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MIBG as an Indicator of the Severity of Heart Failure
Cardiology, Matsuyama Red Cross Hospital
Cardiology, Matsuyama Red Cross Hospital
At the sympathetic endings of myocardial adrenergic nerves, norepinephrine is synthesized from tyrosine, stored in the vesicles, then released in response to a stimulus. The released norepinephrine increases the heart rate by reacting with the myocardial receptor or by strengthening the myocardial contraction. However 80 to 90% of the secreted norepinephrine is reuptaken into sympathetic nerve endings via an active transport mechanism called uptake-1. Some portion is uptaken into regions other than the nerve endings via a diffusion mechanism called uptake-2, but the amount uptaken in this way is very small for the human heart. MIBG is the physiological analogue of norepinephrine. Thus it is uptaken into the vesicles of sympathetic nerve endings via uptake-1 and secreted by exocytosis just like norepinephrine. However, because MIBG does not combine with the receptor, which differs from that of norepinephrine, it is considered to stay for a fairly long period of time in the vesicles. Just like norepinephrine, when the activity of the sympathetic nerve system increases, the exocytosis from the ending also increases, leading to an accelerated washout rate of MIBG.
I-123 MIBG imaging and its semi-quantitative analysis method is shown in Figure 1. All sympathomimetic medicines that could interfere with MIBG uptake were discontinued for three weeks before the injection of MIBG, and potassium iodo must be pretreated at the dose of 40 mg/day starting three days before the analysis to block the thyroid uptake of I-123. 111 MBq was intravenously injected at rest, then the immediate image was taken after fifteen to twenty minutes, and the delayed image was taken after three to four hours. Both planar and SPECT images can be taken. However, because the image quality of MIBG is not always good, more isotopes have to be administered to obtain a good SPECT image. Therefore, the planar frontal image is usually used for analysis. By setting the ROI in the myocardium and mediastinum as the background, the myocardial/mediastinal activity ratio, H/M ratio, is calculated as the index of MIBG uptake by the myocardium, and the washout rate is calculated as the index of MIBG release from the myocardium as shown in Figure 1.
We examined the severity of heart failure and the MIBG uptake by and washout from myocardium in ninety-six patients with heart failure: namely, forty cases of dilated cardiomyopathy, twenty-five cases of ischemic cardiomyopathy, and thirty-one cases of valvular heartdisease.Figure 2 shows a normal case and a case of heart failure of NYHA degree 3. In the case of heart failure, the H/M ratio of the
delayed image is reduced and the washout rate is accelerated. Figure 3 shows the summary of all data, in which the relationship between the severity of heart failure and the washout rate is examined by type of disease. It shows that the washout rate increases with the severity of cardiac disease regardless of the cause.
The same tendency can be observed in the H/M ratio. The H/M ratio of the immediate image is shown in Figure 4 and the H/M ratio
of delayed image is shown in Figure 5. In the immediate image, a slight reduction of the H/M ratio is observed in case of severe cardiomyopathy. However in the delayed image, reduction of H/M ratio is observed in both cardiomyopathy and valvular heart disease in accordance with the severity of heart failure. This is considered to be due to the fact that when heart failure become more severe, depletion of norepinephrine appears in the immediate image of cardiomyopathy with severe myocardial damage, then the accelerated emission appears in the delayed image as an accelerated washout rate.
Figure 6 shows the summary of the data on patients with mitral stenosis. When the left ventricular function is almost normal, the MIBG uptake by the myocardium as indicated by the H/M ratio is almost unaffected by heart failure. However, the washout rate is accelerated in accordance with the severity of heart failure, showing that the spillover of norepinephrine is accelerated with the aggravation of heart failure.
The degree of washout rate is negatively correlated with the reduction of cardiac output as shown in Figure 7. This reduction of cardiac output is considered to elevate the activity of the sympathetic nerve system.
Cohn et al reported the fact that the plasma norepinephrine level is related to the prognosis of heart failure. They have shown that the prognosis worsened when the plasma norepinephrine level increased to 400 pg or more. Thus, attempts have been made to predict the prognosis by MIBG imaging. Merlet et al. showed that the reduction of H/M ratio in MIBG was an important index for predicting the prognosis and more effective than using the LVEF as the index.
We examined the LVEF and the washout rate, and the prediction of cardiac event in all cases of heart failure due to cardiomyopathy. The LVEF and the washout rate show a negative correlation (Figure 8). Even in the cases with a low ejection fraction, it was suggested that the cardiac event occurred frequently in cases with an accelerated washout rate. Thus, we divided the cases into two groups: a group with less
than 60% washout rate and one with more than 60% washout rate as shown in Figure 9. It is obvious that many cardiac events occur in the cases with accelerated washout rate. Almost the same prediction is possible for cardiac events using the delayed image of H/M ratio as reported by Merlet's group.
The clinical applications of MIBG is summarized as following:
1. MIBG is an analogue of norepinephrine and its radioisotope image reflects sympathetic nerve activity in the myocardium.
2. By analyzing the MIBG image known to generate the adrenergic drive acceleration, adrenoreceptor desensitization, and NE stores depletion in heart failure, the H/M ratio is considered to represent the depletion of NE store and the washout rate is considered to suggest an increase of NE spillover caused by the adrenergic drive acceleration.
3. In case of heart failure, reduction of H/M ratio or acceleration of washout rate is observed in accordance with the severity regardless of the underlying disease, and the severity of heart failure can be diagnosed by analyzing the MIBG image.
4. MIBG is useful to accurately predict the prognosis of patients with heart failure and for the efficacy of therapy regardless of the underlying disease.
In conclusion, I would like to introduce the present state of using MIBG imaging in Japan. Approximately half is used for ischemic cardiac diseases, and 24% is used for cardiomyopathy. All of these are used for the complications of heart failures as explained in this presentation. The remaining 24% are used for other cardiac diseases such as valvular heart disease, arrhythmia, hypertension, and diabetes, and a small number of them are used for thyroid disease and Parkinson's disease. MIBG is the only method to provide information on sympathetic activity as imaging at present. I would like to conclude that, in the future, MIBG will be more widely used for clinical cases and its effectiveness will be further established.