Impaired Cardiac Sympathetic Activity Is Associated With Myocardial Remodeling and Established Biomarkers of Heart Failure

Abstract

Background: ¹²³Iodine-meta-iodobenzylguanidine scintigraphy is useful for assessing cardiac autonomic dysfunction and predict outcomes in heart failure (HF). The relationship of cardiac sympathetic function with myocardial remodeling and diffuse fibrosis remains largely unknown. We aimed to evaluate the cardiac sympathetic function of patients with HF and its relation with myocardial remodeling and exercise capacity.

Methods and results: Prospectively enrolled patients with HF (New York Heart Association class II-III) were stratified into HF with preserved left ventricular ejection fraction [LVEF] ≥45%) and reduced LVEF. Ventricular morphology/function and myocardial extracellular volume (ECV) fraction were quantified by cardiovascular magnetic resonance, global longitudinal strain by echocardiography, cardiac sympathetic function by heart-to-mediastinum ratio from ¹²³iodine-meta-iodobenzylguanidine scintigraphy. All participants underwent cardiopulmonary exercise testing. The cohort included 33 patients with HF with preserved LVEF (LVEF, 60±10%; NT-proBNP [N-terminal pro-B-type natriuretic peptide], 248 [interquartile range, 79-574] pg/dL), 28 with HF with reduced LVEF (LVEF, 30±9%; NT-proBNP, 743 [interquartile range, 250-2054] pg/dL) and 20 controls (LVEF, 65±5%; NT-proBNP, 40 [interquartile range, 19-50] pg/dL). Delayed (4 hours) ¹²³iodine-meta-iodobenzylguanidine heart-to-mediastinum ratio was lower in HF with preserved LVEF (1.59±0.25) and HF with reduced LVEF (1.45±0.16) versus controls (1.92±0.24; P<0.001), and correlated negatively with diffuse fibrosis assessed by ECV (R=-0.34, P<0.01). ECV in segments without LGE was increased in HF with preserved ejection fraction (0.32±0.05%) and HF with reduced left ventricular ejection fraction (0.31±0.04%) versus controls (0.28±0.04, P<0.05) and was associated with the age- and sex-adjusted maximum oxygen consumption (peak oxygen consumption); (R=-0.41, P<0.01). Preliminary analysis indicates that cardiac sympathetic function might potentially act as a mediator in the association between ECV and NT-proBNP levels.

Conclusions: Abnormally low cardiac sympathetic function in patients with HF with reduced and preserved LVEF is associated with extracellular volume expansion and decreased cardiopulmonary functional capacity.

Keywords: cardiac magnetic resonance; cardiac sympathetic function; heart failure; interstitial fibrosis.

Figure 1. Study overview.

Patients with HF stratified by LVEF and controls underwent CMR, cardiopulmonary exercise testing (CPET), and cardiac ¹²³I‐MIBG scintigraphy. While ¹²³I‐MIBG H/M was significantly lower among HF individuals, ECV—a marker of interstitial fibrosis—was elevated and demonstrated an indirect effect mediated by the myocardial ¹²³I‐MIBG H/M on NT‐proBNP. CMR indicates cardiac magnetic resonance; ECV, expanded extracellular volume; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; H/M, heart‐to‐mediastinum; ¹²³I‐MIBG, ¹²³iodine‐meta‐iodobenzylguanidine; and LVEF, left ventricular ejection fraction.

Figure 2. ¹²³I‐MIBG H/M, CMR‐ECV, and CPET results across study groups.

A, ¹²³I‐MIBG H/M at 4 h was significantly diminished in HFrEF and HFpEF compared with healthy controls, with HFrEF showing a more pronounced reduction in sympathetic function than HFpEF. B, The extracellular volume (ECV) fraction, a marker of diffuse interstitial fibrosis was significantly higher in HF patients compared with healthy controls, but there was no significant ECV difference between patients with HF with and without reduced ejection fraction. C, The myocardial ECV correlated inversely with ¹²³I‐MIBG H/M at 4 h (Spearman r=−0.34, P=0.0029), suggesting that ECV expansion reduces sympathetic innervation density, leading to a reduced ¹²³I‐MIBG H/M. D, The adjusted peak Vo ₂ was inversely correlated with ¹²³I‐MIBG H/M at 4 h. CMR indicates cardiac magnetic resonance; CPET, cardiopulmonary exercise capacity; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; H/M, heart‐to‐mediastinum; ¹²³I‐MIBG, ¹²³iodine‐meta‐iodobenzylguanidine; Vo ₂, oxygen consumption.