Impaired cardiac sympathetic innervation activity is associated with myocardial extracellular remodeling, functional capacity and biomarkers
Authors: Da Silva L M , Paim L R , Bau A A , Martins C N G , Coy-Cangucu A , Yamaguti R , Antunes-Correa L , Sposito A , Ramos C D , Nadruz Jr W , Neilan T G , Jerosch-Herold M , Coelho-Filho O 
Published: October 2022

Abstract

Background
Despite recent advances in treatment, heart failure (HF) continues to be associated with high mortality rates. In this setting, 123iodine-meta-iodobenzylguanidine (123I-MIBG) scintigraphy emerges as a promising tool for the prediction of clinical outcomes in HF due to its ability to assess cardiac sympathetic innervation. However, 123I-MIBG scintigraphy's correlation with myocardial remodeling and cardiopulmonary exercise capacity has not yet been fully elucidated.

Objectives
To evaluate cardiac sympathetic activity through 123I-MIBG scintigraphy, and to analyze its correlation with myocardial remodeling and exercise capacity in HF patients.

Methods
Symptomatic HF patients (NYHA class II–III) stratified by LVEF as HFpEF (LVEF 45%) and HFrE'F (LVEF &lt;45%) and healthy controls were enrolled. HF patients were euvolemic under optimized treatment at the time of enrollment. All individuals underwent CMR with morphology/function and extracellular volume fraction (ECV) assessment, global longitudinal strain (GLS) by echocardiogram, cardiopulmonary exercise testing (CPET), cardiac sympathetic imaging 123I-MIBG scintigraphy (mIBG), and NT-proBNP.

Results
Eighty individuals were recruited allocated into the following groups: HFpEF (n=33, 59.42±12.63 years, LVEF: 59.82±9.87, NT-proBNP: 409.40±693.37, H2FPEF-score: 5±2), HFrEF (n=28, 53.93±11.40 years; LVEF: 29.81±8.67, NT-proBNP: 1662,34±2016,73) and healthy controls (42.65±13.96 years, LVEF: 65.27±4.73, NT-proBNP: 44,43±33,28) were enrolled. While ECV was elevated in HF groups (HFpEF: 0.32±0.05%, HFrEF: 0.31±0.41% and controls: 0.26±0.03, p&lt;0.05), adjusted maximum oxygen consumption (VO2max) was markedly reduced vs. controls (HFpEF: 18.58±6.29mL/kg/min, HFrEF: 17.60±3.89mL/kg/min, controls: 29.73±9.98mL/kg/min, p&lt;0.001). The MIBG heart-to-mediastinum ratio at 4 hours (H/M) was significantly lower in HF compared with controls (HFpEF: 1.59±0.25, HFrEF: 1.45±0.15 and controls: 1.92±0.25, p&lt;0.001). Interestingly, the H/M ratio was more impaired with HFrEF compared to HFpEF (Fig. 1A). As a result, the mean myocardial washout rate was increased in HF patients (HFrEF 36.38±14.35, HFpEF 29.92±18.33 vs. controls 8.0±27.01, p&lt;0.001). In addition, considering all HF patients, H/M was inversely associated with ECV (R: −0.45, p&lt;0.001, Fig. 1B), NT-proBNP (R: −0.55, p&lt;0.001) and VO2max (R: −0.27, p: &lt;0.024, Fig. 1C). GLS was inversely associated with H/M in HFrEF but not HFpEF (HFrEF: R: −0.535, p&lt;0.001 and HFpEF: R: −0.036, p=NS, Fig. 1D).

Conclusion
Cardiac sympathetic activity assessed by 123I-MIBG was abnormal in patients with HF with reduced and preserved EF as compared to controls. H/M, a validated marker for cardiac sympathetic activity, showed a strong correlation with markers of functional capacity and myocardial remodeling. Sympathetic innervation appears to be a limiting factor for global longitudinal strain in HFrEF, while in HFpEF longitudinal strain is independent of sympathetic activity

Funding Acknowledgement
Type of funding sources: Public Institution(s). Main funding source(s): The São Paulo Research Foundation