Imaging of the Cardiac Sympathetic Nervous System Has Potential Value in the Evaluation of Patients with Heart Failure with Preserved Ejection Fraction

Heart failure (HF) is a major public health problem that affects more than 5.8 million people in the United States and 23 million people worldwide (1). HF is a clinical syndrome, rather than a disease, and can occur in patients with reduced and preserved left ventricular (LV) ejection fraction. Community-based studies indicate that approximately 50% of patients with the clinical diagnosis of HF have preserved EF (HFpEF), whereas the remaining patient population presents with HF with reduced EF (HFrEF) (2,3). The values used to define preserved EF range in the literature from 40% to 55%, but current guidelines recommend an EF of more than 50% with elevated natriuretic peptide (BNP or NTproBNP) levels and relevant structural heart disease, such as left atrial enlargement or LV diastolic dysfunction, as criteria for HFpEF (4,5). Although clinical symptoms and mortality are similar among patients with HFpEF and HErEF, there are pronounced differences between these HF phenotypes in patient demographics, responses to therapy, and underlying pathophysiology of LV remodeling (6,7). Importantly, the prevalence of HFpEF relative to HFrEF is rising at a rate of 1% per year and will thus dominate as the prevalent HF phenotype over the next decade (8). Despite the rising prevalence, there are limited data to support effective therapies for HFpEF, and the role of diagnostic strategies and prognostic biomarkers remain ambiguous (4,9). Excessive cardiac sympathetic nervous system (SNS) activation is a hallmark of HF progression in patients with HFrEF (10–12). A compensatory increase in adrenergic drive causes desensitization/ downregulation of the norepinephrine transporter (or uptake-1 mechanism) on the cardiac presynaptic nerve terminal due to excess norepinephrine in the synaptic cleft. The downregulation of uptake-1 exposes the heart and postsynaptic adrenergic receptors to greater concentrations of norepinephrine, which in turn causes desensitization/downregulation of b-adrenergic receptors, cardiac remodeling, and worsening of HF and prognosis (10). Importantly, in vivo noninvasive assessment of sympathetic innervation with SPECT and PET imaging using radiolabeled analogs of norepinephrine have provided valuable prognostic information in patients with HFrEF beyond currently available biomarkers, such as BNP and LV ejection fraction. The most commonly used SPECT tracer to assess cardiac sympathetic innervation is 123Imetaiodobenzylguanadine (123I-mIBG), whereas the most commonly used PET tracer is 11C-hydroxyephedrine (11C-HED). Both of these tracers are norepinephrine radioanalogs, and their uptake primarily represents presynaptic nerve function (or density) in the heart. LV diastolic dysfunction is a characteristic finding in patients with HFpEF, and increasing severity of diastolic dysfunction is related to HF progression and a worse prognosis in these patients (13,14). Several lines of evidence suggest that dysregulated SNS activity plays an important role in the pathophysiology of HFpEF, particularly in the development of diastolic dysfunction. Preclinical studies show that mimicking an elevation of SNS activity via isoproterenol administration leads to diastolic dysfunction, accompanied by increased myocardial stiffening, fibrosis, and LV hypertrophy (15). Grassi et al. (16) observed that patients with diastolic dysfunction and hypertension display higher SNS activity (e.g., muscle sympathetic nerve activity [MSNA]) and abnormal baroreflex modulation compared with hypertensive patients without diastolic dysfunction, and both these groups show higher MSNA than age-matched controls. In these studies, MSNA was significantly and inversely related to various transthoracic echocardiographic indices of diastolic dysfunction (e.g., E/A wave ratio, deceleration time, and isovolumic relaxation time). Other human studies have observed similar findings with respect to the relationship between SNS activity and HFpEF (15), although many of these studies are limited by the small sample sizes, and not all of these studies report on diastolic parameters. Interestingly, albeit in a limited number of studies, it has been shown that indices of sympathetic presynaptic nerve function derived from planar 123I-mIBG scintigraphy correlate with the severity of diastolic dysfunction, exercise capacity, LV remodeling, response to therapy, and HF severity and are able to predict adverse cardiovascular events in patients with HFpEF (17–19). More specifically, the 123I-mIBG heart-to-mediastinal ratio and 123I-mIBG washout rate have proved to be the most useful indices in these studies. Indeed, the small number of patients, the use of different definitions of HFpEF and diastolic dysfunction, and the application of only semiquantitative analyses of 123I-mIBG planar scintigraphy have limited the generalizability and strength of these findings. Received Dec. 16, 2016; revision accepted Feb. 15, 2017. For correspondence or reprints contact: Albert J. Sinusas, Section of Cardiovascular Medicine, Yale University School of Medicine, P.O. Box 208017, Dana 3, New Haven, CT 06520-8017. E-mail: albert.sinusas@yale.edu Published online Feb. 23, 2017. COPYRIGHT© 2017 by the Society of Nuclear Medicine and Molecular Imaging. DOI: 10.2967/jnumed.116.186130