Cardiovascular > Adrenergic Imaging

Adrenergic Nervous System of the Heart

Physiology& Pharmacology

The sympathetic and parasympathetic innervation of the heart plays a major role in the regulation of cardiac function [14]. Adrenergic fibers that innervate the heart originate in the left and right stellate ganglia [9]. The left stellate innervates the right ventricle, whereas the right stellate innervates the anterior and lateral portions of the heart. The adrenergic fibers travel in the subendocardium following the coronary vessels [9]. At a cardiac level, sympathetic activation results in an increased heart rate (chronotropic effect), augmented contractility (inotropic effect), and enhanced atrioventricular conduction [9].

Sympathetic nervous system dysfunction plays a role in heart failure [18]. Excessive activity of the sympathetic nervous system is a major contributor to heart failure progression, by increaing cardiac work, promoting myocardial fibrosis, and causing down-regulation of post-synaptic adrenergic receptors [42]. Noreponephrine (NE) is produced and stored in vesicles in presynaptic sympathetic nerve terminals [39]. In response to stimuli, the vesicles are released into the synaptic space with free NE binding to post-synaptic myocyte receptors producing the desired cardiac effect [39]. To control the response, there is a transporter protein mediated, sodium, energy dependent process (uptake 1) by which free NE is taken back up into presynaptic terminals for storage or catabolic disposal [39]. Some NE is also taken up by non-neuronal post-synaptic cells (uptake 2) [39]. In patients with heart failure, both increased neuronal release of norepinephrine and decreased efficiency of NE uptake contribute to increased cardiac adrenergic drive [18]. Significant reduction in mortality in heart failure patients can be achieved with the use of beta- and alpha-adrenoreceptor blocking drugs [18]. Systemic biomarkers such as B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) are released in response to myocardial stretch and these markers are significantly associated with sudden cardiac death and ventricular arrhythmias [51].

Metaiodobenzylguanidine (MIBG) is a guanethidine analog that mimics the neuronal transport and storage of norepinephrine [26]. I-123 MIBG has been used to study the cardiac sympathetic nervous system because of its high cardiac uptake (unfortunately, I123 MIBG is not FDA approved for cardiac imaging and therefore not reimbursable [41]). Non-neuronal activity clears rapidly from the heart between 15 and 60 minutes. In the heart, MIBG is taken up and store by the postganglionic, presynaptic nerve endings [21,29]. Similar to NE, there are two mechanisms for MIBG uptake in adrenergic tissues: a presynaptic type I neuronal uptake system and a extraneuronal type 2 uptake system (a minor role in uptake related to a carrier-facilitated process and diffusion into the myocytes) [26,29]. As with norepinephrine, I-123 MIBG uptake is predominantly mediated (70%) via the ATP energy dependent, type I uptake mechanism [9,26]. After depolarization, MIBG is released into the synaptic cleft, like norepinephrine, but it is not further metabolized [21]. MIBG stored within the neuron is also not further metabolized (it is not a substrate for monoamine oxidase [26,39]) allowing it to accumulate to concentrations that permit imaging [39]. Only about 10% of the dose is altered after several days, primarily by deiodination. The agent produces no measurable pharmacologic effects. Uptake of I-123 is usually homogeneous within the myocardium, although uptake may become more heterogeneous or decrease within the inferior (men) or lateral (woman) wall as the patient ages [1,2]. Tracer washout also increases with increasing age [2].I-123 MIBG must compete for uptake with the excess norepinephrine that accumulates in the synaptic cleft of heart failure patients which reduces the amount of I-123 MIBG that accumulates in the presynaptic nerve terminal [53].

¹¹C-meta-hydroxy-ephedrine (HED) is a PET agent that can be used for neuronal imaging [33]. The agent has higher uptake selectivity compared to MIBG and is better in differntiating between innervated and denervated myocardium [33]. Patients with CHF have been found to have lower retention rates of ¹¹C-HED compared to healthy subjects [47].

Technique:

Patients should fast for 6 hours prior to the exam [13]. Thyroid uptake is blocked by the oral administration of 500 mg potassium perchlorate (Lugols solution) or a saturated solution of potassium iodide given 30 minutes before injection of the radiotracer [20]. Other authors recommend giving 1mg of potassium iodide from one day before to 1 day after the exam to block thyroid uptake [30]. Patients are injected at rest [33].

Certain medications and drugs can interfere with catecholamine and I-123 uptake [33,43,53]. Cocaine and various tricyclic antidepressants are strong inhibitors of the noepinephrine uptake-1 transporter and effectively block cardiac uptake of I-123 MIBG [53]. Sympathicomimetics (ephedrine, pseudoephedrine, isoproterenol) and reserpine depelete norepinephrine storage granules which can interfere with I-123 storage in the presynaptic nerve terminal [53]. Ganglionic blockers and clonidine block sympathetic nerve activity and alter MIBG concentration in the heart. Drugs used to improve LV function in heart failure patients can also improve MIBG uptake and include beta-blockers (carvedilol, metoprolol, and bisoprolol), angiotensin-converting enzyme inhibitors, angiotensin receptor blockers (candesartan), and the aldosterone inhibitor spironolactone [53]. Opiods, antipsychotics (phenothiazines), the cardiovascular agent bretylium, and some calcium channel blockers can also affect MIBG uptake [33,43]. Drugs which block norepinephrine uptake or deplete norepinephrine stores (including cocaine and over the counter cold medications) can decrease MIBG uptake and should be stopped for 5 biologic half-lives whenever medically feasible [53]. Other authors suggest they should be held for 24 hours prior to adminsitration of the tracer [33,43]. The beta-blocker labetalol also has signifncant alpha-blocking activity and can inhibit MIBG uptake [54]. Standard heart failure medications such as beta-blockers, angiotensin converting enzyme inhibitors (ACE-I), and/or angiotensin receptor blockers (ARBs) do not need to be withheld [43]. Foods containing vanillin and catecholamine-like compounds (chocolate and blue cheese) should also be avoided [43].

Breast feeding should be stopped for 48 hours after I-123 MIBG injection [53]. The agent is largely excreted by the kidneys and patients with severe renal dysfunction may have increased radiation exposure and decreased image quality [53].

Hypersensitivity reactions have occurred following I-123 MIBG administration [53].

The dose used for the exam is 3-5 mCi (up to 10 mCi) of I-123 MIBG given over 1 minute (the higher dose may be required for patients with severe cardiac dysfunction if SPECT images are to be obtained) [8,9,13,33,43]. The effective dose from an administered activity of 10 mCi is 4.8-5.07 mSv [42,53]. The urinary bladder is the critical organ for I-123 MIBG, but in this same article, they also indicate that the thyroid is the critical organ [53].

Early (10-15 minute post injection) and delayed (4 hour) planar and SPECT imaging is performed. The neuronal accumulation of MIBG reaches its maximum at 4 hours after injection (hence the delayed image represents actual neuronal uptake as opposed to interstitial uptake on the early images) [26,33,55]. A low-energy parallel hole collimator may used for imaging [20], however, other authors recommend using a medium energy or I-123 collimator in order to minimize noise from scatter from some higher energy I-123 emissions (more than 400 keV) which can affect the H/M ratio (septal penetration by the higher energy photons causes contamination of mediastinal counts by lung activity leading to an underestimation of the H/M ratio [45]) [35,43,45,59]. A 20% window is used and centered over the 159 keV I-123 photon peak [9,20]. If a low-medium energy collimator is used, a 15% energy windo is recommended [45]. An anterior planar image of the chest is acquired for 5 to 10 minutes prior to initiation of SPECT imaging using a 128x128 matrix (some centers also acquire a planar LAO image [9]). Planar images are limited by superimposition of thoracic structures that can also demonstrate MIBG uptake (such as the luns and liver) as well as superimposition of different myocardial segments [29]. Tomographic images are performed to overcome these limitations [29]. SPECT images are obtained every 6 degrees for 30-40 seconds in a 64x64 matrix for a 180 degree rotation (RAO to LPO). Unfortunately, if global myocardial uptake of MIBG is severely reduced, it can be difficult to acquire tomographic images of sufficient quality [29].

Findings:

In healthy subjects, MIBG uptake is slightly lower in the inferior wall (likely due to attenuation, but it has also been suggested to be a physiologic finding relating to vagal tone [29]), apex, and septum [14,29]. It has also been reported that myocardial MIBG uptake decreases with age in adults- particularly in the later decades of life (patients over 60 years of age and therefore, myocardial MIBG uptake has to be corrected for age) [26]. Reduced myocardial uptake of MIBG is seen in association with most diseases that result in cardiac injury [31] and can also be seen in association with cardiotoxicity related to chemotherapy [36].

Image interpretation consists of assessment of global tracer uptake on planar images, tracer washout between early and delayed planar images, and regional uptake on tomographic images [33]. Tracer activity on early imaging is dependent primarily on blood flow and is felt to reflect both the extravesicular and intravesicular accumulation of the tracer [36]. The extravesicular concentration of MIBG decreases rapidly, while the intravesicular concentration remains relatively constant [36]. Hence, delayed images reflect the adrenergic neuron terminal concentration [36].

Cardiac MIBG uptake is semiquantified by calculating a heart-to-mediastinum ratio on the planar images [15]. The H/M ratio reflects receptor density and poortrays both the integrity of presynaptic nerve terminals and uptake 1 function [39]. The anterior projection seems to be the preferred projection for quantification as it provides the lowest variation and highest resolution [19]. Various methods have been described. In one method a 7 x 7 pixel ROI is placed over the cardiac region and another 7 x 7 pixel ROI over the midline of the upper mediastinal area in the the region of lowest activity (making sure to avoid activity in the thyroid gland) [13,53]. In another method, left ventricular activity is measured by manual drawn regions of interest surrounding the entire myocardium (excluding ventricular blood pool) [15]. A separate 7 x 7 or 20 x 20 pixel region of interest is placed over the upper mediastinum. The heart-mediastinum ratio is calculated without background subtraction as mean (or average) counts per pixel over the entire left ventricle divided by mean (or average) counts per pixel in the upper mediastinum [9,15,29,55].

A heart-to-mediastinum ratio of greater than 1.8 is considered normal [9]. Other authors report a normal HMR as 2.2 +/- 0.3, and a ration of less than 1.6 as abnormal [33,39,43]. A decreased H/M ratio signifies reduced cardiac adrenergic receptor density [39]. Some studies suggest that a regional defect score is superior to the global heart-to-mediastinum ratio for the prediction of arrhythmic events- implying that regional heterogeneity may be more important than global downregulation for the development of arrhythmia [37].

Another measurement that is calculated is the washout rate [29]- a ratio of cardiac uptake between early and delayed images [37]. The washout rate (WR), compensated for tracer decay, is thought to reflect turnover of catecholamines and thus sympathetic drive/tone (a measure of the ability of the myocardium to retain MIBG) [29,33,37,39]. The clearance rate from the myocardium (washout rate) is calculated by: (Initial myocardial MIBG uptake - Delayed myocardial MIBG uptake *1.21/ Initial MIBG uptake) x 100 [13]. The factor 1.21 is multiplied by the delayed value to correct for I-123 decay [43]. The washout rate between early and delayed images should be less than 10% [9]. Worsening heart failure is associated with a greater MIBG washout rate, often greater than 27% [39]. Non-uniform soft tissue attenuation over the chest can cause variations in the measurements obtained [9]. Note- other authors indicate that the wash out rate is defined as: [H/M_early - H/M_late]/ [H/M_early] x 100%  [53].

In healthy subjects, there is low within subject variability in I-123 MIBG uptake on both planar (about 5%) and SPECT (about 5%) imaging [19]. Assuming this is also true for patients with cardiac disease, the effects of therapeutic interventions can be monitored using I-123 MIBG imaging [19]. Note: Increased lung uptake of I-123 MIBG is associated with a better prognosis, in contrast to increased lung uptake of thallium on MPI [53].

In cardiomyopathies/heart failure:

Cardiac MIBG uptake is decreased in patients with congestive heart failure, cardiomyopathies, and ventricular arrhythmias [26]. In heart failure, sympathetic activity initially increases as manifested by the release of NE in the synaptic cleft [48]. The upregulated neurotransmitter release eventually overwhelms the NE transporter 1 (NET-1) process that then leads to spilling of excess NE into the circulation [48]. As the HF syndrome progresses, there is diminished presynaptic function due to loss of neurons and downregulation of NET-1 (this can be imaged as decreased uptake of MIBG) [48].

In patients with heart failure the assessment of sympathetic activity has important prognostic implications regarding risk stratificaiton and patient survival and will result in better therapy and outcome [10,32,41]. Alterations in the cardiac sympathetic nervous system clearly play a role in the development and progression of congestive heart failure (CHF) [13,15]. Altered autonomic function is also responsible for ventricular arrhythmias or sudden cardiac death [25]. Decreased cardiac output related to left ventricular dysfunction results in a baro-receptor mediated increased in sympathetic tone and circulating norepinephrine levels in an effort to compensate for the decreased cardiac output [15,33]. The consequences of chronically increased sympathetic tone include increased left ventricular afterload, worsening LV function, and progressive CHF [15]. The hyperactivity of the sympathetic nervous system in patients with chronic CHF leads to a downregulation in and desensitization of myocardial beta-adrenergic receptors [29,40].

It has been shown that in CHF patients, the postsynaptic beta1-adrenoreceptor density is reduced and the concentration of inhibiting Gi-alpha proteins is elevated [13]. Cardiac noradrenaline turnover is also increased [13]. It is thought that with progressive heart failure, there is reduced uptake of NE into presymaptic cardiac nerve storage vesicles via the NE uptake-1 transporter [42]. Chronic NE over-exposure of post-synaptic beta-adrenergic receptors on the cardiomyocyte results in beta-receptor desensitization and eventual catoblism and loss of beta-receptors [42]. Beta-adrenergic blocking agents can aid in blocking sympathetic over-stimulation associated with CHF and I-123 MIBG imaging can be used to evaluate the effectiveness of the treatment [15,32]. Other physiologic factors that also play a role in CHF include a decrease in renal blood flow that leads to acceleration of the renin-angiotensin system (with resultant fluid retention and exacerbation of heart failure) and also impaired hematopoiesis [40].

Cardiac MIBG uptake is generally diffusely decreased in patients with dilated cardiomyopathies and in patients with CHF (defects in patients with ischemic cardiomyopathies tend to be more severe in necrotic segments) [11,14]. In these patients, low MIBG uptake is associated with an increased risk for cardiac death [9,11,14,15]. Decreased MIBG uptake on delayed images is closely related to the degree of LV dysfunction in patients with heart failure and also correlates with the level of decreased exercise capacity [8,16]. The poor tracer uptake is likely reflective of underlying cardiac autonomic dysfunction (areas of denervation hypersensitivity) which may place patients at higher risk for arrhythmogenesis [11,35]. The delayed H/M ratio has been reported to be the best predictor for survival in patients with CHF and reduced cardiac function [23]. [52]. In patients with CHF, a normal HMR predicts a <1% yearly risk of cardiac death, while a decreased HMR predicts a poor prognosis [33]. In one study of CHF patients, a HMR<1.2 was associated with a 12 month survival of only 40% [33]. In another study of CHF patients with LVEF

Tracer washout rates have also been studied. Patients with dilated cardiomyopathies typically have accelerated washout rates of MIBG of greater than 25% between early and delayed images (normal less than 10%) [9]. A washout rate of greater than 50% is also associated with an increased risk for cardiac death [9,11] (other quote greater than 27% in chronic CHF patients being associated with a significant increased risk for sudden death (35% cardiac death rate) [29]). The percent change in washout rate between serial exams may also provide information regarding increased risk for cardiac or sudden death (greater than or equal to -5% is associated with an increased risk) [28]. Increased washout can also be seen in other conditions including myocardial hypertrophy and diabetic hearts [11]. MIBG uptake ratios may also help to predict a good response to alpha-blocker therapy in patients with dilated cardiomyopathies [9].

Cardiac resynchronization therapy (CRT) has been shown to be beneficial in patients with advanced chronic heart failure (LVEF <35%) and a QRS duration greater than 120 milliseconds [22,24]. CRT can improve clinical manifestations and quality of life, reduce hospitalizations for CHF, reduce complications, and risk of death (increase survival) [22,24]. Unfortunately, between 20-30% of patients do not respond to CRT [24]. Lower MIBG uptake (H/M ratio below 1.36) is associated with a higher likelihood for lack of response to CRT [22]. The lower MIBG uptake may reflect hearts with more severe myocardial damage that are less likely to respond to CRT [22]. Following successful CRT intervention, there is improved cardiac uptake of MIBG [22]. The presence of left ventricular dyssynchrony also suggests patients that are more likely to respond to CRT [24]. Phase image analysis from gated cardiac examinations can be used to evaluate for the presence of LV dyssynchrony [24]. Extensive LV scarring - particularly when present in the region in which the LV pacing lead is positioned (typically the posterolateral region)- can also result in a decrease likelihood for response to CRT (extensive scarring is predictive of lack of CRT response with a sensitivity of 83% and a specificity of 74%) [24]. This suggests that improvement in LV function is prohibited in the presence of extensive scar tissue [24].

Patients with hypertrophic cardiomyopathies (HCM) also demonstrate derangements in sympathetic activity [12]. HCM is an inherited cardiac muscle disease that is related to a mutation in the genes that encode proteins in the sarcomere [12]. Charateristics of the disorder include disproportionate left ventricular hypertrophy and diastolic dysfunction [12]. Delayed MIBG images demonstrate poor, heterogeneous cardiac tracer retention and increased washout rates [12,29]. In patients with HCM, MIBG washout is significantly higher in patients with ventricular tachycardia (VT) compared to those without VT [29].

Abnormal ¹²³I-MIBG tracer uptake can also be seen on SPECT imaging of patients with arrhythmogenic right ventricular dysplasia- typically with defects in the anterior, septal, and inferior walls (with normal perfusion to these areas on perfusion imaging) [38]. In ARVD patients, the presence of abnormal MIBG SPECT imaging is associated with a significantly increased risk for ventricular tachyarrhythmia (up to 88% of patients) [38]. Reduced tracer uptake is likely a reflection of underlying autonomic dysfunction which places these patients at an increased risk for dysrhythmia and sudden death [38].

In Monitoring Heart Failure Response to Therpy:

Beta blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone inhibitors have improved outcomes for heart failure patients [42]. Beta blockers have been shown to reduce cardiac work, up-regulate post-synaptic adrenergic recpetors, and reduce the risk of death in patients with chronic heart failure [42]. Other physiologic factors that also play a role in CHF include a decrease in renal blood flow that leads to acceleration of the renin-angiotensin system (with resultant fluid retention and exacerbation of heart failure). Inhibition of the renin-angiotensin system can be achieved by blocking the conversion of angiotensin I to angiotensin II (ACE inhibitors) or by blcoking angiotensin receptors (angiotensin receptor blockers) [42]. The use of ACE inhibitors has been shown to improve outcome and mortality in patients with LV dysfunction [42].

Improvement in MIBG uptake following initiation of beta-blocker therapy may predict which patients are more likely to respond to this form of therapy- even prior to documented LV function improvement [14,42,59]. Patients with preserved HMR on neurohormonal inhibitor medication have improved 5 year survival and a decreased mortality rate [59]. Patients that fail to demonstrate an improved HMR following 6 months of optimal medical therapy are at an increased risk for cardiac death [33].

In heart transplantation:

The surgical procedure of heart transplantation causes autonomic denervation of the donor (allograft) heart [7]. Immediately after heart transplantation no activity is detected in the myocardium [14]. Total denervation persists for at least 12 months after transplantation [14]. Regional reappearance of sympathetic nerve fibers occurs in the transplanted heart over time [7]. MIBG uptake indicating partial sympathetic reinnervation can be shown in 40% of patients 3 to 5 years after transplantation [7]. Serial MIBG studies show that reinnervation begins from the anterolateral base of the heart and spreads towards the apex [9,14]. With reinnervation, patchy MIBG uptake is seen primarily in the anterior, anterolateral, and septal regions. MIBG uptake is usually not apparent in the posterior or inferior myocardial regions, except for basal posterior localization [9]. Complete reinnnervation of the heart is not seen- even up to 12 years after transplantation [9].

In myocardial infarction/ischemia:

Sympathetic nerve fibers are more susceptible to oxygen deprivation than myocytes and take longer to recover [29,33]. Uptake of I-123 MIBG is decreased in areas of acute and chronic ischemia [9]. Regional denervation of the heart in the post-ischemic myocardium may persist for 15 days or longer following an ischemic event [27]. Sympathetic denervation has also been shown in patients with stable angina in the absence of myocardial infarction presenting as MIBG defects with preserved perfusion [29].

Myocardial infarction destroys the myocardium and the nervous tissue in the myocardium. However, in the early post-infarction period, the MIBG defect is typically larger than the area of infarcted myocardium (a perfusion-innervation mismatch) [9,14]. This is because infarction can result in destruction of proximal neurons which supplied innervation to distal areas in which myocardial tissue is still viable (perfused and viable, but denervated myocardium) [14,33]. As a result, a defect identified on MIBG scintigraphy following infarction, may be more extensive than the actual area of infarction as demonstrated by thallium.

As an infarct heals, changes in tissue composition, repolarization disruption, and autonomic dysfunction can lead to an increased risk for arrhythmia [39]. There is evidence that both global and regional sympathetic denervation (anatomic loss of sympathetic nerves following infarction) or dysinnervation (sympathetic dysfunction or stunning) predispose patients to ventricular arrhythmias [39]. Patient's that demonstrate a perfusion-MIBG mismatch (perfused, but decreased MIBG activity) have electrophysiologic abnormalities that can predispose to lethal arrhythmias [33]. Denervated, but viable myocardium has been shown to be supersensitive to catecholamines and this may explain an increased risk for arrhythmogenicity in certain patients following MI [14,29]. Reinnnervation to these peri-infarct regions can be demonstrated by reappearance of MIBG uptake usually within 14 weeks following the cardiac event [9]. Unfortunately, reinnervation may be incomplete [9].

On C-11 HED evaluation, every 1% increase in volume of denervated myocardium has been shown to be associated with a 5.7% increase risk for sudden cardiac arrest [56]. Patients in the highest tertile of denervation had a sudden cardiac arrest rate of 6.7% per year [56].

In patients with ventricular tachyarrhythmias:

Electrophysiologic instability is an important trigger of cardiac arrhythmias and is modulated by autonomic function [34]. It has been demonstrated that scar tissue may serve as a substrate for ventricular arrhythmia (VA)- particularly the border zone surrounding a scar that consist of a mixture of both viable tissue and scar (and mIBG uptake in the border zone may predict recurrent VA) [50].

Abnormally decreased I-123 MIBG uptake can be seen in patients with ventricular tachyarrhythmias and is a powerful predictor of recurrent arrhythmic events and an inferior prognosis [30,34,51]. In heart failure patients, MIBG imaging provides incremental risk stratificaiton for the occurence of arrhythmic events (particularly for patients with HMR < 1.6) [49,51,52]. The risk for developing life-threatening arrhythmia and cardiac death is significantly lower for a HMR ≥ 1.6 [51] and in the ADMIRE-HEX study, no patient with a HMR of at least 1.8 experienced a fatal or potentially fatal arrhythmic event, compared to an event rate of 6-10% for patients with a HMR < 1.6 [52]. The presence of stress perfusion defects in non-ischemic cardiomyopathy patients also increases the risk for arrhythmic events (particular in patients with a HMR < 1.6 and a SRS >8) [51].

Regional cardiac sympathetic denervation can be found on SPECT imaging in up to 67% of patients with ventricular tachycardia (compared to 8% of control patients) [39]. I-123 MIBG imaging can effectively indicate which patients are likely to benefit from ICD [43]. The presence of resting perfusion defects is associated with an increased arrhythmic risk in patients with non-ischemic cardiomyopathy and heart failure (EF < 35%) with a decreased H/M ratio on I-123 MIBG imaging [46]. In one study, a H/M ratio < 1.54 was associated with an increased incidence of ICD discharges and on SPECT imaging, patients who had ICD discharges had more extensive autonomic/perfusion mismatches [43]. Unfortunately, due to globally decreased tracer uptake in heart failure patients, SPECT imaging can be challenging [51]. However, even the presence of myocardial scar on SPECT perfusion imaging has been shown to further risk stratify patients with low HMR < 1.6 [56]. In the ADMIRE-HF cohort, patients with a HMR < 1.6, but a summed rest score ≤8 had fewer episodes of sustained VT, resuscitated sudden cardiac arrest, and appropriate ICD therapies when compared to those with SRS > 8 (3.9% vs 11.9%) [56].

Other settings of abnormal myocardial innervation:

Parkinson's disease: Reduction of ¹²³I-MIBG uptake or (¹¹C-hydroxyephedrine (HED) on PET imaging) in the heart (due to cardiac sympathetic neuronal loss) is considered a specific finding for idiopathic Parkinson's disease (IPD) without autonomic failure and can be used to differentiate it from other parkinsonian syndromes [29,57]. ¹¹C-HED PET studies have demonstrated significant heterogeneity of cardiac denervation in IPD patients [57]. A regional pattern of denervation has been described preferentially involving the inferior and lateral LV walls, and relatively sparing the anterior and septal walls [57]. On short term (2 years) followup, IPD patients with baseline abnormal scans demonstrate progressive decline in cardiac sympathic neuronal integrity, but patients with normal HED scans have demonstrated no subsequent denervation and this may represent a protected phenotype [57]. Another study of IPD patients, also demonstrated a subgroup with early disease that had normal or mildly abnormal MIBG scans- this group of patients was characterized as female-dominant, young onset, slow progression in motor dysfunction, and preserved cognitive function [58].

A significant decrease in MIBG uptake is seen in the inferior and lateral segments in hypertensive patients with cardiac hypertrophy [29].

Cardiac sympathetic denervation/autonomic dysfunction in diabetic patients can also be evaluated with MIBG [29]. Decreased MIBG uptake in diabetics is associated with an increased mortality rate [29].

PET Adrenergic Imaging:

Norepinephrine (NE) is stored in neuronal vesicles and synthesized from tyrosine- tyrosine is converted to dihydroxyphenylalanine (DOPA) by rate-limiting tyrosine hydroxylase; DOPA is converted to dopamine by DOPA-decarboxylase which is actively transported into sotrage vesicles by vesicular monoamine transporter (VMAT); within the vesicle dopamine is converted to NE by dopamine beta-hydroxylase; some NE is further converted to epinephrine by phenylethanolamine-N-methyltransferase [44]. A sympathetic nerve impulse leads to docking of vesicles to the axonal membrane where its contents are released into the sympathetic cleft [44]. Over 80% of NE utilized by the heart is synthesized in the cardiac sympathetic neurons which necessitates the active recapture of the neurotranmitter from the synapse [44]. The active recapture is mediated by the NE reuptake transporter (uptake-1) which returns synaptic NE to the neuronal cytosol for packaging into vesicles or degradation by monoamine oxydase and catechol-O-methyltransferase [44]. Uptake-1 is saturable, can be blocked by reuptake inhibitors (such as cocaine and desipramine), and is dependent on ATP and sodium [44]. A small portion of synaptic NE undergoes transport via the uptake-2 pathway [44]. Uptake-2 is non-saturable and is not dependent on ATP or sodium [44]. Corticosteroids and clonidine have been shown to inhibit uptake-2 [44].

C11-hydroxyephedrine (HED- a norepinephrine analog) has been used for mapping cardiac sympathetic activity [29]. The agent is resistant to metabolism by monoamine oxidase and catecholamine O-methyltransferase, has a high affinity for the uptake 1 transporter mechanism, and is partially packaged into vesicles by vesicular monoamine transporter (VMAT) [29,51]. HED is believed to undergo continuous relaease and reuptake by sympathetic neurons [29]. The distribution of the tracer in the myocardium is normally homogeneous without the decreased activity in the inferior wall noted on SPECT MIBG imaging [29]. A marker for the quantification of C11-HED uptake is the retention index which is defined as the ratio between activity in the myocardium and th integral of the arterial blood-time activity curve [51]. The C11-HED global retention index closely correlates with the late I123-MIBG HMR [51]. The volume of viable denervated myocardium on C11-HED imaging shows a significant association with the time to sudden cardiac arrest [51].

[F18] 6-fluorodopamine may also be useful for cardiac imaging and the agent has a longer half-life [29]. The tracer is accumulated mainly via the presynaptic uptake 1 mechanism and then sequestered into sotrage vesicles and beta-hydroxylated to fluoroepinephrine [29].

Conditions/drugs which decrease cardiac MIBG uptake

• Pheochromocytomas/Elevated circulating levels of norepinephrine which competes with MIBG for the type I uptake system
• After eating
• Administration of yohimbine (due to increased adrenergic activity)
• Administration of tricyclic antidepressants (imipramine, desipramine) - produce a moderate reduction in cardiac MIBG uptake
• Administration of sympathomimetics (pseudoephedrine or phenylpropanoloamine)
  
• Administration of ladetalol- strong inhibitory effect on cellular uptake of MIBG [54]
• Administration of slective serotonin reuptake inhibitors or serotonin-norepinephrnie reuptake inhibitors
  
• Administration of reserpine- produces norepinephrine depletion through the irreversible inactivation of vesicular monoamine transporter, thereby preventing NE storage in vesicles and increasing the rate of enzymatic degradation [54]
• Cocaine use- cocaine and other monoamines have an inhibitory effect on cardiac MIBG uptake [54]
  
• Cardiovascular autonomic neuropathy of diabetes mellitus: Cardiovascular autonomic neuropathy is a serious complication of diabetes and the prevalence can be as high as 20-30% of patients with non-insulin dependent diabetes (NIDDM) [21]. Decreased cardiac MIBG uptake in diabetic patients is associated with an increased mortality [9,21]. Improvement in glycemic control has been shown to result in partial restoration of sympathetic innervation [14].
• Following cardiac transplantation (within 1 year, beyond this time about 50% of patients may demonstrate uptake indicative of re-innervation)
• Following ascending aortic aneurysm surgical repair- most likely the result of mechanical damage to the cardiopulmonary nerves surrounding the aorta [10].
• Following chemotherapy with doxorubicin: Decreased myocardial MIBG uptake can be seen following doxorubicin therapy, with limited morphologic damage [9]. Decreased MIBG uptake follows a dose dependent decline with about 25% of patients demonstrating some decrease in MIBG uptake at cumulative doses of 240-300 mg/m2 [9]. Decreased MIBG uptake precedes deterioration of ejection fraction [9,14]. Evidence of sympathetic damage can be used to select patients at risk of severe functional impairment and who may benefit from cardioprotective agents or changes in the schedule of antineoplastic drugs [9].
• Congestive heart failure secondary to pressure or volume overload
• Dilated cardiomyopathy- washout is also increased in these patients [6]
• Acute Myocarditis [6]
• Myocardial infarction [6]
• Sympathetic nerve destruction by stellate ganglionectomy
• Epicardial phenol application, and Shy-Drager syndrome.
• Parkinson's disease [10,14]. MIBG abnormalities observed in Parkinson's patients may be due to postgangliotic sympathetic dysfunction and has been correlated with severity and length of disease [14].
• LV hypertrophy due to essential hypertension [14]. MIBG abnormality is mainly observed in the inferior and lateral walls and the degree of abnormality correlates with the severity of hypertrophy [14].

Conditions which increase cardiac MIBG uptake

• Administration of clonidine (an alpha-2 antagonist which slows nerve traffic)
  
• Administration of amiodarone [54]
  
• Heart failure secondary to coronary artery disease

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