Impaired Myocardial Sympathetic Innervation Is Associated with Diastolic Dysfunction in Heart Failure with Preserved Ejection Fraction: ¹¹C-Hydroxyephedrine PET Study

Abstract

See an invited perspective on this article on page 781.Diastolic dysfunction is important in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Sympathetic nervous hyperactivity may contribute to the development of diastolic dysfunction. The aim of this study was to determine the relationship between myocardial sympathetic innervation quantified by 11 C-hydroxyephedrine PET and diastolic dysfunction in HFpEF patients. Methods: Forty-one HFpEF patients having an echocardiographic left ventricular ejection fraction of 40% or greater and 12 age-matched volunteers without heart failure underwent the echocardiographic examination and 11 C-hydroxyephedrine PET. Diastolic dysfunction was classified into grades 0-3 by Doppler echocardiography. Myocardial sympathetic innervation was quantified using the 11 C-hydroxyephedrine retention index (RI). The coefficient of variation of 17-segment RIs was derived as a measure of heterogeneity in myocardial 11 C-hydroxyephedrine uptake. Results: Grade 2-3 diastolic dysfunction (DD 2-3 ) was found in 19 HFpEF patients (46%). They had a significantly lower global RI (0.075 6 0.018 min 21 ) than volunteers (0.123 6 0.028 min 21 , P , 0.001) and HFpEF patients with grade 0-1 diastolic dysfunction (DD 0-1 ) (0.092 6 0.024 min 21 , P 5 0.046). HFpEF patients with DD 2-3 had the largest coefficient of variation of 17-segment RIs of the 3 groups (18.4% 6 7.7% vs. 14.1% 6 4.7% in HFpEF patients with DD 0-1 , P 5 0.042 for post hoc tests). In multivariate logistic regression analysis, a lower global RI (odds ratio, 0.66 per 0.01 min 21 ; 95% confidence interval, 0.38-0.99; P 5 0.044) was independently associated with the presence of DD 2-3 in HFpEF patients. Conclusion: Myocardial sympathetic innervation was impaired in HFpEF patients and was associated with the presence of advanced diastolic dysfunction in HFpEF.

Low‐level transcutaneous vagus nerve stimulation attenuates cardiac remodelling in a rat model of heart failure with preserved ejection fraction

“…HFpEF is characterized by autonomic imbalance with increased sympathetic nerve activity, which is closely associated with diastolic dysfunction (Aikawa et al., ; Grassi et al., ), while clinical studies have shown that sympathetic hyperactivity contributes to the development of diastolic dysfunction in patients with hypertension and to disease progression in patients with HFpEF (Florea & Cohn, ). Consistent with our results, a recent study revealed that right cervical VNS decreased sympathetic activity and attenuated the HS diet‐induced increase of BP in DS rats (Annoni et al., ).…”

Imaging of the Cardiac Sympathetic Nervous System Has Potential Value in the Evaluation of Patients with Heart Failure with Preserved Ejection Fraction

“…In summary, the study by Aikawa et al (20) was the first to show a relationship between impaired cardiac SNS innervation noninvasively assessed with 11 C-HED PET imaging and the severity of diastolic dysfunction using transthoracic echocardiography in HFpEF patients. Despite the methodologic limitations, this study provides the foundation for further exploration of the role of the SNS in HFpEF.…”

“…Notwithstanding the ambiguity in the new algorithm, the classification of diastolic dysfunction in the current article is at odds with the 2009 ASE/EACVI algorithm. Specifically, it appears that some patients were classified as having diastolic dysfunction despite having normal left atrial volumes ( Table 2 in Aikawa et al (20)). However, the 2009 guidelines of the ASE/EACVI suggest that an enlarged left atrial volume index ($34 mL/m 2 ) is an absolute criterion for diastolic dysfunction, especially for grades 2 and 3 dysfunction.…”

“…First, and most importantly, these authors define diastolic dysfunction based on the 2009 recommendations of the ASE and European Association of Cardiovascular Imaging (EACVI, formerly EAE) despite the recent publication of new guidelines by these same organizations (22). As shown in the supplemental materials for the Aikawa et al (20) article, when the authors used the most recent guidelines for diastolic function assessment, 70% of patients were reclassified, and global RI became similar among the HFpEF patients despite differences in the severity of diastolic dysfunction. It is possible that the reclassification of patients using the current guidelines led to a nonsignificant finding between different grades of diastolic dysfunction, because the recently recommended algorithm does not explicitly describe how to classify patients with atrial fibrillation.…”

“…In this current issue of The Journal of Nuclear Medicine, Aikawa et al (20) performed PET imaging with 11 C-HED in 41 subjects with HFpEF (LV ejection fraction $ 40%) and 12 normal volunteers in an effort to establish the relationship between impaired cardiac SNS innervation and LV diastolic dysfunction in HFpEF patients. As outlined above, although previous studies have already reported similar relationships with 123 I-mIBG planar scintigraphic indices in HFpEF patients (18,19), the novelty of this study relates to use of 11 C-HED PET imaging, which allows for improved global and regional quantification of SNS innervation due to better spatiotemporal resolution and more quantitative image analysis than conventional 123 I-mIBG planar imaging.…”