyopathy. The treatments for dilated cardiomyopathy that are currently available are summarized in Table 1. Some of the pharmacotherapies that are included in these treatments will be selected and discussed in this review.
Beta-Adrenergic Blockers in the Treatment of Dilated Cardiomyopathy: Mode of Action and Multicenter Study in Japan Waagstein et al [1] first reported in 1975 that ~-adrenergic blockers can provide beneficial effects on patients with congestive cardiomyopathy. They attributed the favorable effects of ~-adrenergic blockers in congestive cardiomyopathy to the blockage of the adrenergic ~1 receptors of the myocardium. ReCently, upregulation of ~-adrenergic receptors, allowing restoration of catecholamine responsiveness in the myocardium, has been claimed to be a beneficial effect of ~-adrenergic blocker treatment in dilated cardiomyopathy. In our laboratory, we continuously intravenously infused 8 mg/kg of metoprolol into normal rabbits for 14 days. The adenylate cyclase activity stimulated by isoproterenol, Gpp(NH)p, NaF, and forskolin was significantly higher in the metoprolol group than in the controls. There was no significant difference in Bmax in the rabbit heart. The Gs protein showed no significant changes in either number or activity between the two groups. We concluded that metoprolol augments adenylate cyclase activity without upregulation of ~-adrenergic receptor number in the normal rabbit heart. We are now trying to elucidate the mechanism of action of ~-adrenergic blockers
State-of-the-Art-Lecture, Fourth International Symposium on Cardiovascular Pharmacotherapy, Geneva, Switzerland, April 1991. Address for correspondence and reprint requests: Third Division, Department of Internal Medicine, Kyoto University Hospital, 54 Kawaracho Shogoin, Sakyoku, Kyoto 606, Japan.
8
Kawai
Table 1. Treat~r;entof dilatedcardio~Tyopathy • • • • • • • • • •
To remove cause, if present Rest and restriction of salt intake Diuretics, digitalis [3-adrenergicagonists (dopamine, dobutamine, denopamine, etc) Vasodilating agents Antiarrhytbmic agents, pacemaker Anticoagulants, antiplatelets [3-adrenergicblocking agents Immunosuppressive agents Cardiac transplantation
in the treatment of dilated cardiomyopathy using the cardiomyopathic hamster, Bio 53.58. A multicenter study on the effect of 13-blockers was carried out in Japan in 95 patients with dilated cardiomyopathy and suspected postmyocarditis collected from 23 institutions throughout the country. Metoprolol was given to more than 80% of patients given [3-blockers. There were 18 patients who improved from NYHA functional class III to class II, six patients from class II to class I, three patients from class III to class I, and one patient from class IV to class III. Only four patients worsened. The heart rate decreased from 83 to 70 beasts/min, and the LV enddiastolic dimension decreased from 66 to 62 mm. The E F increased from 27.8 to 35.6 The exercise tolerance time examined by the treadmill test also increased significantly from 7.6 to 9.5 min. The increase in the exercise tolerance was more prominent in class III patients than in class II patients.
Beta-Adrenergic Blocker with or without Intrinsic Sympathomimetic Action: Choice a n d Selection Recently, 13-adrenergic blockers with intrinsic sympathomimetic action (ISA), such as pindolol, have been reported to favor the upregulation of [3-adrenergic receptors in the failing heart [2]. Previous studies indicated no beneficial effects of I3-adrenergic blockers with ISA on dilated cardiomyopathy for short-term use. Carteolol, a I3-adrenergic blocker with ISA, has a vasodilating action that is mediated in part by 13adrenoceptor stimulation. We evaluated long-term therapy of carteolol in 16 patients with dilated cardiomyopathy. Although the number of patients is still limited, all patients who received carteolol either improved or were unchanged when evaluated in terms of NYHA functional class after 3-month treatment. Pulse rate decreased significantly, cardiothoracic ratio tended to be decreased, and ejection fraction increased significantly.
In order to assess the possible superiority of carteolol to metoprolol in the treatment of dilated cardiomyopathy, we gave oral daily doses of 1 mg/kg and 10 mg/kg of carteolol and 30 mg/kg of metoprolol, starting on day 14 after infection, to DBA/2 mice inoculated with the encephalomyocarditis (EMC) virus. Such mice are known to develop pathologic changes similar to dilated cardiomyopathy in humans approximately 3 months after inoculation. The administration of carteolol or metoprolol was continued until day 104 after infection, when the mice were sacrificed. The heart weight and heart weight/body weight (HW/ BW) ratio of mice given 1 and 10 mg/kg/day of carteolol were significantly lower than those of the infected control group. The HW of mice given 10 mg/kg/day of carteolol and the HW/BW ratio of mice given 1 and 10 mg/kg/day were also significantly lower than those of mice given metoprolol. On the other hand, the HW and HW/BW ratio of mice given metoprolol showed no significant changes from the infected control group. There were no significant changes in the body weight among these four groups. Dilatation and hypertrophy of the heart were less severe in mice given 10 mg/kg/day of carteolol (center, Figure 1) than in mice of the infected control group (left, Figure 1) and in mice given 30 mg/kg/day of metoprolol (right, Figure 1). We conclude from our murine study that carteolol prevents the development of myocardial lesions similar to dilated cardiomyopathy in the chronic stage following myocarditis [3]. 131selective blocking agents, such as metoprolol, exert no such effect.
Immunosuppressive Drugs and Antiviral Agents in the Treatment o f Murine Viral Myocarditis Our group has aimed, clinically as well as experimentally, to prove the direct link between acute myocarditis and dilated cardiomyopathy, with the hope of achieving benefits in the treatment of myocarditis, resulting in the prevention of progress to dilated cardiomyopathy. Since our study demonstrated the presence of a crucial role for immune mechanisms in the pathogenesis of viral myocarditis, we investigated the effect of some of the immunosuppressive agents on our murine viral myocarditis model. The effect of prednisolone on viral myocarditis was studied in BALB/c mice, 4-5 weeks old, inoculated with EMC virus (0.1 ml of suspension containing 102.5 TCD 50, i.p.). There were two types of experiments: In experimerit 1, prednisolone was given intramuscularly, 10 mg/kg once a day, on days 4-13; and in experiment 2, on days 8-17. The control mice in each experiment were given intramuscular injections of 0.1 ml of distilled water. Each group in experiment 1 comprised 20 mice.
Pharmacotherapy of Dilated Cardiomyopathy
9
Fig. 1. Effect of carteolol and metoprolol o~ the heart of DBA/2 mice inoculated with EMC virus. Left: infected control mouse; center: mouse given 10 mg/kg/day of carteolol; ~ght: mouse given 30 mg/kg/day of metoprolol.
The survival rate of the prednisolone group was lower (p < 0.05) than that of the control group on days 21-23. Why did this happen? Viral titers in the myocardium were maximal on day 4 in the control group. In the prednisolone group in experiment 1, viral titers were almost identical to those of the control group on day 8, but remained elevated on day 10 (p < 0.01), at which time only 1 of 5 control mice had a demonstrable but very low viral titer. Viruses were not isolated on day 14 in either group, both in experiment 1 and in experiment 2. In the control group, almost no neutralizing antibodies were detected on day 4. The average neutralizing antibody titers were elevated on days 8 and 10, and reached maximum levels on day 14. On the other hand, the average titers in the prednisolone group in experiment 1 were lower than those of the control group on days 8 and 10 (p < 0.01 for each). However, they increased to the same level as those of the control group on day 14. In experiment 2, where prednisolone was started after day 8 when the neutralizing antibody titers were already elevated, the average neutralizing antibody titers in the prednisolone group were elevated to the same level as the control group on day 14. As a result, the survival rate of the prednisolone group in experiment 2 showed no significant difference from that of the control group throughout the experiment until day 27 [4]. Similar results were obtained with cyclosporine. These animal experiments indicated that the use of steroids or other immunosuppressive agents in the treatment of viral myocarditis was associated with greater mortality if administered early in the illness, when neutralizing antibody titers are still low. AIthough the extrapolation of the results from animal studies to humans should be made with caution, one should be fully aware of the fact that immunosuppressive treatment for inflammatory myocarditis due to viral infection may aggravate the clinical course of the disease [5].
Currently, antiviral agents have become available for clinical use. It has been demonstrated by our group that the nucleoside analogue ribavirin and recombinant interferon effectively inhibit myocardial virus replication and reduce the inflammatory response and myocardial damage in EMC virus murine myocarditis. Recently, we found a synergistic effect from the combined use of ribavirin and a-interferon on the inhibition of myocardial viral replication. When 1000 U/g of a-interferon and O. 1 mg/g of ribavirin, each dose having no suppressive effect on the viral replication in a single use, were given in the combined use, they significantly suppressed the virus titer in the myocardium. With the use of these antiviral agents, immunosuppressive treatment in acute myocarditis should be reevaluated, as it may become more promising and hopefully be able to prevent the development of dilated cardiomyopathy.
Immunoactive
Peptide in the
Treatment of Murine Myocarditis
Viral
FK565 is a new synthetic immunoactive peptide composed of hepatanoic acid and three amino acids. Recent studies demonstrated that FK565 mainly activates macrophages and produces interleukin 1 (IL-1), thus enhancing the host defense ability of mice. We administered FK565 to 4-week-old male BALB/c mice inoculated intraperitoneally with EMC virus. The survival rate on day 14 was 80% in mice treated intraperitoneally with 0.01 mg/kg/day of FK565, 70% in mice treated with 1 mg/kg/day, both starting 1 day prior to infection, and 60% in mice treated with 1 mg/kg/day starting on the same day as virus inoculation. The survival rate was only 30% in mice treated with 1 mg/kg/day of FK565 1 day after infection and 20% in the control infection group treated with phosphate-buffered saline solution. Initi-
10
Kawai
ation of treatment with FK565 either before or on the same day of virus inoculation improved the survival rate as compared with control group (p < 0.01) Administration of FK565 starting before or simultaneously with virus inoculation also proved effective in the inhibition of myocardial virus replication and reduced inflammatory responses and myocardial damage as compared with control mice.
Beneficial Effects o f Captopril in M u r i n e Viral Myocarditis Captopril has been proved to be effective for the treatment of congestive heart failure, mainly due to reduction of afterload and preload via its vasodilating effect [6]. It has also been reported that captopril may alleviate reperfusion-induced myocardial dysfunction through its free-radical scavenger action, which is probably related to the presence of a sulfhydryl moiety [7]. We gave captopril orally in daily doses of 10, 30, and 100 mg/kg to 4-week-old BALB/c mice inoculated with EMC virus starting on days 4-14 after infection. The survival rate of infected mice treated with captopril improved dose dependently on days 12-14; mice treated with 100 mg/kg of captopril showed a significantly higher survival rate than those in the placebo group. Likewise, histologic changes were less prominent in the treated groups in a dose-dependent manner. Thus, captopril improved virus-induced myocardial injury and congestive heart failure in mice in a dose-dependent manner. More important to note is that captopril had bene-
ficial effects, even when the treatment was started around the peak of virus replication.
Acknowledgments This work was supported in part by a research grant from the Ministry of Health and Welfare, a grant-in-aid for General Scientific Research from the Ministry of Education, Scienceand Culture, Japan, and the Kanazawa Research Fund.
References
1. Waagstein F, Hjahmarson A, Vernauskas E, Wallentin I. Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy. Br Heart J 1975;37:1022-1036 2. Golf S, Hansson V. Effects of beta blocking agents on the density of beta adrenoceptors and adenylate cyclase response in human myocardium: Intrinsic sympathomimetic activity favours receptor upregulation. Cardiovasc Res 1986;20: 637-644. 3. Tominaga M, Matsumori A, Okada I, et al. ~-blocker treatment of dilated cardiomyopathy. Beneficial effect of carteolol in mice. Circulation 1991;83:2021-2028. 4. Tomioka N, Kishimoto C, Matsumori A, Kawai C. Effects of prednisolone on acute viral myocarditis in mice. J Am Coll Cardiol 1986;7:868-872. 5. Kawai C, Takatsu T. Clinical and experimental studies on cardiomyopathy. N Eugl J Med 1975;293:592-597. 6. Suzuki H, Matsumori A. Myocardial injury due to viral myocarditis improved by captopril in mice (abstract). Circulation 1990;82(Suppl III):674. 7. Westlin W, Mullane K. Does captopril attenuate reperfusion-induced myocardial dysfunction by scavenging free radicals? Circulation 1988;77(Suppl I):30-39.
