Impaired Cardiac Sympathetic Innervation Activity is Associated with Myocardial Extracellular Remodeling, Functional Capacity and Biomarkers

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 <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<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<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<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<0.001). In addition, considering all HF patients, H/M was inversely associated with ECV (R: −0.45, p<0.001, Fig. 1B), NT-proBNP (R: −0.55, p<0.001) and VO2max (R: −0.27, p: <0.024, Fig. 1C). GLS was inversely associated with H/M in HFrEF but not HFpEF (HFrEF: R: −0.535, p<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