Neuroimmune modulation mediated by IL-6: A potential target for the treatment of ischemia-induced ventricular arrhythmias.

BACKGROUND: Neural remodeling in the left stellate ganglion (LSG), as mediated by neuroimmune reactions, promotes cardiac sympathetic nerve activity (SNA) and thus increases the incidence of ventricular arrhythmias (VAs). Interleukin-6 (IL-6) is an important factor of the neuroimmune interaction. OBJECTIVE: The present study explored the effects of IL-6 on LSG hyperactivity and the incidence of VAs. METHODS: Eighteen beagles were randomly allocated to a control group (saline with myocardial infarction [MI], n = 6), adeno-associated virus (AAV) group (AAV with MI, n = 6), and IL-6 group (overexpression of IL-6 via AAV vector with MI, n = 6). Ambulatory electrocardiography was performed before and 30 days after AAV microinjection into the LSG. LSG function and ventricular electrophysiology were assessed at 31 days after surgery, and a canine MI model was established. Samples of the LSG were collected for immunofluorescence staining and molecular biological evaluation. Blood samples and 24-hour Holter data were obtained from 24 patients with acute MI on the day after they underwent percutaneous coronary intervention to assess the correlation between IL-6 levels and SNA. RESULTS: IL-6 overexpression increased cardiac SNA and worsened postinfarction VAs. Furthermore, sustained IL-6 overexpression enhanced LSG function, promoted expression of nerve growth factor, c-fos, and fos B in the LSG, and activated the signal transducer and activator of transcription 3/regulator of G protein signalling 4 signaling pathway. Clinical sample analysis revealed a correlation between serum IL-6 levels and heart rate variability frequency domain index as well as T-wave alternans. CONCLUSION: IL-6 levels are correlated with cardiac SNA. Chronic overexpression of IL-6 mediates LSG neural remodeling through the signal transducer and activator of transcription 3/regulator of G protein signalling 4 signaling pathway, elevating the risk of VA after MI.

Reclassification of Heart Failure with Preserved Ejection Fraction Following Cardiac Sympathetic Nervous System Activation: A New Cutoff Value of 58.

Heart failure (HF) with preserved left ventricular ejection fraction (LVEF) is a heterogeneous syndrome. An LVEF of 50% is widely used to categorize patients with HF; however, this is controversial. Previously, we have reported that patients with an LVEF of ≥ 58% have good prognoses. Further, cardiac sympathetic nervous system (SNS) activation is a feature of HF. In this retrospective, observational study, the cardiac SNS activity of HF patients (n = 63, age: 78.4 ± 9.6 years; male 49.2%) with LVEF ≥ 58% (n = 15) and LVEF < 58% (n = 48) were compared using 123I-metaiodobenzylguanidine scintigraphy. During the follow-up period (median, 3.0 years), 18 all-cause deaths occurred. The delayed heart/mediastinum (H/M) ratio was significantly higher in the LVEF ≥ 58% group than in the LVEF < 58% group (2.1 ± 0.3 vs. 1.7 ± 0.4, p = 0.004), and all-cause mortality was significantly lower in patients in the former than those in the latter group (log-rank, p = 0.04). However, when these patients were divided into LVEF ≥ 50% (n = 22) and LVEF < 50% (n = 41) groups, no significant differences were found in the delayed H/M ratio, and the all-cause mortality did not differ between the groups (log-rank, p = 0.09). In conclusion, an LVEF of 58% is suitable for reclassifying patients with HF according to cardiac SNS activity.

Factors Influencing Cardiac Sympathetic Nervous Function in Patients With Severe Aortic Stenosis: Assessment by 123I-Metaiodobenzylguanidine Myocardial Scintigraphy.

BACKGROUND: Numerous studies have shown that 123I-metaiodobenzylguanidine (MIBG) scintigraphy, an index of cardiac sympathetic nervous (CSN) activity, is useful for predicting prognosis in patients with heart failure. However, the factors influencing the CSN activity of patients with severe aortic stenosis (AS) remain unclear. METHODS: We enrolled 91 patients with severe AS who underwent 123I-MIBG scintigraphy, coronary computed tomography (CCT), and transthoracic echocardiography. When CCT angiography (CCTA) showed an obstructive epicardial artery, invasive coronary angiography was performed within 1 week of CCTA. RESULTS: There were 21 male and 70 female patients with a mean age of 84±5 years. Eighty-five (85) patients (93%) had hypertension and 13 patients (14%) had diabetes. Two (2) patients (2%) had previous myocardial infarction and eight (9%) had a previous coronary intervention. All patients had severe AS: aortic valve area was 0.63±0.18 cm2 and the mean pressure gradient was 56±19 mmHg. Regarding 123I-MIBG parameters, early heart-to-mediastinum (H/M) ratio was 3.1±0.5, delayed H/M ratio was 2.8±0.6, and the washout rate (WR) was 35%±13%. Multivariable linear regression analysis showed that coronary artery disease (ß=-0.30, p=0.002) was an independent predictor of delayed H/M ratio, and that aortic valve area (ß=-0.20, p=0.048) was an independent predictor of WR. CONCLUSIONS: Our findings suggest that coronary artery disease is an independent predictor of delayed H/M ratio, and aortic valve area is an independent predictor of WR in patients with severe AS.

Impact of Prosthesis-Patient Mismatch After Transcatheter Aortic Valve Replacement on Changes in Cardiac Sympathetic Nervous Function.

The impact of prosthesis-patient mismatch (PPM) after transcatheter aortic valve replacement (TAVR) on changes in cardiac sympathetic nervous (CSN) function remains unclear. Using 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy, we investigated the impact of PPM after TAVR on CSN activity.We enrolled 44 of 117 patients with severe aortic stenosis who underwent TAVR for analysis in the present study. We conducted 123I-MIBG scintigraphy at baseline and at about 9 months after TAVR. Differences between baseline and post-TAVR 123I-MIBG parameters were compared between cases with and without PPM.There were 17 and 27 patients with and without PPM, respectively. Those without PPM exhibited significantly decreased left ventricular mass index (122 ± 36 g/m2 versus 108 ± 30 g/m2, P < 0.001) following TAVR, whereas those with PPM did not (117 ± 21 g/m2 versus 110 ± 17 g/m2, P = 0.09). Significant improvements in delayed heart-to-mediastinum (H/M) ratio (2.8 ± 0.4 versus 3.0 ± 0.4, P = 0.004) and washout rate (WR) (33% ± 10% versus 24% ± 12%, P < 0.001) were observed after TAVR in patients without PPM but not in those with PPM. Multivariable linear regression analysis revealed PPM to be a negative predictor of improvements in delayed H/M ratio and WR.Delayed H/M ratio and WR improve significantly after TAVR in the absence of PPM, whereas these improvements are not observed in patients with PPM. Hence, the presence of PPM is a negative predictor of improvements in delayed H/M ratio and WR in patients undergoing TAVR.