The use of MIBG scintigraphy in heart failure was first reported in 1988 by Schofer, who showed that the cardiac MIBG abnormality was significantly related to the left ventricular ejection fraction in patients with idiopathic dilated cardiomyopathy [12]. After that, other studies showed that delayed imaging of cardiac MIBG is a powerful predictor of overall cardiac death in patients with heart failure [13, 14]. In addition, both delayed imaging of cardiac MIBG and washout rate were powerful predictors of sudden cardiac death in patients with heart failure [15–18]. Myocardial adrenergic nerve activity is accelerated in proportion to heart failure severity, while myocardial washout activity is related to heart failure severity and correlates well with New York Heart Association functional classification [19]. The usefulness of reduced cardiac MIBG uptake in delayed imaging and an excessive washout rate in patients with heart failure have been established.

In addition, in patients with dilated or hypertrophic cardiomyopathy, reduced cardiac MIBG uptake and excessive washout rate are associated with reduced contractile strength during a dobutamine stress test or exercise, and cardiac MIBG uptake degree can be used to evaluate the existence of left ventricular functional reserve in such diseases [20–23].

In patients with heart failure, cardiac function is depressed, and systemic sympathetic nerve hyperactivity is observed as a compensatory mechanism to maintain cardiac output. This results in a chronic increase in noradrenaline release from the nerve endings. The neuronal uptake capacity is eventually exceeded, leading to increased overspill of noradrenaline into the plasma and a net neuronal loss [24]. This likely accounts for the increased washout rate in patients with heart failure [17]. As the cardiac dysfunction progresses, neuron loss and Net1 downregulation occur, which diminish presynaptic function and likely account for the decreased cardiac MIBG uptake seen in advanced disease [25]. In addition, recent studies revealed that during congestive heart failure, sympathetic neural tone is upregulated, but there is a paradoxical reduction in noradrenaline synthesis and reuptake in the cardiac sympathetic nervous system. This is because the cholinergic differentiation cytokines, leukemia inhibitory factor, and cardiotrophin-1 were strongly upregulated in congestive heart failure, and congestive heart failure causes target-dependent cholinergic transdifferentiation of the cardiac sympathetic nervous system via these cytokines secreted from the failing myocardium [26].

In patients with ischemic heart disease such as myocardial infarction and unstable angina, cardiac MIBG imaging and perfusion imaging findings are consistent with the site and size of the damaged region. Cardiac MIBG uptake is reduced on early imaging because it does not accumulate in the nerve endings in the absence of blood flow. The sympathetic neuronal damage measured by MIBG is often larger than the infarct size (the so-called mismatch defect) [27–30]. This region of damaged sympathetic nerves and surviving myocardial cells indicates that sympathetic nerves are more sensitive to ischemia than myocardial cells. In patients with vasospastic angina, a marked reduction in cardiac MIBG uptake is often observed on delayed imaging due to excessive washout. This is the result of impaired noradrenaline retention and sympathetic nerve hyperexcitability. This finding demonstrates the concept of “memory imaging” of ischemia because the emergence and the region of the ischemic attack can be diagnosed retrospectively even after the normalization of electrocardiogram and echocardiogram abnormalities [31–33]. The mismatch defect is also observed in patients with old myocardial infarction, indicating the existence of “ischemic but viable tissue” [34, 35]. This mismatch defect is also observed in various myocardial disorders such as dilated cardiomyopathy [36, 37] and hypertrophic cardiomyopathy [38], but its diagnostic significance in these disorders has yet to be determined. This mismatch is also observed in patients with subarachnoid hemorrhage with left ventricular systolic dysfunction and is thought to be associated with an excessive release of noradrenaline from myocardial sympathetic nerves, which can damage both myocytes and nerve terminals [39].

The transplanted heart is completely denervated. Because of surgical denervation, presynaptic nerve terminals disappear, and myocardial storage of the neurotransmitter noradrenaline is depleted [40]. Therefore, the denervated transplanted heart has to rely on circulating catecholamines to adapt the cardiac output to meet the increased demand. However, there are usually no associated symptoms in daily life. Their ability to maintain systemic blood pressure during postural stress is unaffected, and increased systemic vascular resistance and well-preserved systolic blood pressure without orthostatic hypotension were observed during the head-up tilt test [41].

However, under exercise stress, this adaptation is limited and cannot achieve a normal increase in heart rate and cardiac muscle contractility [42]. Under stress conditions, the restoration of innervation is important to achieve an adequate contractile response. One study showed that transplant recipients who achieve reinnervation have a greater capacity for exercise than those who do not achieve denervation [43]. The chronotropic response to exercise is reported to increase at 3–6 weeks after transplantation [44].

In patients with pheochromocytoma, the cardiac MIBG uptake is decreased on early imaging. Since these patients show high levels of plasma noradrenaline, the excess circulating noradrenaline caused by pheochromocytoma was thought to damage the cardiac sympathetic nerve function [45]. However, since the abnormal scintigraphic findings improved after tumor resection [8, 46], the abnormal MIBG finding was presumed to be caused by the high plasma catecholamine concentration itself [8]. In addition, both patients with pheochromocytoma and those with high serum noradrenaline levels with neuroblastoma showed reduced cardiac MIBG uptake before treatment and significantly increased cardiac MIBG uptake after treatment. One of the possible explanations for the reduced cardiac MIBG uptake before treatment in patients with neuroadrenergic tumors is the competition between circulating MIBG and oversecreted noradrenaline and adrenaline in the sympathetic nerve terminals [47]. The downregulation of the uptake pathway and the rapid turnover of MIBG in the cardiac sympathetic neurons due to the effects of excess catecholamines are also postulated [47, 48]. However, not all patients show improved cardiac MIBG uptake. Some patients with pheochromocytoma show only slight improvements in cardiac MIBG uptake with persistent cardiac dysfunction. Thus, another possible mechanism underlying reduced MIBG uptake in pheochromocytoma is that regional excess of catecholamines on the myocardium directly induces focal myofibril degeneration with inflammatory cellular infiltration [49]. Myocardial cell damage can result from reduced coronary perfusion and hypoxia caused by a vasospasm that is mediated by an adrenergic receptor [50] and a change in the calcium ion permeability of the cell membrane [46]. Functionally, excess noradrenaline leads to reduced global myocardial pump function [51]. These forms of pathological damage result in a decreased MIBG uptake owing to the reduced number of sympathetic nerve endings, impaired neuronal uptake function, and reduced synthesis or rapid turnover of noradrenaline within the neurons. Catecholamine-induced cardiomyopathy may be reversible after primary tumor removal, but persistent dysfunction can occur due to the long-term accumulation of myocardial damage [47].

According to previous studies, the left ventricular ejection fraction at rest is normal in diabetic patients [2, 52]. However, diabetic patients with reduced cardiac MIBG uptake showed an impaired response to exercise, as indicated by a smaller increase in ejection fraction, and it is suggested that subclinical left ventricular dysfunction is related to derangement of adrenergic cardiac innervation [2, 52, 53]. In diabetic rats, the MIBG washout rate was high, but unlike heart failure patients, this is not likely due to the systemic sympathetic hyperactivity. Rather, it is likely due to reuptake and/or pooling mechanism dysfunction since the plasma and myocardial noradrenaline concentrations in diabetic rats were significantly lower than those in nondiabetic rats [54]. Other details of clinical findings in diabetic patients are covered elsewhere (Chap. 15).

The first cardiac MIBG study in patients with neurodegenerative disorders, including PD, was reported by Hakusui et al. in 1994. Reduced cardiac MIBG uptake was observed in both patients with autonomic failure, mainly orthostatic hypotension, and in those without orthostatic hypotension [55, 56]. The details of the transition and the clinical significance of MIBG scintigraphy in PD are saved for another chapter, but an overview of the physiological significance of reduced cardiac MIBG uptake in patients with PD is provided here.

Orimo et al. reported that tyrosine hydroxylase-immunoreactive nerve fibers in the heart were markedly decreased in patients with PD, which suggests that the involvement of postganglionic sympathetic nerves accounts for reduced cardiac MIBG uptake in patients with PD [57]. Recently, their group showed that the degree of cardiac MIBG uptake is correlated with that of cardiac sympathetic denervation in pathologically confirmed Lewy body disease [58].

But, patients with PD and reduced cardiac MIBG uptake show normal left ventricular function on echocardiography [1], and the clinical symptoms of autonomic disorders associated with cardiac denervation are difficult to recognize. Reduced cardiac MIBG is not observed in patients with multiple system atrophy, a disease with characteristics of orthostatic hypotension, but is commonly observed in patients with PD with or without orthostatic hypotension; thus, many studies reported that reduced cardiac MIBG uptake is not associated with orthostatic hypotension [59–61]. However, reduced cardiac MIBG uptake is associated with a reduced overshoot of phase IV on the Valsalva maneuver, which indicates that reduced cardiac MIBG uptake clinically reflects cardiac sympathetic dysfunction in patients with PD [62]. The uptake of MIBG and 6-[18F]-fluorodopamine, which can also detect cardiac sympathetic denervation, was reportedly much lower in patients with orthostatic hypotension than in those without [63, 64]; thus, cardiac denervation is likely to be associated with orthostatic hypotension in patients with PD. A recent report on PD showed that under orthostatic stress, cardiac sympathetic denervation with failure to increase total peripheral resistance leads to large reductions in systolic blood pressure; however, patients without cardiac denervation exhibited a positive inotropic response against vasodilatation, which may prevent orthostatic hypotension [65]. On the other hand, patients with sufficient peripheral adrenergic innervation to elicit an increase in total peripheral resistance through vasoconstriction, a potential cardiac denervation effect, would be masked, and a normal blood pressure response is maintained (Fig. 17.3). Thus, cardiac sympathetic nerves play an important role in regulating blood pressure, and impaired cardiac contractility is one of the important contributing factors to the development of orthostatic hypotension in patients with PD.

Fatigue and exercise intolerance in patients with PD may be also explained by the cardiac sympathetic dysfunction that results in the failure to increase contractility in response to the release of noradrenaline from sympathetic nerves [4]. Patients with PD often complain of fatigue, and cardiac MIBG uptake was indeed more reduced in the fatigued group than in the non-fatigued group [66]. Blood pressure and heart rate response to exercise differ among many studies. Some patients with PD reportedly had a statistically lower systolic blood pressure change upon exercising [67], whereas others reportedly had blood pressure changes that did not differ from those of control subjects [68]. Regarding the chronotropic response, some authors reported that the heart rate change is higher in patients with PD than in control subjects [69], whereas others reported that chronotropic insufficiency against cardiac stress testing was already observed in individuals who developed the motor features of PD several years after cardiac stress testing and that it may constitute an early sign of cardiac sympathetic dysfunction in PD [70]. The exercise study on cardiac sympathetic dysfunction showed that patients with PD having reduced cardiac MIBG uptake had lower cardiac contractility than cardiac non-denervated subjects and control subjects during exercise (Fig. 17.4), suggesting that this response represents impaired exercise capacity of patients with PD and cardiac sympathetic denervation [71]; this result was consistent with those of previous studies conducted in heart transplant and diabetic patients as described above.

In other diseases, such as Brugada syndrome, reduced cardiac MIBG uptake is considered important finding in the pathophysiology and arrhythmogenesis of the disease, but whether this is a primary adrenergic dysfunction or an imbalance of sympathetic and parasympathetic innervation of the heart is unclear [72]. In addition, many other diseases such as postural tachycardia syndrome [73, 74], spinocerebellar ataxia type 2 [75], amyloidosis [76], amyotrophic lateral sclerosis [77], and temporal lobe epilepsy [78] demonstrate reduced cardiac MIBG uptake. The reduced uptake in these diseases may be due to neuropathy, sympathetic hyperactivity, or dysfunction of postganglionic cardiac sympathetic fibers. However, these reports are sporadic, so further studies reflecting the pathophysiology or those that can consider the physiological background are warranted.

Uptake-1 in the synaptic cleft is the main mechanism underlying MIBG uptake, a process that is inhibited by cocaine. Cocaine interacts with the catecholamine transport protein involved in the neuronal uptake-1 system. Tricyclic antidepressant also affects MIBG uptake [80]. In dogs, pretreatment with desmethylimipramine (also known as desipramine) 1 h before MIBG administration led to a tenfold reduction in uptake of the radiopharmaceutical by the adrenal medullae [81]. A reduced uptake of MIBG caused by other tricyclic antidepressants, such as imipramine, amitriptyline, clomipramine, and doxepin, has also been well documented [82, 83]. Labetalol, an antihypertensive agent with combined alpha- and beta-blocking properties that has been used to manage patients with suspected pheochromocytoma, also reduces MIBG uptake [84]. The inhibitory effect of labetalol on MIBG uptake in the sympathomedullary tissues is likely to be a result of the drug’s little-known additional properties of blocking uptake-1 and depleting the storage vesicle contents [84]. In contrast, conventional alpha- or beta-adrenergic receptor blockers do not have such an inhibitory effect.

Reserpine and tetrabenazine are known to inhibit active transport into the neurosecretory vesicles [79]. MIBG is transported across the neurosecretory vesicle membrane and can reduce MIBG uptake. Other Rauwolfia alkaloids as well as antidepressants such as viloxazine may also have similar action and interfere with MIBG uptake [79].

MIBG translocation across the neurosecretory vesicle membrane also occurs via a monoamine transport system, which is shared by noradrenaline, serotonin, and MIBG. The translocation of these neurotransmitters depends upon the concentration of the relevant substrate in the cytoplasm. Adrenergic neuron blockers such as guanethidine share the same transport system and compete with MIBG for this pathway. Selegiline, a drug used to treat PD, works by inhibiting monoamine oxidase (MAO) to slow noradrenaline breakdown and may increase noradrenaline leading to the competition for transport into the vesicles with MIBG.

Many medicines are known to deplete the storage vesicle contents, most commonly sympathomimetic drugs such as reserpine, labetalol, guanethidine, and amphetamines. Although weak, selegiline has a known amphetamine effect, and its breakdown product methamphetamine may reduce MIBG uptake. Phenylpropanolamine and phenylephedrine may also reduce MIBG uptake. Even small amounts of the medications delivered intranasally may be sufficient to reduce MIBG uptake.