The role of PET Cardiac Neurotransmission Imaging in Heart Failure.

Sophia I. Koukouraki

Assistant Professor

Department of Nuclear Medicine, Medical School, University of Iraklion,Crete, Greece

Abstract:

Congestive Heart Failure (CHF) is increasing throughout the world. Heart failure patients can be evaluated with non invasive imaging techniques including echocardiography, MRI and nuclear medicine imaging modalities. Single photon emission tomography (SPECT) and positron emission tomography (PET) evaluate cardiac sympathetic innervation in vivo. SPECT techniques with 123 I metaiodobenzylguanidine (MIBG) offer informations about the cardiac sympathetic function but the value for the quantitative assessment of myocardial adrenergic nervous system is limited due to the restricted spatial resolution. PET imaging provides further information into the pathophysiology of the failing heart.

PET has many clinical applications in patients with heart failure such as assessment of sympathetic innervation in patients with HF, risk assessment regarding ventricular arrhythmias and sudden cardiac death (SCD), selection of patients who are likely to benefit from implantable cardioverter defibrillator (ICD) implantation.

Keywords: SPECT and PET neurotransmission imaging, Heart failure

INTRODUCTION

Heart Failure (HF) is an important condition with increased morbidity and mortality [1].In addition to myocardial blood flow the neurohormonal system plays an important role in patients with HF. As CHF develops, compensatory mechanisms such neurohormonal mechanisms are activated to maintain heart rate, blood pressure and tissue perfusion. An impairement of cardiac autonomic function reflects the severity of the cardiac disease and seems to increase the risk of death in these pts [2].

At present heart failure patients can be evaluated with different non invasive imaging techniques including echocardiography, MRI and nuclear medicine imaging modalities (SPECT and PET). Imaging of cardiac sympathetic innervations was first reported in the 1980s with the use of 123 I-MIBG SPECT imaging [3,4].

NEURONAL IMAGING WITH PET IN HEART FAILURE

Molecular imaging techniques have been developed for global and regional assessment of presynaptic and postsynaptic targets of the cardiac autonomic nervous system. SPECT and PET imaging modalities are able to evaluate the cardiac sympathetic innervation in vivo. SPECT techniques with 123 I metaiodobenzylguanidine (MIBG) offer information about the cardiac sympathetic function, including uptake, reuptake, storage and release of norepinephrine at presynaptic nerve terminals. However, methodological problems limit the value of this method for the quantitative assessment of myocardial adrenergic nervous system due to the restricted spatial resolution [5,6].

Recent emphasis is given on the development of novel imaging modalities including PET imaging providing further information into the pathophysiology of the failing heart in order to be used for early detection of HF as for monitoring new therapeutic interventions.

PET tracers

PET tracers for neurotransmission cardiac imaging are classified in: a). Tracers of sympathetic neuronal integrity, b) tracers of adrenergic receptors (11C-CGP12177, 11C-CGP 12388: 11C-GB 67).and c) tracers of the parasympathetic nervous system. Regarding the tracers of sympathetic neuronal integrity there are two subgroups: 1) radiolabeled endogenous neurotransmitters or true adrenergic neurotransmitters which are molecular identical to endogenous neurotransmitters and they follow the metabolic pathways of catecholamines within the myocardium and sympathetic neurons and 2) radiolabeled catecholamine analogues or false neurotransmitters that are resistant to specific steps of catecholamine degradation, follow the same uptake and release mechanisms, without being metabolized like the endogenous transmitters. Examples of tracers of sympathetic neuronal integrity are: 11C-Hydroxyephedrine (11C-HED), 11C-Epinephrine (11C-EPI), 18F–fluorobenzilguanidine (LMI1195) 11C-Phenylephrine (11C-PHE), 18 F Fluorodopamine. Regarding the third group, the tracers of the parasympathetic nervous system (PNS), only few tracers are available like Vesamicol derivatives, 11C-MQNB, 18F A85380, 18F-fluoroethoxybenzovesamicol (FEOBV). PET imaging of cardiac parasympathetic neurons is complicated due to the low density of cholinergic neurons within the ventricular myocardium [7-18].

CLINICAL APPLICATION OF NEURONAL IMAGING WITH PET IN HEART FAILURE

The most important clinical applications in patients with heart failure are: a) the assessment of sympathetic innervation, b) the risk assessment regarding ventricular arrhythmias and sudden cardiac death (SCD)and c) the selection of patients who are likely to benefit from implantable cardioverter defibrillator (ICD) implantation.

Assessment of sympathetic innervation in patients with HF

Sympathetic function is abnormal in CHF patients, who demonstrate increased sympathetic nerve activity. Heart failure patients with severe deprived cardiac sympathetic innervation tend to have worse prognosis when compared to HF patients with relatively preserved neuronal integrity. PET imaging is used for accurate assessment of regional neuronal defects [18,19].

11C-HED PET imaging is an accurate tool to demonstrate global reduction and regional abnormalities of tracer uptake. Moreover, the degree of abnormality was positively correlated to markers of severity of HF. There are several possible explanations for HED decreased retention. A possible mechanism may be the increased sympathetic nerve firing rates in HF. The increased wall stress of a dilated left ventricle, may result in metabolic abnormalities, leading to decreased activity of uptake-1 function and vesicular storage mechanism. The subsequent reduction of neuronal reuptake may play a key role in changes of sympathetic pathway in HF. Moreover, reduced HED retention indicates loss of neuronal tissue and is associated with poor prognosis in CHF. 11C-HED uptake is a better predictor of death than EF or heart rate viability.

Selection of patients with heart failure who are likely to benefit from implantable cardioverter defibrillator (ICD) implantation. Risk assessment regarding ventricular arrhythmias and sudden cardiac death (SCD)

Autonomic dysfunction plays a key role in the generation of life-threatening arrhythmias and SCD. The incidence of SCD in patients with HF is high and is a major cause of death [20]. If a patient at risk of SCD can be identified, an ICD can be implanted. The criterion currently used to identify patients at risk and to determine those to get an ICD, is the left ventricular ejection fraction (LVEF) lower than 30%-35%. However, in a large number of patients who receive an ICD, the device never has to deliver therapy. On the other hand, most patients who die suddenly have LVEF > 35% who were not qualified for ICD placement [21].

A parameter other than LVEF is needed to better qualify patients at risk who need an ICD. The development of PET neuronal tracers promises to be a powerful tool for guidance of therapy in pts at risk for SCD. There is the hypothesis that the inhomogeneity in myocardial sympathetic innervation increases the risk of deaths independently of left ventricular function. The PAREPET (Prediction of Arrhythmic Events with Positron Emission Tomography) study was considered an initial step in evaluating primary prevention ICD candidates. The volume of denervated myocardium had the strongest correlation with sudden cardiac death [22].

Assessment of cardiac innervation in HF patients who underwent cardiac transplantation

HF therapy has become increasingly complex as the proposed therapeutic options have significant risks. Cardiac transplantation is the treatment of choice for patients with end stage HF. Acute transplant rejection is the leading cause of graft failure during the first year following the surgery. Since the process of rejection is at first usually clinically silent its early identification is important to limit the extension of necrosis. During cardiac transplantation, postganglionic sympathetic fibers of the donor heart are interrupted, resulting in complete sympathetic denervation of the transplanted heart. Overtime, some sympathetic reinnervation occurs. PET methods can provide information about the pathophysiology of the transplanted heart and may have an important role in improving outcome for transplanted patients[23,24]

Conclusion

The important role of cardiac imaging in the management of pts with HF continues to grow. Echocardiography remains a first line test in HF and provides valuable information on left ventricular and valvular function. Imaging tools such as SPECT and PET imaging provide additional insight into myocardial tissue. The ability to image cardiac neuronal system with radiotracers is a powerful tool to assess HF patients, and to guide the therapeutic approach. Although SPECT imaging is widely available and technically less demanding, PET imaging has important advantages including a high spatial and temporal resolution and absolute quantification. It also can provide a wide range of different radiolabeled catecholamines, catecholamine analogues and receptor ligands. Assessment of sympathetic nerve activity in patients with HF provides important prognostic information and can identify patients who are at increased risk or SCD. Moreover, therapeutic treatment strategies are evaluated by PET imaging.

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