**8. Conclusions**

260 12 Chapters on Nuclear Medicine

The development of chemotherapy has played a significant role in the management of cancer patients. Of the classic cytotoxic agents, antracyclines are the still one of the most important agents for cancer therapy and are well known for their dose dependent acute and chronic cardiotoxicity, resulting in irreversible and progressive cardiac dysfunction and heart failure. Although new anticancer molecular targeting agents improved the prognosis of cancer patients, some agents may have serious cardiovascular side effect. Standard clinical approaches utilize the serial monitoring of the left ventricular ejection fraction to identify chemotherapy induced cardiotoxicity. For this purpose, radionuclide ECG gated blood-pool scintigraphy has been used as a gold standard technique. However, ejection fraction impairment is relatively late manifestation of myocardial damage. Therefore, the development of more sensitive methods is required to identify the cardiotoxicity before the

In a rat model of doxorubicin cardiotoxicity (cumulative dose: 7.5mg/Kg, 10mg/Kg, 12.5mg/Kg), planar scintigraphy detected the increase of 99mTc-annexin V uptake dose dependently and correlated with expression of left ventricular atrial natriuretic factor messenger RNA (Bennink, et al., 2004). Another study with doxorubicin treated rats (cumulative dose: 7.5mg/Kg and 15mg/Kg) demonstrated that dose dependent increase in 99mTc-annexin V uptake by SPECT/CT and TUNEL positivity. In contrast in this syudy, echocardiography detected ventricular dysfunction only at the highest doxorubicin dose ( Gabrielson, et al., 2008). These data suggest that apoptosis imaging could serve as a more sensitive early marker of doxorubicin cardiotoxixity than left ventricular dysfunction, might providing the opportunity to modify or stop the chemotherapy before clinically overt heart

Acute rejection remains a limiting factor of cardiac transplantation. The histopathologic manifestation of transplant rejection comprises perivascular and interstitial mononuclear inflammatory cell infiltration associated with myocyte apoptosis and necrosis. To monitor the acute rejection, endomyocardial biopsies are required frequently. Current guidelines recommend 15-20 endomyocardial biopsies in the first year after transplantation to monitor potential allograft rejection. However, invasive endomyocardial biopsy may be associated with a small risk of complications. If non-invasive imaging for the detection of transplant

Study with rat model of allograft rejection demonstrated that significant 99mTc-annexin V uptake correlated well with the histologic grade of rejection and scattered positive TUNEL stainings were observed in graft-infiltrating inflammatory cells, endothelial cells, and myocytes. In addition, after the treatment of rejection with cyclosporine, no TUNEL positivity was observed and 99mTc-annexin V uptake decreased to baseline (Vriens, et al., 1998). In 18 patients with cardiac allograft recipients, 5 had positive myocardial uptake of 99mTc-annexin V at 1 h after the tracer injection and all these 5 patients showed at least moderate transplant rejection and caspase-3 staining in their biopsy specimens. On the other hand, 11 of 13 patients with no cardiac uptake of 99mTc-annexin V demonstrated no finding of rejection and other 2 patients showed only focal lymphomononuclear cell infiltration (Narula, et al., 2001). In another clinical study with 10 patients with cardiac transplant, 2

**6. Apoptosis imaging in cardiotoxicity induced by chemotherapy** 

onset of ventricular dysfunction.

**7. Apoptosis imaging heart transplantation** 

rejection is feasible, endomyocardial biopsies might be reduced.

failure.

For the imaging apoptosis, for the time being, it appears that agents that bind to markers expressing cell surface of apoptotic cells, such as annexin V and its derivatives, have advantage in terms of the sensitivity and specificity over other tracers. Based on the research achievement to date including experiences with 99mTc-annexin V imaging in patients, 99mTcannexin V and its related tracers are considered as one of the most suitable tracers for clinical application at this stage, and also the positron labeled tracers such as 18F-annexin V are desired to apply clinical imaging. In cardiac diseases that involve cardiomyocytes, myocytes loss implies loss of cardiac function because cardiomyctes cannot be regenerated through cell division. In acute coronary syndrome, measurement of cardiac biomarkers are standard diagnostic tool, but they reflect the results of cardiomyocytes death. Whereas, apoptosis imaging such as 99mTc-annexin V can identify the cells starting or undergoing apoptosis, however, part of PS exposure of these cells might be reversible and some cells are capable of surviving. Therefore, apoptosis imaging might be beneficial for future strategy of the patient's management. Other than acute coronary syndrome, including heart failure, myocarditis, cardiomyopathies, and transplanted rejection, apoptotic cell death has turned out one of the crucial players in underlying pathophysiologies. Hence, apoptosis imaging in patients with various cardiac diseases will enhance the understanding of the ongoing pathophysiology, identification of high risk patients, and lead to effective therapies to salvage the myocardium in risk and be helpful in monitoring the effect of therapy.
