Original Article
Imaging of cardiac sympathetic dysfunction with 18F-FDOPA PET/CT in patients with heart failure: a pilot study

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Abstract

Background

Routine use of cardiac sympathetic imaging in HF has been limited by the lower availability/sensitivity of radiotracers. This study was aimed to assess the feasibility of 18F-FDOPA (commonly available PET-radiotracer) in assessment of cardiac autonomic dysfunction.

Methods

Twenty-four controls (46.5 ± 11.1 years, 16men) and 24 patients (43.5 ± 11.0 years, 18men) with diagnosed HF (Framingham-Criteria) underwent cardiac-PET/CT. Region(s) Of Interest were drawn over entire left ventricular myocardium (LV), individual walls, and mediastinum (M). Coefficient of Variation (CV) was calculated from individual wall counts.

Results

HF patients had significantly lower myocardial 18F-FDOPA uptake (P < .001, independent t test) than controls [32.4% ± 9.5% global reduction; highest in apex (39.9% ± 7.0%)]. A cut-off of LV/M ≤ 1.68 could differentiate patients from controls with sensitivity and specificity of 100% and 95.8%, respectively. LV/M correlated positively with EF (Pearson coefficient = 0.460, P .031). During follow-up, 3 patients were lost to follow-up, 4 died (survival-20.5 ± 4 months), 2 worsened, and 15 remained stable/showed mild improvement. Patients who worsened/died during follow-up had higher CV than those with stable/improving symptoms [0.16 ± 0.05 vs 0.11 ± 0.05, P value .069 (independent t test); Cox regression P = .084].

Conclusion

Myocardial 18F-FDOPA uptake in patients with HF is significantly reduced. Higher reduction is seen in those with lower EF. CV, a maker of regional heterogeneity, is a potential prognostic marker.

Introduction

In its most simple definition, heart failure (HF) is the inability of the heart to ensure adequate perfusion to different organs within the body. Though, this definition may give an appearance that HF is a disease of the cardiovascular system, multiple studies over the course of past few decades have shown it to be anything but. In fact, its pathophysiology is characterized by a complex interplay of the cardiovascular, neuro-hormonal, and autonomic systems, which dictate the choice of treatment and consequently the quality of life and ultimately survival.1,2 Among these different systems, role of the autonomic system in the natural progression of the disease is particularly significant. Both arms of the autonomic system, i.e., sympathetic and parasympathetic systems are affected, with the former being augmented and the latter being suppressed.1 This has led to the development of many therapies including beta-receptor blockade as a means to prevent re-modeling and modulation of autonomic pathways.2,3 It continues to be a focus of research for development of future therapies. It is precisely due to these reasons that imaging of the autonomic dysfunction has gained prominence in the management of these patients. Sympathetic system imaging with the use of sympathomimetics like 123I-MIBG (meta-iodobenzylguanidine) and l1C-HED (Hydroxyephedrine) has demonstrated a clear role of SPECT/CT and PET/CT in assessment of the extent of the dysfunction and prognostication.4, 5, 6, 7 Studies have demonstrated the denervation as assessed by the sympathetic PET/CT imaging to be a predictor of sudden cardiac arrest and a potential approach to select patients more likely to benefit from an implantable cardiac defibrillator.8 Additional research is also being carried out to develop tracers which can assess parasympathetic system (most tracers at present are experimental and not used routinely).9

Despite these tracers showing significant benefit in the patient management and follow-up, their penetration in routine clinical care is limited.5 While on the one hand, 123I-MIBG suffers from the lower resolution and sensitivity that are inherent to SPECT systems (compared to PET); on the other hand, 11C-HED and other 11C bases tracers are limited to centers with an on-site cyclotron (half-life of only 20 minutes).10 Similarly, 18F-Fluoride-based tracers like Fluorodopamine and Flubrobenguane have not found widespread use beyond the realm of research.11,12 It is in this backdrop, we decided to search for a more commonly available PET tracer for cardiac sympathetic imaging. Among the available tracers, 18F-FDOPA (6-[18F]-l-fluoro-l-3, 4-dihydroxyphenylalanine) fit the bill as it is a part of the norepinephrine pathway, is widely available [due to use in other indications, like neuro-oncology, Neuro-endocrine tumors, and Parkinson’s Disease (PD)], can be synthesized via kit-based modules, half-life of 18F permits long distance transport (half-life—110 minutes) and overall has favorable cost profile.13, 14, 15, 16, 17, 18 In this pursuit, we conducted a feasibility study in patients with advanced Idiopathic PD (IPD), who underwent 18F-FDOPA imaging for striatal dysfunction and we were able to show significantly reduced uptake in the heart on account of sympathetic denervation and dysfunction.19 On the basis of these encouraging results validating the feasibility of 18F-DOPA in imaging cardiac sympathetic innervation we planned to demonstrate its feasibility in patients with HF.

Because of the difference in the pathology of sympathetic involvement in patients with IPD vs HF, it was decided to limit the scope of this study to the demonstration of the feasibility of this tracer in imaging of myocardial sympathetic dysfunction, in ambulatory HF (NYHA II and III) patients, who were undergoing routine follow-up in the HF OPD.2,20 The secondary aim was to search for any prognostic significance of the cardiac uptake of the tracer. The results as documented in the following sections will allow us to conduct further studies in patients with more advanced disease.

Section snippets

Methodology

Twenty-four patients (18 men; 6 women; Mean age: 43.5 ± 11.0 years) with clinical diagnosis of HF [Framingham criteria and clinical/investigative testing21] who presented to the cardiology out-patient department were recruited for the study between April 2019 and March 2020. Inclusion criterion was age ≥ 18 years, those who signed informed consent, who were NYHA II/III, ambulatory, and had been diagnosed ≥ 6 months. Exclusion criteria were medications that influence the sympathetic system

Controls

Sixteen men and eight women were selected as controls, with a mean age of 46.5 ± 11.1 years. No significant correlation was found between the regional/global myocardial uptake and the age (P > .05 for all Pearson correlations). Similarly, no relationship was observed with the sex of the controls (independent sample t test P > .05 for all parameters).

Cases

Eighteen men and six women with HF were recruited. Their mean age was 43.5 ± 11.0 years. Mean time since first diagnosis of HF was 5 ± 3 years

Discussion

Sympathetic nervous system plays an active and essential role in the modulation of the cardiac function. Its dysfunction is commonly encountered in many cardiovascular disorders and dictates patient prognosis and survival.2,6 With an aim to assist clinicians in the patient-specific tailoring and monitoring of treatments, many modalities to assess sympathetic activity have been and are being developed. One such modality, which has gained significant prominence, is the functional imaging using

Conclusion

Cardiac 18F-FDOPA PET/CT is a feasible and widely available modality for the assessment of sympathetic dysfunction in the patients with heart failure. The uptake of this tracer is significantly reduced in patients with HF and variability of uptake within the myocardium may serve as a prognostic indicator for worsening disease. This feasibility study paves way for the exploration of this tracer in patients with more severe disease.

New knowledge gained

18F-FDOPA, an analogue of L-DOPA can be used to image sympathetic dysfunction in patients with Heart Failure. Its uptake correlates positively with the EF. It has potential to prognosticate patients as well. This commonly available radiotracer (due to many indications) can catalyze the process of widespread adoption of sympathetic imaging in patients with HF.

Funding

No funding was received for this work.

Data availability

All the data can be made available upon request.

Disclosure

None of the authors or their relatives have any conflicts of interest to disclose.

Ethical approval

Ethical approval was obtained prior to initiation of the study.

Consent to participate

All patients and controls signed the consent form.

Consent for publication

All authors have reviewed the final draft and consent to journal’s terms and conditions.

Funding

No funding was received for this work.

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    Thayumanavan Thanigainathan and Anshul Sharma have contributed equally to this work and are first authors.

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