Anthracyclines, such as doxorubicin, are most commonly associated with cardiotoxicity. The anticancer effects of anthracyclines are mediated primarily through inhibition of DNA synthesis, transcription, and replication (Smith et al. 2010). Simultaneously, oxygen-derived free radicals are formed, causing direct damage to proteins, lipids, and DNA, which may lead to myocyte apoptosis in the heart. This process is thought to be the key mechanism in anthracycline cardiotoxicity. Alternate hypotheses include calcium overload of myocytes, alterations in adrenergic function, and inhibition of protein synthesis (Panjrath and Jain 2006). A meta-analysis of 55 randomized controlled trials demonstrated an increased risk of clinical cardiotoxicity by anthracycline-based regimens by 5.43 fold, subclinical cardiotoxicity by 6.25 fold, and cardiac death by 4.94 fold compared with non-anthracycline regimens (Smith et al. 2010). Risk factors for developing cardiotoxicity comprise a high cumulative anthracycline dose, mediastinal radiation therapy, combination chemotherapy, combination chemotherapy with monoclonal antibody therapy, preexisting cardiovascular disease, emphysema, diabetes, female sex, and very young or older age (Panjrath and Jain 2006; Yeh et al. 2004). Toxic effects on the myocardium due to anthracyclines may occur early, during or immediately after infusion, or late, after months up to 20 years after therapy. Toxic effects on the myocardium during or immediately after infusion are usually self-limiting with discontinuation. Chronic effects may persist after discontinuation of therapy, or may present after months or years, and can progress to overt cardiac dysfunction or CHF. Therefore, early detection before irreversible functional cardiac impairment has occurred is crucial.

[¹²³I]-MIBG scintigraphy was investigated as an early marker for cardiotoxicity after anthracycline therapy. In a rat model, a clear dose-dependent reduction in MIBG uptake was demonstrated after doxorubicin therapy (Wakasugi et al. 1992). The reduction in MIBG uptake was larger and more linear dose-dependent than impairment of LVEF. Furthermore, MIBG uptake was significantly reduced after 6 weeks of therapy with only mild myocyte damage at histopathological examination, whereas LVEF decreased only slightly after 7 weeks and showed a remarkable decrease after 8 weeks of therapy, suggesting MIBG to be a sensitive biomarker for early detection of doxorubicin-induced cardiomyopathy (Wakasugi et al. 1993). The subendocardial layer appeared to be more vulnerable to doxorubicin than the subepicardium (Jeon et al. 2000). Congestive heart failure due to Adriamycin in an early stage in a rat model was found to accelerate exocytotic release of norepinephrine from cardiac adrenergic neurons, rather than disturb the neuronal uptake function (Wakasugi et al. 1995). In an advanced stage, nonexocytotic metabolic release is induced due to energy depletion, increasing norepinephrine release. Both mechanisms lead to a reduction of myocardial MIBG uptake.

In a case report, [¹²³I]-MIBG scintigraphy with SPECT of a patient after doxorubicin therapy without cardiac symptoms and normal LVEF was described, showing reduced uptake in several segments and a high washout rate (WR) (Takano et al. 1995). After 10 months the patient died of CHF, and at necropsy structural changes, corresponding to the impaired segments at the [¹²³I]-MIBG, were found in a dilated left ventricle (Figs. 23.1 and 23.2). Conversely, in segments with preserved [¹²³I]-MIBG uptake, myocardial nerve fibers had a normal aspect.

In patients receiving doxorubicin therapy, the dose-dependent reduction in [¹²³I]-MIBG uptake (heart/mediastinum ratio (H/M ratio)) was confirmed in several studies (Lekakis et al. 1996; Takano et al. 1996; Takeishi et al. 1994; Valdes Olmos et al. 1995). Even at low dosage, the H/M ratio showed a decline, whereas LVEF derived by echocardiography or multi-gated radionuclide ventriculography was preserved. The 4-h WR tended to increase but did not reach statistical significance in a small, proof-of-concept study (Valdes Olmos et al. 1995). Complementary SPECT examinations to identify segment abnormalities were of good quality in patients with normal H/M ratio, though 4-h SPECT images of patients with abnormal tracer retention were of poorer quality and needed a longer acquisition time.

When [¹²³I]-MIBG scintigraphy was compared with [¹¹¹In]-antimyosin scintigraphy in the evaluation of cardiotoxicity after doxorubicin therapy, [¹¹¹In]-antimyosin detected early myocardial damage at intermediate doses of doxorubicin, whereas H/M ratio was only impaired at high cumulative doses (Carrio et al. 1995). In four patients with symptomatic anthracycline-induced cardiomyopathy, [¹²³I]-MIBG and [¹¹¹In]-antimyosin scintigraphy was performed 2–116 months after the onset of CHF, showing a persistent decreased H/M ratio in [¹²³I]-MIBG and an increased heart-to-lung ratio (H/L ratio) in [¹¹¹In]-antimyosin scintigraphy in all patients, suggesting permanent damage to the cardiac adrenergic nerve endings and myocytes (Nousiainen et al. 2001). H/M and heart/lung (H/L) ratios remained impaired even in patients who had recovered clinically, and LVEF had returned to near normal.

All of these studies included only a limited number of patients and lacked appropriate follow-up. No studies have been performed yet for other chemotherapeutic agents, such as alkylating agents or antimetabolites, using [¹²³I]-MIBG scintigraphy as a biomarker to evaluate cardiotoxicity.