Cardiac Sympathetic Activity and Rhythm Control Following Pulmonary Vein Isolation in Patients with Paroxysmal Atrial Fibrillation—A Prospective 123I-mIBG-SPECT/CT Imaging Study

Background: Pulmonary vein isolation (PVI) and antiarrhythmic drug therapy are established treatment strategies to preserve sinus rhythm in atrial fibrillation (AF). However, the efficacy of both interventional and pharmaceutical therapy is still limited. Solid evidence suggests an important role of the cardiac sympathetic nervous system in AF. In this blinded, prospective observational study, we studied left ventricular cardiac sympathetic activity in patients treated with PVI and with antiarrhythmic drugs. Prospectively, Iodine-123-benzyl-guanidine single photon emission computer tomography (123I-mIBG-SPECT) was performed in a total of 23 patients with paroxysmal AF, who underwent PVI (n = 20) or received antiarrhythmic drug therapy only (n = 3), respectively. 123I-mIBG planar and SPECT/CT scans were performed before and 4 to 8 weeks after PVI (or initiation of drug therapy, respectively). For semiquantitative SPECT image analysis, attenuation-corrected early/late images were analyzed. Quantitative SPECT analysis was performed using the AHA 17-segment model of the left ventricle. Results: PVI with point-by-point radiofrequency ablation led to a significantly (p < 0.05) higher visual sympathetic innervation defect score when comparing pre-and post PVI. Newly emerging innervation deficits post PVI were localized predominantly in the inferior lateral wall. These findings were corroborated by semiquantitative SPECT analysis identifying inferolateral segments with a reduced tracer uptake in comparison to SPECT before PVI. Following PVI, patients with an AF relapse showed a different sympathetic innervation pattern compared to patients with sufficient rhythm control. Conclusions: PVI results in novel defects of cardiac sympathetic innervation. Differences in cardiac sympathetic innervation remodelling following PVI suggest an important role of the cardiac autonomous nervous system in the maintenance of sinus rhythm following PVI.

Overview of the Global Prevalence and Diagnostic Criteria of Takotsubo Syndrome

Takotsubo syndrome (TTS) is an acute and reversible abnormal condition of the heart also known as stress cardiomyopathy, apical ballooning syndrome, or broken heart syndrome. It is an uncommon disease that mostly occurs among Asians though studies have shown its occurrence in other parts of the world. The typical takotsubo syndrome patient has a unique circumferential left ventricular contraction abnormality that extends beyond a coronary artery supply territory and appears to follow the anatomical cardiac sympathetic innervation.

Comparison of low energy and medium energy collimators in the quantitative assessment of 123I-MIBG cardiac sympathetic innervation imaging

Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): University Clinic Hospital of Valencia Aim The assessment of cardiac sympathetic innervation by 123I-metayodobenzylguanidine (123I-MIBG) has proved useful in patients with heart failure and neurodegenerative disorders. The standard quantification of global cardiac uptake is to obtain the heart to mediastinum (HM) ratio in planar images, while SPECT images provide better evaluation of regional extent of denervated areas. Although low energy (LE) collimator has been widely used in these patients, septal penetration of high-energy photons of 123I could affect image quality and quantification accuracy. We have compared in the same patients the effect of collimator type on image quality and quantitative assessment of HM ratio. Methods In a group of 14 patients (11 men, 57-77 y/o, 66.4 ± 5.6) submitted for cardiac sympathetic study, we obtained successive planar anterior chest images 4h after the IV administration of 10 mCi of 123I-MIBG with a low-energy-high-resolution (LEHR) and a medium-energy (ME) collimators. Images were obtained with the same gammacamera Brightview Philips for 10 min on 256x256 matrix, with 159 Kev photopeak and unchanged patient position. For quantification of HM ratio, we use in each patient the same manual heart ROI and rectangular upper mediastinum ROI in the two acquired images to obtain the corresponding HM ratio. Results The image quality was better in all the patients with ME collimator acquisition than with LEHR collimator acquisition, and the HM ratio showed higher values with ME: 1.65-2.61 (mean 2.15 ± 0.28) than with LEHR: 1.27-1.85 (mean: 1.51 ± 0.18) with a mean difference of 0.64 ± 0.15 (0.38-0.88) between ME and LEHR and a mean ratio LEHR/ME of 0.70 ± 0.04 (0.64-0.79). In 9 patients with HM ratio ≤ 1.60 obtained from LEHR collimator acquisition, the mean difference with HM ratio obtained with ME collimator was 0.61 ± 0.12 and mean ratio LEHR/ME was 0.69 ± 0.03 and in 5 patients with HM ratio(LEHR) &gt;1.60, mean difference with HM ratio(ME) was 0.69 ± 0.19 and mean ratio LEHR/ME was 0.71 ± 0.02. Conclusion Use of a ME collimator provides better image quality than LEHR collimator in planar images and higher values of HM ratio, providing a more accurate quantification of cardiac uptake in the patients submitted for evaluation of cardiac sympathetic innervation by 123I-MIBG, and could also improve the evaluation of regional impairment and extent of denervated areas by SPECT.

Sympathetic innervation pattern in NICM patients with ventricular tachycardia -anteroseptal versus inferolateral substrates-

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation - Projektnummer 447558597) Background Among patients with non-ischemic cardiomyopathy (NICM) two dominant ventricular tachycardia (VT) substrate locations, namely anteroseptal (AS) and inferolateral (IL), have been identified. The poor outcome after catheter ablation of AS substrates (ASS) compared to IL substrates (ILS) has been attributed to its deep intramural location. However, region specific tissue charateristics, including sympathetic innervation, as important determinant of arrhythmogeneity, may also contribute to the outcome disparity. Aim To evaluate the association between regional sympathetic denervation, myocardial fibrosis and VT substrates according to two dominant VT substrate locations. Methods Twenty-nine patients from the ‘Leiden Nonischemic Cardiomyopathy Study’, who underwent electroanatomical substrate mapping and radiofrequency catheter ablation (RFCA), LGE-CMR and 123-I-MIBG imaging between 2011-2018 were included. The 16-segment model was used to describe the distribution of endocardial low unipolar voltage (UV &lt;25th IQR) (=electroanatomical surrogate for fibrosis), the location of abnormal local electrograms and VT related sites (= surrogate for VT substrate) and the presence of LGE. Regional cardiac sympathetic innervation was determined by 123-I-MIBG imaging and analyzed according to the 16-segment model. Regions with sympathetic denervation were correlated with low UV areas, VT substrate location and LGE. Patients were categorized according to the dominant VT substrate location in ASS or ILS. Results Ten patients had a dominant ASS, 12 patients a dominant ILS and 1 patient had ASS and ILS; 6 patients had other VT substrate locations. All but one patient with ASS and one with ILS also showed corresponding low UV (=surrogate for fibrosis) in segments with VT substrates. Eight patients with IL VT substrates but only 4 with AS substrates showed corresponding LGE in the VT related segments. All patients with inferolateral VT substrates showed sympathetic denervation in IL segments (100% matching segments), but only 3/11 (27%) with anteroseptal substrates had sympathetic denervation in AS segments (P = 0.0002). UV was not significantly different between matching (VT substrate and denervation) and not matching ASS segments (5.74 ± 2.69 mV vs. 4.64 ± 1.85 mV, P = 0.78) and between matching ASS and ILS segments (5.74 ± 2.69 mV vs. 7.61 ± 2.91, P = 0.43). LGE location was matching with sympathetic denervation in all patients with ILS but only in 33% of patients with ASS. Conclusion Despite low endocardial UV (=surrogate for fibrosis) for AS and IL segments harboring VT substrates, regional sympathetic denervation coincided with fibrosis only for IL VT substrates. The mismatch between regional fibrosis and preserved innervation for AS VT substrates may contribute to a VT substrate difficult to control by RFCA.

Global cardiac sympathetic denervation is associated with diffuse myocardial fibrosis in non-ischemic cardiomyopathy

Funding Acknowledgements Type of funding sources: None. Background Occurrence of ventricular tachycardias (VT) has been related to changes in sympathetic innervation and myocardial tissue in ischemic cardiomyopathy. In non-ischemic cardiomyopathy (NICM) patients with VT, the relation between global cardiac sympathetic innervation and non-ischemic fibrosis is less clear. The current gold standard in electrophysiology to identify non-ischemic fibrosis relies on unipolar endocardial voltage mapping. Objective To establish the relationship between global cardiac sympathetic innervation and global fibrosis. Methods 29 patients (93% male, 58 ± 14 years, mean LVEF 38%±13) from the ‘Leiden Nonischemic Cardiomyopathy Study’ undergoing VT ablation between 2011-2018 were included. Endocardial voltage mapping was performed and the mean endocardial unipolar voltage (UV) was taken as a surrogate for global fibrosis. Global cardiac sympathetic innervation was analyzed by 123-I-MIBG imaging using heart-to-mediastinum ratio (HMR). A cut-off of 1.8 was used to delineate between normal (&gt;1.8) and denervated (&lt;1.8). HMR was correlated with mean UV. Results For patients with global cardiac sympathetic denervation a linear relationship was present between HMR and mean UV (R = 0.5278, P = 0.0431. There was no significant linear relationship for patients with normal cardiac sympathetic innervation between HMR and mean UV (R=-0.1696, P = 0.5795). Conclusion Global cardiac sympathetic denervation is related to myocardial fibrosis in patients with NICM and VT. The data support an interplay between denervation and fibrosis which may contribute to arrhythmogeneity, as observed in ICM. Abstract Figure.

Neural Mechanisms and Therapeutic Opportunities for Atrial Fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with an increased risk of all-cause mortality and complications. The autonomic nervous system (ANS) plays a central role in AF, with the heart regulated by both extrinsic and intrinsic properties. In the extrinsic ANS, the sympathetic fibers are derived from the major paravertebral ganglia, especially the stellate ganglion (SG), which is a source of cardiac sympathetic innervation since it connects with multiple intrathoracic nerves and structures. The major intrinsic ANS is a network of axons and ganglionated plexi that contains a variety of sympathetic and parasympathetic neurons, which communicate with the extrinsic ANS. Simultaneous sympathovagal activation contributes to the development of AF because it increases calcium entry and shortens the atrial action potential duration. In animal and human studies, neuromodulation methods such as electrical stimulation and renal denervation have indicated potential benefits in controlling AF in patients as they cause SG remodeling and reduce sympathetic outflow. This review focuses on the neural mechanisms relevant to AF and the recent developments of neuromodulation methods for AF control.

Xiao-Qing-Long-Tang Maintains Cardiac Function during Heart Failure with Reduced Ejection Fraction in Salt-Sensitive Rats by Regulating the Imbalance of Cardiac Sympathetic Innervation

Objective. The anatomical and functional imbalances of sympathetic nerves are associated with cardiovascular disease progression. Xiao-Qing-Long-Tang (XQLT), an ancient Chinese herbal formula, has been used to treat cardiovascular diseases in eastern Asia for thousands of years. We determined the effect of XQLT in maintaining cardiac function during heart failure with reduced ejection fraction (HFrEF) with respect to its neurobiological effects in salt-sensitive rats. Methods. Dahl salt-sensitive (DS) rats were fed a high-salt diet to establish an HFrEF model and were divided into model (DS, administered normal saline) and XQL groups (administrated XQLT) randomly, with SS-13BN rats being used as the control. The bodyweight and blood pressure of rats were observed regularly. Electrocardiogram, echocardiography, and plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) were determined to assess cardiac function. The sympathetic tune and myocardial morphological changes were evaluated. Western blot and qRT-PCR were used to assay the expression of the nerve growth factor (NGF) and leukemia inhibitory factor (LIF). Tyrosine hydroxylase (TH), choline acetyltransferase (CHAT), and growth-associated protein 43 (GAP43) were assayed to confirm sympathetic remodeling. The micromorphological changes in cardiac sympathetic nerve endings were observed by transmission electron microscopy. Results. Four weeks after XQLT treatment, cardiac function and bodyweight were higher and blood pressure was lower than that of the DS group. Myocardial noradrenaline (NA) increased, while the plasma NA level decreased significantly. The morphology demonstrated that XQLT significantly alleviated myocardial damage. XQLT decreased the expression of LIF, increased the expression of NGF, enhanced the TH+/GAP43+ and TH+/CHAT + positive nerve fiber density, and improved the TH and GAP43 protein expression, but had no effect on CHAT. Moreover, XQLT improved the micromorphology of sympathetic nerve endings in the myocardium. Conclusion. XQLT maintains cardiac function during HFrEF in salt-sensitive rats, in part, by regulating the imbalance of cardiac sympathetic innervation.

Role of peripheral 5-HT5A receptors in 5-HT-induced cardiac sympatho-inhibition in type 1 diabetic rats

5-HT inhibits cardiac sympathetic neurotransmission in normoglycaemic rats, via 5-HT1B, 5-HT1D and 5-HT5A receptor activation. Since type 1 diabetes impairs the cardiac sympathetic innervation leading to cardiopathies, this study aimed to investigate whether the serotonergic influence on cardiac noradrenergic control is altered in type 1 diabetic rats. Diabetes was induced in male Wistar rats by streptozotocin (50 mg/kg, i.p.). Four weeks later, the rats were anaesthetized, pithed and prepared for producing tachycardic responses by electrical preganglionic stimulation (C7-T1) of the cardioaccelerator sympathetic outflow or i.v. noradrenaline bolus injections. Immunohistochemistry was performed to study 5-HT1B, 5-HT1D and 5-HT5A receptor expression in the stellate ganglion from normoglycaemic and diabetic rats. In the diabetic group, i) i.v. continuous infusions of 5-HT induced a cardiac sympatho-inhibition that was mimicked by the 5-HT1/5A agonist 5-carboxamidotryptamine (without modifying noradrenaline-induced tachycardia), but not by the agonists indorenate (5-HT1A), CP 93,129 (5-HT1B), PNU 142633 (5-HT1D), or LY344864 (5-HT1F); ii) SB 699551 (5-HT5A antagonist; i.v.) completely reversed 5-CT-induced cardiac sympatho-inhibition; and iii) 5-HT5A receptors were more expressed in the stellate ganglion compared to normoglycaemic rats. These results show the prominent role of the peripheral 5-HT5A receptors prejunctionally inhibiting the cardiac sympathetic drive in type 1 diabetic rats.

Prognostic significance of cardiac sympathetic innervation and contractility in heart failure patients submitted to cardiac resynchronization therapy

Introduction In chronic heart failure patients, cardiac resynchronization therapy (CRT) does not lead to the expected result in 30% of cases. There is a lack of prognostic data related to the cardiac sympathetic activity and contractility assessment in ischemic (IHF) and non-ischemic (CHF) heart failure patients. Purpose To assess the prognostic value of radionuclide cardiac sympathetic innervation and contractility assessment in IHF and NIHF patients submitted to CRT. Methods This study included 38 HF patients (24 male; mean age of 56±11 years), who were submitted to CRT: NYHA class II/III (n=10/28), mean QRS=159.3±17.9ms. The etiology of HF was ischemic in 16 patients and non-ischemic in 22 of them. Before CRT all patients underwent 123I-metaiodobenzylguanidine (123I-MIBG) imaging for cardiac sympathetic activity evaluating. The following indexes were estimated: early and delayed heart to mediastinum ratio (eH/M and dH/M), summed MIBG Score (eSMS and dSMS). Moreover all patients underwent gated myocardial perfusion scintigraphy with the assessments of LV dyssynchrony indexes: standard deviation (SD) and histogram bandwidth (HBW). In addition, all patients underwent gated blood-pool SPECT with both ventricles ejection fraction (EF) and stroke volume (SV) assessment. Results One year after CRT all patients were divided into two groups: responders (IHF group n=11; NIHF group n=15) and non-responders (IHF group n=5; NIHF group n=7). Among baseline scintigraphic parameters the following ones showed significant differences between responders vs. non-responders. In IHF patients - HBW: 162 (115.2–180) degree vs. 115.2 (79.2–136.8) degree, p&lt;0.05; RV_EF: 54.5 (41–56)% vs. 44.5 (37–49.5)%, p&lt;0.05; RV_SV: 80 (69–101)ml vs. 55.5 (50–72.5)ml, p&lt;0.05. In group of NIHF patients responders and non-responders were significantly differed in the following preoperative parameters: eH/M: 2.27 (2.02–2.41) vs. 1.64 (1.32–2.16), p&lt;0.05; dH/M: 2.18 (2.11–2.19) vs. 1.45 (1.23–1.61), p&lt;0.05; eSMS: 7 (5–7) vs. 15.5 (10–28.5), p&lt;0.05; dSMS: 10 (10–13) vs. 16.5 (15.5–29), p&lt;0.05, SD: 54.3 (43–58) degree vs. 65 (62–66) degree, p&lt;0.05; HBW: 179.5 (140–198) degree vs. 211 (208–213) degree, p&lt;0.05. Univariate logistic regression in IHF patients showed that LV dyssynchrony indexes – SD (OR=1.55; 95% CI 1.09–2.2; p&lt;0.5) and HBW (OR=1.13; 95% CI 1.02–1.24; p&lt;0.5), as well as RV indexes – RV_EF (OR=1.11; 95% CI 1.001–1.23; p&lt;0.5), RV_SV (OR=1.07; 95% CI 1.003–1.138; p&lt;0.5) were predictors of CRT response. In the group of NIHF patients, dH/M (OR=1.47; 95% CI 1.08–2; p&lt;0.5), SD (OR=0.83; 95% CI 0.73–0.95; p&lt;0.5), HBW (OR=0.96; 95% CI 0.93–0.99; p&lt;0.5) showed the predictive value in terms of CRT response. Conclusion(s) The positive response to CRT in IHF patients showed a link with LV dyssynchrony and preserved RV contractility. Whereas in NIHF patients the functional state of cardiac sympathetic activity, as well as LV dyssynchrony, were associated with CRT response. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Russian Foundation for Basic Research