Mitral valve regurgitation (MR) secondary to myxomatous degeneration of mitral valve and chordae tendineae is the most common cardiac disease in dogs. Dogs suffering from MR account for approximately 75% of all dogs with congestive heart failure (CHF).[1, 2] MR increases the left atrial pressure (LAP), and this increase in LAP in turn causes dilatation of the left atrium and pulmonary edema. As a result, it leads to the clinical signs of cough, dyspnea, and even death. Therefore, reduction in LAP is an important factor in the treatment of dogs with CHF caused by MR.
Isosorbide dinitrate (ISDN) causes venous vasodilation, and leads to a reduction in preload and cardiac oxygen consumption.[3-6] Furthermore, ISDN causes a decrease in arterial pressure and reduction in afterload. In human medicine, ISDN is widely used for the treatment of ischemic heart disease, including angina pectoris. Moreover, ISDN is also used for congestive heart failure.[8-11] In veterinary medicine, on the other hand, the usage of ISDN for CHF secondary to MR is not yet established.
The sustained-release form of ISDN (sr-ISDN) maintains an effective serum concentration for more than 6 hours. Previous study has shown that the effective dose-response curve for sr-ISDN in anesthetized dogs with experimentally induced MR appeared to be between 2 and 8 mg/kg. However, no study has been conducted to evaluate the effects of oral administration of sr-ISDN on LAP in conscious dogs with MR. In addition, there is no report of the evaluation of the effects of ISDN on the autonomic nervous system. In this study, the effects of different dosages of sr-ISDN on LAP and its duration of action in dogs with experimentally induced MR were evaluated. Moreover, the effects of sr-ISDN on hemodynamics and the autonomic nervous system were evaluated by echocardiography and Holter monitoring.
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- Materials and Methods
As noted in the introduction, the goal of this study was to investigate the effects of sr-ISDN in dogs with MR. In this study, LAP did not decrease in the 2 mg/kg group. However, significant decrease was observed in the 5 and 10 mg/kg groups. Moreover, duration time of sr-ISDN was dose dependent. Peak E and E/Ea were decreased significantly in the 5 and 10 mg/kg groups. When comparing the different dosage groups, there was no significant difference in HR and HRV. Only in the 10 mg/kg group, SBP decreased significantly.
Previous studies reported that ISDN has beneficial acute hemodynamic effects in humans and dogs with MR because of their preload and afterload reducing properties. Nagasawa et al reported that there was a slight decrease in preload and afterload at 2 mg/kg sr-ISDN. However, in this study, there was no significant change in parameters in the 2 mg/kg group. Compared with the previous study, this study was performed in conscious dogs. This result indicates that 2 mg/kg sr-ISDN does not affect conscious dogs with experimentally induced MR. However, this result also may indicate that 2 mg/kg sr-ISDN assists the work of circulatory system under general anesthesia. In this study, LAP was significantly decreased by administration of 5 and 10 mg/kg sr-ISDN. Compared with our previous study, the effect of high-dose sr-ISDN on reducing the maximum values of LAP was nearly equal to that of diuretic. This result suggests that high dose of sr-ISDN has a significant effect on LAP. However, this result also suggests that high dose of ISDN is required to decrease LAP.
In this study, duration of effect was dose dependent. According to the previous study, the plasma concentration of isosorbide-2-mononitrate (2-ISMN) and isosorbide-5-mononitrate (5-ISMN), which are metabolites of ISDN, peaked at 4 and 8 hours after ISDN administration, respectively. These peaks of the metabolites were later than the peak of ISDN. These metabolites of ISDN are also vasodilators, and previous investigators have reported the relative vasodilatory activities of 2-ISMN and 5-ISMN as 1/6 and 1/50 of ISDN, respectively. In this study, plasma concentrations of ISDN, 2-ISMN, and 5-ISMN were not measured. Therefore, it is not certain that these metabolites show significant effects on hemodynamics. However, it is possible that these metabolites affected duration of effect.
Our previous study reported that E wave and E/Ea can be used for the evaluation of preload and presumption of the reduction in LAP in the short term. Moreover, previous studies have shown that E/Ea is a good index for estimation of LAP and left ventricular filling pressure.[17-19] In this study, E wave and E/Ea of the 5 and 10 mg/kg groups decreased significantly after administration of sr-ISDN. This result was similar to the result of LAP. These results indicate that E wave and E/Ea can be useful for the evaluation of sr-ISDN treatment and the monitoring of reduction in LAP.
Cardiac output decreased significantly in the placebo and 10 mg/kg groups at 12 hours after administration. This result was mainly caused by the reduction in average HR in the placebo and 10 mg/kg groups. In the 10 mg/kg group, reduction in venous return volume may be associated with this result.
There was little measureable effect on afterload, and this means that most of the hemodynamic effect is via preload reduction demonstrated by the decrease in LAP. In the 10 mg/kg group, both SBP and LAP decreased significantly. However, in the 5 mg/kg group, only LAP decreased significantly. These results indicate that it is difficult to evaluate the effects of sr-ISDN treatment by BP measurements. In clinics, BP measurements are suitable ways to monitor serious hypotension rather than to evaluate the effects of sr-ISDN treatment.
Congestive heart failure is not only a series of hemodynamic abnormalities, but also changes to the autonomic nervous system are apparent. Elevated HR are associated with increased mortality in human patients with a history of acute myocardial infarction or heart failure.[21, 22] Monitoring of HRV is an effective method to evaluate the autonomic modulation of the heart.[23, 24] There is no previously published report on the effects of ISDN on automatic nerves in dogs with MR. In this study, there was no significant difference between any groups in HR and HRV. Activation of the sympathetic nervous system and renin-angiotensin-aldosterone system are known to be two of the causes of nitrate tolerance.[25, 26] Although there is no significant difference between any groups in HR, HR tended to increase in the 10 mg/kg group. It is possible that the Holter monitor is not sensitive enough to detect the effect of sr-ISDN on the autonomic nervous system.
In our previous reports, we evaluated the effects of ACE inhibitors, furosemide, and pimobendan on the dogs with experimentally induced MR.[13, 27, 28] This study and the previous studies indicate that the most effective method to reduce LAP is decreasing the circulating blood volume by diuresis. However, in practice, dogs suffering from severe MR are treated by combination of medicines. Further studies are needed to evaluate these combinations in the treatment of dogs with MR.