Introduction

Life-threatening ventricular arrhythmias (VA) are a major cause of death in patients with congestive heart failure (HF). Although impaired left ventricular ejection fraction (LVEF) remains the primary criterion for implantable cardioverter-defibrillator therapy to prevent sudden cardiac death, it still has low sensitivity and specificity for the population at risk [1].

As such, it is mandatory to identify other variables with prognostic value to predict the occurrence of VA.

The sympathetic nervous system may give rise to VA through several pathophysiological pathways including increased global sympathetic activity and regional cardiac sympathetic denervation resulting from ischemia, hibernation, or infarction [2]. In fact, an impaired function of presynaptic sympathetic nerve terminals is considered to reflect impaired reuptake and thus impaired removal of the neurotransmitter from the synaptic cleft [3], resulting in overexposure of the myocardium to catecholamines and in a pre/post-synaptic signaling imbalance [4].

Radionuclide imaging techniques, with Single-Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) imaging, using radiolabeled catecholamines, have been successfully used to identify global and regional impairments of sympathetic nerve terminals in the myocardium and their contribution to disease development and progression.

The most widely available tracer to assess cardiac sympathetic innervation using SPECT imaging is currently Iodine-123-labeled metaiodobenzylguanidine (123I-MIBG) [5,6,7]. Many studies have demonstrated that cardiac uptake of 123I-MIBG is reduced in individuals with heart failure and indicate that 123I-MIBG can be used as an independent predictor of heart failure progression and cardiac mortality [7,8,9]. Unfortunately, 123I-MIBG imaging suffers from evident limitations, mainly due to the fact that its main prognostic parameters, i.e., the heart-to-mediastinum ratio and the cardiac washout rate, are generally derived from planar scans of the chest, thus allowing only a semiquantitative evaluation of the global activity of sympathetic innervation [10]. Hence, PET may be a preferred technique, able to provide also a regional evaluation of the cardiac sympathetic innervation activity, which is considered to have a higher impact on clinical practice [11].

We present here the most relevant and recent literature findings, highlighting the current role of PET in the evaluation of cardiac sympathetic activity in patients with heart failure.

Materials and methods

Search strategy

A comprehensive literature search strategy using PubMed databases was carried out looking for articles on the role of Positron emission tomography/Computed Tomography (PET/CT) in the assessment of myocardial sympathetic innervation in patients with heart failure. The string used for the search included a combination of the terms: ‘myocardial sympathetic innervation’, ‘heart failure’, ‘myocardial PET imaging’, ‘radiolabeled catecholamines’, ‘11C-hydroxyephedrine’, ‘sudden cardiac death’, ‘regional denervation’, ‘myocardial infarction’. The search was extended to all radiopharmaceuticals tracing myocardial sympathetic innervation. The search was updated until October 2017 and was limited to the previous 5 years, taking into consideration only original papers published in English. The reason for this choice is that the large amount of references suggested limiting the search to the most recent findings, which were nevertheless reported in relation to previously published material. The references of the retrieved articles were also checked so as not to miss important clinical studies.

Review articles, articles not in the field of interest, single/double case reports, and commentaries were excluded. Papers on future perspectives in the field and experimental data were also considered eligible.

Study selection

Only original articles were selected in the systematic review according to the following inclusion criteria: a) evaluation of the role of PET in the assessment of cardiac sympathetic innervation in patients with heart failure and b) a minimum sample size of ten patients (in order to minimize the publication bias). Two researchers (C.E.P. and F.C.) independently reviewed the titles and the abstracts of the retrieved literature, selecting relevant articles according to the inclusion criteria mentioned above. Disagreements were resolved in a consensus meeting.

Results

The initial literature search revealed 142 papers published in the past 25 years. From a first check, considering only the articles of the previous 5 years, 40 out of 142 articles were selected. Applying the selection criteria, 21 of the 40 papers were excluded (11 reviews, 5 commentaries and letters, 5 papers not relevant for the aim of the study). Finally, 19 articles resulted eligible for the inclusion in this review. Specifically, 15 papers described clinical studies, while 4 were preclinical/experimental. The characteristics of all included articles are shown in Table 1.

Table 1 Prospect of the studies included in the review, listed according to the study design and in chronological order. See the text for patient numbers, tracer and clinical relevance
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PET: radiolabeled tracers in the assessment of myocardial sympathetic innervation

The assessment of sympathetic innervation using PET may have incremental value in evaluating the arrhythmic substrate [12]. The superior spatial resolution of PET allows for a more detailed assessment of regional sympathetic innervation and innervation/perfusion mismatch areas. Also, dynamic imaging protocols enable absolute quantification of sympathetic nerve retention of tracers [13]. In addition, dependent on specific characteristics of the tracer used, several biological aspects of the cardiac neuronal function can be visualized [14].

11C-hydroxyephedrine (HED)

To date, the most commonly used and studied tracers for PET imaging is the norepinephrine (NE) analogue 11C-hydroxyephedrine (HED). Similarly to 123I-MIBG, 11C-HED shows high affinity for presynaptic NE uptake-1 allowing the visualization of presynaptic sympathetic nerve function [15, 16]. 11C-HED uptake is commonly quantified via a retention index, which is defined as the ratio of the activity in the myocardium in the final image of a 40- or 60-min dynamic sequence to the integral of the image-derived arterial blood-time activity curve [17]. Recent studies found a close correlation between 11C-HED retention index and late 123I-MIBG heart-to-mediastinum rate [15, 18]. In addition, by calculating the influx rate (K1) from blood to myocardium of 11C-HED scan, Harms et al. [19] recently demonstrated, in a study including 17 patients with known ischemic cardiomyopathy, the feasibility of assessing perfusion and innervation defects to evaluate mismatch areas using a single dynamic 11C-HED PET scan. Moreover, in patients with ischemic or dilated cardiomyopathy, absolute quantification of 11C-HED kinetics can be performed noninvasively, enabling a more comprehensive analysis of sympathetic innervation without arterial cannulation [20].

Animal studies suggest that non neuronal uptake can vary between 123I-MIBG and 11C-HED [21]. Specifically, 11C-HED appears to have significantly less extraneuronal uptake and higher resistance to degradation by metabolic enzymes. These features make the detection of regional variations in myocardial sympathetic innervation more robust using 11C-HED. The potential impact of this tracer in translational cardiovascular imaging has been elegantly shown in a recent paper, wherein higher susceptibility of sympathetic neurons compared to myocytes was confirmed in a rat model of myocardial transient ischemia (Fig. 1). Specifically, the authors reported a denervated zone larger than the perfusion defect, thus identifying a peri-infarct susceptibility area at increased risk to trigger VA. Interestingly, partial reinnervation was observed in the chronic phase as shown by recovery of subepicardial 11C-HED uptake, thus highlighting a crucial role of the therapy [22].

Fig. 1
figure 1

Reprinted with permission of Springer from Werner et al. Eur J Nucl Med Mol Imaging. 2016;43:312-8 [22]

In vivo serial PET scan using 11C-HED and 18F-FDG in a rat model of myocardial transient ischemia. 11C-HED uptake defect (arrows) was observed only after ischemia. Myocardial viability performed with 18F-FDG was preserved at the 11C-HED defect zone. The 11C-HED uptake at 1 week demonstrated reduction at month 2.

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Other tracers

11C-epinephrine (EPI), A tracer that also evaluates cardiac sympathetic innervation [23], was mainly been employed in pre-clinical research [24, 25], but may be considered superior to HED, since it traces the entire pathway of catecholamine uptake, metabolism, and vesicular storage. Münch et al. directly compared EPI to HED in a study performed in healthy volunteers and patients after heart transplantation [26]. Interestingly, retention of EPI was higher than that of HED in normal hearts, but retention of EPI was lower than that of HED in transplanted (denervated) hearts, presumably reflecting lower non-specific uptake. Thus, EPI might have inherently higher sensitivity to detect changes in sympathetic innervation of the heart. Sasano et al. [27] also showed that the extent of viable but denervated myocardium quantified with 11C-EPI and 13NH3 PET was associated with inducible ventricular tachicardias (VTs) in a porcine model. Importantly, the area of denervated but viable myocardium was related to the site of initiation of the induced VTs as well as decreased endocardial voltage obtained by voltage mapping.

In addition, the uptake of multiple presynaptic tracers was explored in viable but denervated myocardium in a similar porcine myocardial infarction model [28]. In the viable infarct border zone, neuronal vesicular catecholamine storage and protection from metabolic degradation are more severely altered than catecholamine uptake. This alteration may reflect an intermediate state between normal innervation and complete denervation in advanced disease [28].

11C-phenylephrine (PHEN) is a substrate for monoamine oxidase (MAO) and is thought to be useful in the assessment of vesicular leakage [29]. In a validation study of PHEN, which was compared to HED in healthy humans, the two tracers gave initial uptake images of similar quality and uniformity, although PHEN showed much faster washout. This property of PHEN allows the calculation of storage half-life, which can provide additional useful information about the functional integrity of the cardiac sympathetic innervation [30].

To overcome the limitations related to the use of radionuclides with a short half-life, tracers labeled with Fluorine-18 have been studied. Due to the longer half-life of Fluorine-18 (110 min), they can be distributed to centers that do not have an on-site cyclotron. Moreover, clinical imaging with 18F labeled tracers present more flexibility in the study design for the assessment of regional myocardial sympathetic activity.

The development of Fluorine-18–labeled radiopharmaceuticals is essential for a broader dissemination of sympathetic innervation imaging by PET in clinical practice. In this regard, 18F-LMI1195 has been developed to overcome the limitations of conventional tracers and presents similarities with 123I-MIBG based on its benzylguanidine structure [31]. Preliminary studies suggest that 18F-LMI1195 is stored and released similarly to norepinephrine in the nerve terminals [31, 32]. The relationship between myocardial denervation and sudden cardiac death (SCD), along with the potential for an effective Fluorine-18-labeled tracer suggest the potential for 18F-LMI1195 to help identifying high-risk patients for SCD and guide resynchronisation therapy [33]. In the first-in-human preliminary description of 18F-LMI1195, Sinusas et al. suggest that the tracer is well tolerated and yields a radiation dose comparable to that of other commonly used PET radiopharmaceuticals. The kinetics of myocardial and adjacent organ activity suggests that cardiac imaging should be possible with acceptable patient radiation dose [34].

Two additional radiopharmaceuticals, i.e., 18F–4F-MHPG and 18F–3F-PHPG, were proven in animal models to yield accurate quantitative measures of regional nerve density along with a favorable heart-to-liver ratio. Initial biological studies demonstrated a slow uptake and longer retention time in sympathetic neurons, suggesting that these radiotracers may have the potential to show slight cardiac innervation impairment. A major advantage of these two tracers is the intrinsic potential for a robust absolute quantification of the myocardial uptake, as highlighted by a recent first-in-human study [35].

PET with 11C-CGP12177 has been employed to image the postsynaptic side of the adrenergic system [15, 32]. Reduction of myocardial β-adrenoreceptor density, as measured by 11C-CGP12177, has been shown in patients with dilated cardiomyopathy and it has been related to the severity of HF [36]. Furthermore, myocardial β-adrenergic receptor density predicted improvement of cardiac function by carvedilol treatment, whereas cardiac contractile reserve as assessed by dobutamine stress echocardiography did not [37].

PET in clinical studies

The occurrence of inhomogeneity in myocardial sympathetic denervation can be related to myocardial infarction and may create a myocardial substrate particularly vulnerable to arrhythmic death [38, 39].

In addition, also reversible ischemia (from angina or silent ischemia) can cause an inhomogeneity in myocardial sympathetic innervation, occurring in both stunned and hibernating myocardium [40]. In pre-clinical models of hibernating myocardium, there is evidence of an increased risk of arrhythmic death from spontaneous ventricular tachycardia (VT)/ventricular fibrillation (VF), which is often unrelated to infarction and heart failure [38, 41, 42]. In this regard, PET imaging with 11C-HED accurately demonstrates extensive sympathetic denervation [43, 44].

Fujita et al. [45] demonstrated in a retrospective analysis of observational study that low global 11C-HED retention is a marker of poor overall survival in patients with LV dysfunction.

Recently, PET with 11C-HED was employed to quantify the extent of regional sympathetic denervation and predict the risk of SCD in candidates for a primary prevention implantable cardioverter defibrillator (ICD) with ischemic cardiomyopathy [40, 43, 46]. In the prospective PAREPET observational cohort study, including 204 subjects with ischemic heart failure (LVEF ≤ 35%), 11C-HED PET was used in combination with perfusion imaging with 13N-ammonia and viability with insulin-stimulated 18F-FDG. The primary end-point was a life-threatening arrhythmia, defined as arrhythmic death or ICD discharge for VT/VF > 240 bpm [40]. A higher rate of SCD was reported in patients with perfusion/innervation mismatch, consistent with the presence of viable but denervated myocardium. Of note, the PAREPET study also showed that the extent of the denervated myocardium is significantly correlated to the risk of SCD. Specifically, a denervated area greater than 37.6% of the LV predicts a higher risk. Interestingly, this holds true independently of LVEF and infarct size. Also a subsequent study confirmed the important prognostic role of the mismatch between myocardial innervation and perfusion, capitalizing on innervation and perfusion imaging with 11C-HED and [15O]H2O PET [47].

Hirofumi et al. [48] investigated the relationship between sympathetic innervation (assessed by 11C-HED PET), contractile function (measured by echocardiography), and the oxidative metabolism (using 11 C-acetate PET) of the non-infarcted myocardium in 19 patients with prior myocardial infarction. They showed that the remodeled LV presents with impaired sympathetic innervation and function even in the non-infarcted myocardial tissue (r = 0.566). Of note, the oxidative metabolism in the non-infarcted myocardium seems to be independent from pre-synaptic sympathetic neuronal function and rather linked to normal regulatory mechanisms (r = 0.649). This mismatch zone originates from residual viable myocardium that has sustained ischemic nerve injury and is related to the heterogenic scar zone as assessed with late gadolinium-enhanced (LGE) cardiac magnetic resonance imaging (CMR).

Impaired innervation was also demonstrated in non-infarcted myocardium in ischemic and dilated cardiomyopathy (ICMP and DCMP). Factors affecting sympathetic nerve integrity in remote myocardium are still unknown. However, perfusion abnormalities such as microvascular dysfunction, even in the absence of detectable coronary artery disease (CAD), may underline a sympathetic dysfunction. In this regard, a recent study aimed to investigate the interrelations between myocardial perfusion, contractile function, and sympathetic innervation in non-infarcted myocardium in 70 patients with ICMP and DCMP and LVEF ≤ 35% [49].11C-HED- and [15O]H2O PET were performed to quantify MBF at rest and under stress conditions as well as sympathetic innervation. The authors found that the hyperaemic MBF is independently associated with sympathetic innervation in non-infarcted and non-ischemic remote myocardium in patients with ICMP and DCMP. This confirms that microvascular dysfunction plays an important role to determine sympathetic nerve integrity. Nevertheless, it remains unclear whether the impaired hyperaemic MBF is the primary cause of this relation.

Obstructive sleep apnea (OSA) and heart failure (HF) with reduced ejection fraction (HFrEF) are two states of increased metabolic demand and sympathetic nervous system activation that often coexist. In a randomized trial with 45 patients with HFrEF and OSA undergoing 11 C-acetate and 11C-HED PET, Hall et al. [50] demonstrated a significant increase in hydroxyephedrine retention in the group of patients allocated to CPAP, indicating reduced myocardial sympathetic dysregulation. Unfortunately, the authors failed to demonstrate significant favorable alterations in myocardial function or energetics overall in the treated group and further outcome-based investigation of the consequences of CPAP is warranted.

A few papers have evaluated the value of 11C-HED PET to identify predictors of regional sympathetic denervation in patients with heart failure with preserved left ventricular ejection fraction (HFpEF). HFpEF is functionally characterized by diastolic dysfunction accompanying myocardial fibrosis [51, 52]. Aikawa et al. [53] demonstrated that myocardial sympathetic denervation, as assessed by 11C-HED PET, was impaired in HFpEF patients and was associated with the presence of advanced diastolic dysfunction independently of LV ejection fraction.

More recently, the same authors [54] evaluated 34 patients with HFpEF (LVEF ≥ 40%) and 11 age-matched control volunteers without HF. All subjects underwent cardiac magnetic resonance imaging to measure LV size and function, and the extent of myocardial late gadolinium enhancement (LGE) and 11C-HED PET to identify predictors of regional sympathetic denervation. These were quantified by means of 11C-HED retention index (RI, %/min). They found that global 11C-HED RI was significantly lower and more heterogeneous in HFpEF patients than in volunteers. Moreover, regional 11C-HED RI was positively correlated with systolic wall thickening (r = 0.42) and negatively with the extent of LGE (r = − 0.43). Segments with a large extent of LGE in HFpEF patients had the lowest regional 11C-HED RI among all segments. Multivariate analysis demonstrated that systolic wall thickening and the extent of LGE were significant predictors of regional 11C-HED RI in HFpEF patients. In conclusion, the authors suggested that regional sympathetic denervation is associated with contractile dysfunction and fibrotic burden in HFpEF patients, thus providing an integrated measure of myocardial damage in HFpEF.

In a recent paper featuring young subjects with type 1 diabetes (IDDM) without evidence of cardiovascular disease, Duvernoy et al. [55] found no significant differences in LV function, innervation, or oxidative metabolism between IDDM and controls. Furthermore, T1DM women presented with greater myocardial oxidative metabolism requirements than men.

Finally, a few papers analyzed the role of 11C-labeled catecholamines PET to identify imaging parameters that could predict the response to therapy.

In patient with end-stage HF, cardiac resynchronization therapy (CRT) may be the treatment option of choice. Capitanio et al. [56] evaluated the variation of cardiac adrenergic activity in patients with idiopathic heart failure (IHF, NYHA III-IV) after CRT using 11C-HED PET/CT. They found that the improvement in homogeneity of myocardial neuronal function reflected a selective increase of tracer uptake in regions with more severe neuronal damage. These finding supported the presence of a myocardial regional variability in response of cardiac sympathetic system to CRT and a systemic response involving remote tissues with rich adrenergic innervation.

Post-transplant reinnervation is a unique model to study sympathetic neuronal regeneration in vivo but the differential role of subcellular mechanisms of catecholamine handling in nerve terminals is still unclear. Bravo et al. [57] speculated that there may be subtle differences in the regenerative capacity of subcellular mechanisms of nerve terminal function. Ten heart transplant recipients were included at > 1 year post transplantation. Three different 11C-labeled catecholamine analogues were used to evaluate catecholamine transport (11C-HED), vesicular storage (11C-EPI), and metabolic degradation (11C-1phenylephrine). Quantification of myocardial blood flow was performed with 13N-NH3 PET. The results of this paper suggest that the regeneration of subcellular components of sympathetic nerve terminal function does not occur simultaneously. In the reinnervating transplanted heart, a region with normal catecholamine transport and vesicular storage is surrounded by a borderzone, where transport is already restored but vesicular storage remains inefficient, suggesting that vesicular storage is a more delicate mechanism. This observation may have implications for other pathologies involving cardiac autonomic innervation such as myocardial ischemia, infarction, heart failure, metabolic, and neurodegenerative diseases, where impaired innervation has been identified and where the presence and contribution of nerve regeneration is less well defined [43, 58,59,60]. Of note, vesicular storage may not only require more time for restoration but it may also be damaged at an earlier stage in disease, as suggested by preclinical work in myocardial infarction [27]. Whether this has implications for adverse outcome, or whether it may emerge as a target for regenerative therapies, should be a subject of future studies.

Conclusion

It is undoubtedly clear that the assessment of myocardial sympathetic activity in patients with heart failure will play a pivotal role in clinical practice. Its capability to predict the occurrence of life-threatening ventricular arrhythmias (VA) in the presence of still viable but denervated myocardium (Fig. 2) [12, 40] and the effectiveness of resynchronization therapy [56] makes this technique ideal in the era of personalized medicine.

Fig. 2
figure 2

Reprinted under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/) from J Nucl Cardiol. 2016;23:218-34 [12]. No changes were made

Representative image showing the potential arrhythmic substrate in two patients with ischemic cardiomyopathy candidates for ICD implantation for primary prevention of sudden cardiac death who underwent 15O-H2O PET, 11C-HED PET, and LGE-CMR. Patient 1 a–c shows a basal inferior wall myocardial infarction with contrast enhancement in this region (a) and a corresponding perfusion defect (c) with an extensive innervation defect (b) that exceeded the infarct size, resulting in a significant innervation-perfusion mismatch. Patient 2 d–f shows a large inferior wall myocardial infarction with transmural contrast enhancement as well as subendocardial contrast enhancement at the anterolateral wall (d). 15O-H2O PET and 11C-HED PET indicate corresponding perfusion and innervation defects with only limited innervation-perfusion mismatch. CMR cardiovascular magnetic resonance, LGE late gadolinium enhancement, PET positron emission tomography.

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An important advantage of PET imaging over other techniques is  the potential for a full quantitative analysis of myocardial denervation. A quantitative analysis bears great importance to overcome limitations due to global downregulation of myocardial catecholamine storage, which is frequently reported in patients with heart failure [61, 62].

Furthermore, PET allows also to evaluate the myocardial sympathetic innervation activity along with other molecular-targets, capitalizing on different half-lives of different radiopharmaceuticals used in multi-radioisotope investigations. This represents a unique approach to provide useful prognostic information in patients with heart failure. Very specific insights may be provided by combining information on myocardial sympathetic activity and other variables identifying, for example apoptosis, extracellular matrix activation, or angiogenesis [62].

In this regard, translational molecular imaging is expected to play an important role in boosting the research on the intimate pathophysiological mechanisms underlying LV denervation. This will also provide an invaluable tool to direct optimized targeted therapies.