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

Background ATTR-related Familial Amyloid Polyneuropathy (FAP) is a hereditary disease that primarily affects peripheral nerve function. Few studies have investigated cardiac involvement and myocardial tissue remodeling in FAP. Aim To investigate subclinical myocardial tissue remodeling in FAP patients without cardiomyopathy using a multiparametric CMR protocol. Results Thirty-one FAP patients (46.9±16.1 years, 57% female, 60% Val30Met mutation) and 33 healthy controls (41.3±13.7 years, 58% female) were enrolled, undergoing a multiparametric CMR protocol for assessment of ventricular morphology and function, native myocardial T1, extracellular volume fraction (ECV) and intracellular lifetime of water). Cardiopulmonary exercise capacity was evaluated with a cycle ergometer. Cardiac high-sensitive troponin T (cTnT) and NT-proBNP were measured to assess for cardiac injury. The majority of ATTR-PN patients were in stage 1 (70%) with mild symptoms of sensory, motor and autonomic neuropathy. Adjusted maximum oxygen consumption was reduced among FAP patients compared to healthy controls (FAP: 22.2±8.2 mL/kg/min vs. controls: 30.3±10.2 mL/kg/min, p<0.001). Although none of FAP patients reported heart failure symptoms, NT-proBNP (FAP: 251.240±624.446 ng/dL, vs. controls: 34.3±29 ng/dL, p<0.005) and cTnT (FAP: 13.2 [3.0, 19.0] ng/dL, vs. controls: 3.6 [3.0, 6.0] ng/dL, p<0.005) were elevated, and both correlated with ECV (cTnT: R=0.81, P<0.001; NT-proBNP: R=0.61, P=0.001, Fig. 1). While LVEF was preserved among FAP patients (FAP: 67.9±8.2% vs. controls: 65.4±4.3%, p=NS), LVmass index was increased compared to control subjects (FAP: 58.5±18.8 vs. and controls: 42±9.2 g/m2, p<0.005). Both native T1 (FAP: 1,303.924±120.152, vs. controls: 1,212.78±76.01 ms, p<0.05) and ECV (FAP: 0.36±0.1, vs. controls: 0.26±0.02, p<0.001) were markedly elevated among FAP patients. In contrast the intracellular lifetime of water, a validated marker of cardiomyocyte size was reduced in the FAP group (FAP: 0.082±0.04 vs. controls: 0.14±0.05, p<0.001). There was a trend for ECV to increase linearly with FAP stage, and native T1 trended higher in stage 1 and 2 patients compared to stage 0. Both ECV (R=0.89, p<0.001) and native T1 (R=0.62, p<0.001) were correlated with LVmass index (Fig 2). Conclusion In FAP without clinical signs of cardiac involvement, significant extracellular matrix expansion was present. The increase of LV mass in these patients is associated with expansion of the extracellular matrix, possibly as a result of diffuse replacement fibrosis, and below-normal cardiomyocyte diameter. These findings from serum biomarkers and CMR tissue phenotyping provide evidence of sub-clinical cardiac involvement through adverse myocardial tissue remodeling in FAP patients presenting with mostly mild symptoms of peripheral neuropathy. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Pfizer

Introduction: Physiological and pathological cardiac hypertrophy differ in terms of mechanisms, phenotypes, and outcomes. We aimed to characterize the cardiac tissue phenotype of athletes and HF patients. Methods: Prospectively enrolled participants underwent CMR and CPET. HF patients (NYHA class II-III) were classified as HFpEF (LVEF>=45%) or HFrEF (LVEF<45%). Results: One-hundred and eighty participants were categorized in four groups: athletes (n=44, 32±12 years), HFpEF (n=47, 61±11 years, H2FPEF score 5±2), HFrEF (n=47, 54±10 years), and healthy controls (n=42, 41±13 years). LVEF was markedly reduced in HFrEF (athletes 65±6%, HFpEF 59±11, HFrEF 29±9, controls 66±4, p<.001). LV mass index (athletes 65±6%, HFpEF 59±11, HFrEF 29±9, controls 66±4, p<.001) and cardiomyocyte mass index (athletes 64±15g/m 2 , HFpEF 66±24, HFrEF 82±36, controls 42±8, p<.001) were greater in athletes and in HF patients (Fig 1A). Athletes and HFpEF patients had concentric LV remodeling, while HFrEF patients showed eccentric remodeling (Fig 1B). Intracellular lifetime of water was longer in athletes and shorter in HFrEF (athletes .17±.07s, HFpEF .15±.05, HFrEF .13±.05, controls .14±.05, p<.001) (Fig 2A). ECV was similarly increased in both HF groups (athletes .28±.04%, HFpEF .31±.05, HFrEF .31±.05, controls .28±.04, p<.001) (Fig 2B). Native T1 (athletes 1175±55ms, HFpEF 1261±61, HFrEF 1274±61, controls 1229±75, p=.01) correlated with CPET maximal oxygen consumption (VO 2 max) in HF patients (r=-.023, p=.048) (athletes 52±10, HFpEF 18±6, HFrEF 17±4, controls 29±9, p<.001). Conclusion: Physiological hypertrophy was characterized by increased cardiomyocyte diameter, normal ECV, and shorter native T1 due to its greater cardiomyocyte volume. Contrastingly, pathological hypertrophy’s longer native T1 was a result of its higher ECV and correlated with VO 2 max in HF. Cardiomyocyte diameter was smaller in HFrEF than in HFpEF.