Regional interaction between myocardial sympathetic denervation, contractile dysfunction, and fibrosis in heart failure with preserved ejection fraction: ¹¹C-hydroxyephedrine PET study

Purpose: This investigation aimed to identify significant predictors of regional sympathetic denervation quantified by ¹¹C-hydroxyephedrine (HED) positron emission tomography (PET) in patients with heart failure with preserved left ventricular ejection fraction (HFpEF). Methods: Included in the study were 34 patients (age 63 ± 15 years, 23 men) with HFpEF (left ventricular ejection fraction ≥40%) and 11 age-matched volunteers without heart failure. Cardiac magnetic resonance imaging was performed to measure left ventricular size and function, and the extent of myocardial late gadolinium enhancement (LGE). ¹¹C-HED PET was performed to quantify myocardial sympathetic innervation that was expressed as a ¹¹C-HED retention index (RI, %/min). To identify predictors of regional ¹¹C-HED RI in HFpEF patients, we propose a multivariate mixed-effects model for repeated measures over segments with an unstructured covariance matrix. Results: Global ¹¹C-HED RI was significantly lower and more heterogeneous in HFpEF patients than in volunteers (P < 0.01 for all). Regional ¹¹C-HED RI was correlated positively with systolic wall thickening (r = 0.42, P < 0.001) and negatively with the extent of LGE (r = −0.43, P < 0.001). Segments in HFpEF patients with a large extent of LGE had the lowest regional ¹¹C-HED RI among all segments (P < 0.001 in post hoc tests). Multivariate analysis demonstrated that systolic wall thickening and the extent of LGE were significant predictors of regional ¹¹C-HED RI in HFpEF patients (both P ≤ 0.001). Conclusion: Regional sympathetic denervation was associated with contractile dysfunction and fibrotic burden in HFpEF patients, suggesting that regional sympathetic denervation may provide an integrated measure of myocardial damage in HFpEF.