Sympathetic Nervous Dysfunction Research Articles

Cardiac Presynaptic Sympathetic Nervous Function Evaluated by Cardiac PET in Patients with Chronotropic Incompetence Without Heart Failure.

Chronotropic incompetence (CTI), the inability of the heart to increase its rate with increased activity, leads to exercise intolerance and predicts overall mortality. We previously reported that cardiac β-adrenergic receptor downregulation occurs in patients with CTI without heart failure (HF), indicating postsynaptic sympathetic nervous dysfunction. However, cardiac presynaptic sympathetic nervous system function in CTI is not fully understood. Notably, 11C-hydroxyephedrine PET assesses cardiac presynaptic sympathetic nervous system function. Therefore, we investigated cardiac presynaptic sympathetic nervous system function using cardiac 11C-hydroxyephedrine PET in patients with CTI without HF. Methods: We performed cardiac PET in 13 patients with CTI without HF and 9 age-matched healthy controls using 11C-hydroxyephedrine (mean age, 75.1 ± 6.3 y; 59.1% male). The global hydroxyephedrine retention index was determined as myocardial tracer (11C-hydroxyephedrine) activity between 30 and 40 min divided by the activity input integral. CTI was defined as failing to achieve 80% of the heart rate reserve during bicycle ergometer exercise testing. Results: The clinical characteristics, including echocardiographic parameters, did not significantly differ between patients with CTI and controls. Peak heart rate was significantly lower in patients with CTI than in controls (107.0 ± 8.2 vs. 138.4 ± 13.6 beats/min, P < 0.001). The global hydroxyephedrine retention index was significantly higher in patients with CTI than in controls (0.14 ± 0.04 vs. 0.10 ± 0.05 min-1, P = 0.046). Conclusion: Hydroxyephedrine retention index was significantly higher in patients with CTI without HF than in controls. Our data suggested that impaired norepinephrine release in presynaptic sympathetic nerves contributes to the mechanism of CTI without HF.

Cardiac Sympathetic Nerve Function in Patients with Severe Aortic Stenosis Prior and After Transcatheter Aortic Valve Implantation

Background: While the non-invasive assessment of cardiac sympathetic nerve dysfunction is readily accessible, its applicability in invasive intervention for structural heart disease has received limited investigation. Our study aimed to clarify the cardiac sympathetic nerve function in patients with severe Aortic stenosis (AS) and its postoperative changes after transcatheter aortic valve implantation (TAVI) using 123I-metaiodobenzylguanidine scintigraphy (MIBG) in combination with 5-year mortality prediction model. Methods: Consecutive 26 patients (83±5ys, male 4) with severe AS who underwent MIBG prior TAVI procedures were retrospectively enrolled. Of those, 15 patients underwent postoperative-follow up MIBG. The early and delayed heart-to-mediastinum ratio (e- and d-H/M), and washout rate (WR) were obtained from MIBG planner imaging. The MIBG 5-year mortality prediction model was employed to compare pre and after TAVI. Cardiac function and wall thickness were evaluated with transthoracic echocardiography. Results: Preoperative e-H/M, d-H/M, and WR were 2.4±0.5, 2.3±0.4, and 29±14% respectively, and WR showed significant correlation to left ventricular ejection fraction (LVEF) and brain natriuretic peptide (BNP) (r=-0.4 and 0.6; p=0.03, and 0.001 for LVEF and BNP, respectively). 102±28 days after TAVI, either H/M or WR did not show significant improvement among enrolled patients (2.5±0.3, 2.3±0.4, and 30±11% for e-, d-H/M, and WR for after TAVI), while the BNP level was significantly reduced (128±691 and 94±194 pg/dl, for pre vs. after, p=0.008). Five patients showed a significant recovery in WR (37.0±13.8 and 28.8±8.5% for pre and post, p=0.04), and left ventricular wall thickness was significantly thinner compared to those who did not recover (15.2±3.2 vs 11.2±2.4, p=0.02; 14.2±2.9 vs 10.8±1.8, p=0.02 for intraventricular septum and posterior wall, respectively). In 5-year prediction risk model, 7 patients showed a significant reduction in mortality risk, and the patients who did not show risk reduction had significantly reduced renal function (eGFR 57.5±18.8 vs. 38.2±11.3 ml/min/1.73m2, p=0.03 for recovered vs. not recovered). Conclusion: After a 3-month follow-up after TAVI, diverse response in cardiac MIBG parameters were observed among patients with severe AS, despite successful valve replacement. Cardiac MIBG serves as a non-invasive tool that can comprehensively evaluate and surrogate the severity of heart failure resulting from a multi-factorial condition.

Abstract 17680: MIBG Myocardial Scintigraphy is Useful for Predicting CTRCD Caused by Trastuzumab

Introduction: Trastuzumab is known to reduce the mortality rate, recurrence rate, and metastasis rate in Human epidermal growth factor receptor type 2 (HER2)-positive breast cancer patients, and it is recommended to administer it for 12 months to all early-stage HER2-positive breast cancer patients. However, trastuzumab administration can lead to Cancer Therapeutics-Related Cardiac Dysfunction (CTRCD). The guidelines suggest that regular echocardiography every 3 months is useful for early detection of CTRCD, but there are no tests available to predict it before its onset.The purpose of this study is to determine whether cardiac sympathetic nerve evaluation using MIBG myocardial scintigraphy before trastuzumab administration can predict the development of CTRCD three months after administration. Methods: MIBG myocardial scintigraphy was performed before trastuzumab administration in 35 HER2-positive breast cancer patients, and cardiac function assessment was conducted using echocardiography before administration, at 1 month, and at 3 months. Simultaneously, NT-proBNP and troponin levels were measured. CTRCD was defined as a decrease in global longitudinal strain (GLS) of 10% or more from before administration at the 3-month follow-up. Results: Anthracycline and trastuzumab regimens were used in 21 patients (60%). CTRCD occurred in 17 patients at the 3-month follow-up. There were no significant differences in age or previous medication between the CTRCD group and the non-CTRCD group, but the early H/M ratio in MIBG myocardial scintigraphy was significantly lower in the CTRCD group (2.77±0.36) compared to the non-CTRCD group (3.10±0.36) (p&lt;0.01). There were no significant differences in the delay H/M ratio or washout rate. None of the echocardiographic parameters, NT-proBNP levels, or troponin levels showed significant differences and did not become predictive factors. Conclusions: MIBG myocardial scintigraphy is useful for predicting CTRCD caused by trastuzumab. Preclinical studies have suggested that HER2 transactivation from β-adrenergic receptors in the myocardium confers cardioprotection. Suppression of HER2 signaling during cardiac sympathetic nerve dysfunction potentially contributes to the development of CTRCD.

Peripheral BDNF Regulates Somatosensory-Sympathetic Coupling in Brachial Plexus Avulsion-Induced Neuropathic Pain.

Brachial plexus avulsion (BPA) is a combined injury involving the central and peripheral nervous systems. Patients with BPA often experience severe neuropathic pain (NP) in the affected limb. NP is insensitive to the existing treatments, which makes it a challenge to researchers and clinicians. Accumulated evidence shows that a BPA-induced pain state is often accompanied by sympathetic nervous dysfunction, which suggests that the excitation state of the sympathetic nervous system is correlated with the existence of NP. However, the mechanism of how somatosensory neural crosstalk with the sympathetic nerve at the peripheral level remains unclear. In this study, through using a novel BPA C7 root avulsion mouse model, we found that the expression of BDNF and its receptor TrκB in the DRGs of the BPA mice increased, and the markers of sympathetic nervous system activity including α1 and α2 adrenergic receptors (α1-AR and α2-AR) also increased after BPA. The phenomenon of superexcitation of the sympathetic nervous system, including hypothermia and edema of the affected extremity, was also observed in BPA mice by using CatWalk gait analysis, an infrared thermometer, and an edema evaluation. Genetic knockdown of BDNF in DRGs not only reversed the mechanical allodynia but also alleviated the hypothermia and edema of the affected extremity in BPA mice. Further, intraperitoneal injection of adrenergic receptor inhibitors decreased neuronal excitability in patch clamp recording and reversed the mechanical allodynia of BPA mice. In another branch experiment, we also found the elevated expression of BDNF, TrκB, TH, α1-AR, and α2-AR in DRG tissues from BPA patients compared with normal human DRGs through western blot and immunohistochemistry. Our results revealed that peripheral BDNF is a key molecule in the regulation of somatosensory-sympathetic coupling in BPA-induced NP. This study also opens a novel analgesic target (BDNF) in the treatment of this pain with fewer complications, which has great potential for clinical transformation.

Differences in autonomic nervous system activity between long-acting injectable aripiprazole and oral aripiprazole in schizophrenia

BackgroundDistinct oral atypical antipsychotics have different effects on autonomic nervous system (ANS) activity. Among them, oral aripiprazole has been linked to dysfunction of the ANS in schizophrenia. Long-acting injectable aripiprazole is a major treatment option for schizophrenia, but the effect of the aripiprazole formulation on ANS activity remains unclear. In this study, we compared ANS activity between oral aripiprazole and aripiprazole once-monthly (AOM) in schizophrenia.MethodsOf the 122 patients with schizophrenia who participated in this study, 72 received oral aripiprazole and 50 received AOM as monotherapy. We used power spectral analysis of heart rate variability to assess ANS activity.ResultsPatients who received oral aripiprazole showed significantly diminished sympathetic nervous activity compared with those who received AOM. Multiple regression analysis revealed that the aripiprazole formulation significantly influenced sympathetic nervous activity.ConclusionCompared with oral aripiprazole, AOM appears to have fewer adverse effects, such as sympathetic nervous dysfunction.

Application of Physiological Autonomic Activity Tracking GUI and Computational Algorithms for Measuring Persistent Vagal Nerve Dysfunction After Recovery from SARS‐CoV‐2 Infection

Post‐Acute Sequelae of SARS‐CoV‐2 infection (PASC) is now recognized as a constellation of symptoms such as postural hypotension, anxiety, and “brain fog” in addition to autonomic nervous system dysfunction such as tachycardia and labile hypertension. Better quantification of these conditions, specifically, autonomic nervous system dysfunction, is desired for future diagnostics, treatment modalities, and gaining a further understanding of PASC. This research has led to application of a novel autonomic activity tracking algorithm and GUI suite from previous work, see Figure 1, to study the physiological autonomic activity in six patients who had recovered from acute SARS‐CoV‐2 infection a mean of six months prior but were still experiencing symptoms. By measuring skin sympathetic nervous activity (SKNA), heart rate variability, and the cutaneous electrogastrogram (EGG), all before and after a water meal challenge, the data was fed into a custom analysis pipeline, shown in Figure 1. Each of the PASC patients were compared to a mean response of 34 healthy controls, each undergoing a 20‐minute baseline recording and another 20‐minute recording after ingestion of an 8 oz water test meal. All six patients showed significantly abnormal heart rate variability on frequency domain analysis in predominantly the low frequency (LF) and very low frequency (VLF) bands, and less so in the high frequency (HF) band, suggesting sympathetic nerve dysfunction. Three patients showed a significant decrease in SKNA while two showed a significant increase. All patients showed an abnormal cutaneous EGG. As shown in Figure 2, the temporal responses of aSKNA, VLF, LF, HF, and EGG for the PASC patients revealed that on average they were statistically different (p<0.05) from the healthy controls’ responses respectively during 98.4%, 78.4%, 86.76%, 47.9%, and 86.1% of the 40‐minute time period in testing, 20 minutes of baseline and 20 minutes after ingestion. In conclusion, we are looking at the sympathetic, parasympathetic, and enteric nervous systems synced temporally for applications with classification and further stratification of PASC based on the temporal dynamics of their autonomic nervous system mediated coordination from digestion. This shows that SARS‐CoV02 infection appears to have a significant effect on sympathetic and parasympathetic autonomic nervous system function and may be responsible for the disturbances noted in PASC. This work provides the framework and example of use for further applications in autonomic disorder physiological response exploration and furthermore can be expanded to other areas of neuromodulation.

Prognostic Significance of Cardiac 123I-MIBG SPECT Imaging in Heart Failure Patients With Preserved Ejection Fraction

ObjectivesThe authors sought to elucidate the prognostic value of cardiac sympathetic nerve dysfunction as evaluated using iodine-123-labeled metaiodobenzylguanidine (123I-MIBG) single-photon emission computed tomography (SPECT) imaging in patients with heart failure (HF) with preserved left ventricular ejection fraction (HFpEF). BackgroundCardiac sympathetic nerve dysfunction assessed by 123I-MIBG imaging is associated with poor outcomes in chronic HF patients with reduced left ventricular ejection fraction (HFrEF). However, no information is available on the prognostic vale of cardiac 123I-MIBG SPECT imaging in patients with HFpEF. MethodsWe studied 148 patients admitted for acute decompensated HF (ADHF) with nonischemic HFpEF and who underwent cardiac 123I-MIBG imaging at discharge. The cardiac 123I-MIBG heart-to-mediastinum ratio (H/M) was measured on the delayed planar image (late H/M). SPECT analysis of the delayed image was conducted, and the tracer uptake in all 17 regions on the polar map was scored on a 5-point scale by comparison with a sex-matched normal control database. The total defect score (TDS) was calculated by summing the score of each of the 17 segments. The primary endpoint was the association between TDS and cardiac events (the composite of emergent HF hospitalization and cardiac death). ResultsDuring a mean follow-up period of 2.4 ± 1.6 years, 61 patients experienced cardiac events. TDS was significantly associated with cardiac events after multivariate Cox adjustment (P < 0.0001). Patients with high TDS levels had a significantly greater risk of cardiac events than those with middle or low TDS levels (63% vs 40% vs 20%, respectively; P < 0.0001; HR: 4.69; 95% CI: 2.29 to 9.61; and HR: 2.46; 95% CI: 1.14 to 5.29). C-statistic of TDS was 0.730 (95% CI: 0.651 to 0.799), which was significantly higher than that of late H/M (0.607; 95% CI: 0.524 to 0.686; P = 0.0228). ConclusionsCardiac 123I-MIBG SPECT imaging provided useful prognostic information in nonischemic ADHF patients with HFpEF. (Clinical Trial: Osaka Prefectural Acute Heart Failure Syndrome Registry [OPAR]: UMIN000015246)

Endothelial NADPH oxidases protect against sympathetic nervous system hyperactivity-induced cardiac dysfunction and remodeling in mice: contribution of SGLT2

Abstract Background NADPH oxidase-derived reactive oxygen species (ROS) contribute to cardiac dysfunction, often characterized by coronary microvascular dysfunction, an inflammatory response and cardiomyocyte hypertrophy. Hyperactivity of the sympathetic nervous system (SNS) induces oxidative stress, promoting cardiac dysfunction and the development of heart failure. Selective inhibitors of sodium-glucose co-transporter 2 (SGLT2), have shown remarkable cardioprotective effects in clinical studies. Recently, SGLT2 inhibitors have been reported to prevent endothelial dysfunction and pro-inflammatory responses in endothelial cells in response to angiotensin II involving NADPH oxidases. Purpose Therefore, the aim of the study was to determine whether endothelial NADPH oxidases promote SNS-induced cardiac dysfunction and to clarify the role of SGLT2. Methods Male wild-type mice and mice lacking the NADPH oxidase subunit p22phox in the endothelium (p22phox ecKO, 11-week-old) were treated with isoproterenol (100 mg/kg) for five consecutive days and sacrificed at day 14. Hemodynamic measurements of left (LV) and right (RV) ventricles were performed by a transthoracic approach. Heart tissue sections were stained with Sirius red to evaluate fibrosis and wheat germ agglutinin to assess cardiomyocyte size. Cultured human microvascular endothelial cells (HMEC-1) were stimulated with 100 nM isoproterenol and ROS levels were assessed by dihydroethidium fluorescence. The expression level of target genes and proteins was assessed by quantitative real-time PCR and Western blot, respectively. siRNA approaches were used to down-regulate either the NADPH oxidase subunit p22phox or SGLT2. Results The isoproterenol treatment increased LV and RV systolic pressures in wild-type mice but not in p22phox ecKO mice. p22phox ecKO mice were protected against isoproterenol-induced fibrosis, cardiac remodeling characterized by upregulation of mRNA levels of ANP, BNP and β-MHC, and pulmonary congestion. LV remodeling was associated with upregulation of the NADPH oxidase subunits p22phox, Nox2, and Nox4 as well as of SGLT2 in wild-type mice, however no such effects were observed in p22phox ecKO mice. Exposure of HMEC-1 to isoproterenol stimulated the formation of ROS and caused an upregulation of p22phox and SGLT2 protein levels in a time- and concentration-dependent manner. No such effects were observed following silencing of either p22phox or SGLT2, or use of a selective SGLT2 inhibitor. Conclusion Deletion of the NADPH oxidase subunit p22phox in the endothelium protected against SNS hyperactivity induced LV cardiac dysfunction and remodeling, and prevented upregulation of SGLT2. Since depletion of SGLT2 prevented the pro-oxidant response to isoproterenol in endothelial cells, the endothelial NADPH oxidase/SGLT2 pathway seems to have a prominent role in promoting cardiac remodeling and dysfunction in SNS hyperactivity. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Deutsches Herzzentrum München

Renal Denervation by Noninvasive Stereotactic Radiotherapy Induces Persistent Reduction of Sympathetic Activity in a Hypertensive Swine Model.

BackgroundWe have previously reported the feasibility of noninvasive stereotactic body radiotherapy (SBRT) as a novel approach for renal denervation.Methods and ResultsHerein, from a translational point of view, we assessed the antihypertensive effect and chronological evolution of SBRT‐induced renal nerve injury within 6 months in a hypertensive swine model. Hypertension was induced in swine by subcutaneous implantation of deoxycorticosterone acetate pellets in combination with a high‐salt diet. A single dose of 25 Gy with SBRT was delivered for renal denervation in 9 swine within 3.4±1.0 minutes. Blood pressure levels at baseline and 1 and 6 months post‐SBRT were comparable to control (n=5), whereas renal norepinephrine was significantly lower at 6 months (P<0.05). Abdominal computed tomography, performed before euthanasia and renal function assessment, remained normal. Standard semiquantitative histological assessment showed that compared with control (1.4±0.4), renal nerve injury was greater at 1 month post‐SBRT (2.3±0.3) and peaked at 6 months post‐SBRT (3.2±0.8) (P<0.05), along with a higher proportion of active caspase‐3–positive nerves (P<0.05). Moreover, SBRT resulted in continuous dysfunction of renal sympathetic nerves and low level of nerve regeneration in 6 months by immunohistochemistry analysis.ConclusionsSBRT delivering 25 Gy for renal denervation was safe and related to sustained reduction of sympathetic activity by aggravating nerve damage and inhibiting nerve regeneration up to 6 months; however, its translation to clinical trial should be cautious because of the negative blood pressure response in the deoxycorticosterone acetate–salt hypertensive swine model.

Prognostic value of cardiac 123 I-metaiodobenzylguanidine imaging for predicting cardiac events after transcatheter aortic valve replacement.

AimsIn patients with aortic valve stenosis (AS), cardiac sympathetic nervous (CSN) dysfunction and its improvement after transcatheter aortic valve replacement (TAVR) have been reported. The prognostic impact of CSN function remains unclear. This study investigated the prognostic value of cardiac 123I‐metaiodobenzylguanidine (MIBG) imaging for predicting cardiac events after TAVR.Methods and resultsThis single‐centre prospective observational study enrolled patients with AS between July 2017 and May 2019. MIBG scintigraphy was performed before and soon after TAVR to evaluate the late heart–mediastinum ratio (L‐H/M). Patients were classified into three pairs of groups based on the baseline and post‐TAVR L‐H/M (≥2.0 or <2.0) and on the presence of TAVR‐related improvement in L‐H/M. The study endpoint was the occurrence of major adverse cardiac events (MACE), defined as a composite of all‐cause death, non‐fatal myocardial infarction, and hospitalization due to heart failure. Among the 187 consecutive patients who underwent TAVR, 107 (27 men; median age: 86 years) were evaluated. Over a median follow‐up of 366 days, 15 (14.0%) patients had MACE. The incidence of MACE was significantly low in patients with L‐H/M improvement and/or high post‐TAVR L‐H/M (≥2.0). Baseline L‐H/M and frailty were associated with poor response of L‐H/M to TAVR treatment. TAVR‐related improvement in L‐H/M had significant effects on MACE, with an adjusted hazard ratio of 0.233 (95% confidence interval, 0.064–0.856; P = 0.028).ConclusionsTAVR‐related improvement in L‐H/M was an independent predictor of cardiac events, 1 year after TAVR. Cardiac MIBG imaging is useful for predicting cardiac events after TAVR.

Abstract 14945: Prognostic Value of Cardiac 123 I-MIBG Imaging for Predicting Cardiac Events After Transcatheter Aortic Valve Replacement

Introduction: In patients with aortic valve stenosis (AS), cardiac sympathetic nervous (CSN) dysfunction and its improvement after transcatheter aortic valve replacement (TAVR) have been reported; however, the prognostic impact of CSN function remains unclear. This study investigated the prognostic value of cardiac 123 I-metaiodobenzylguanidine (MIBG) imaging for predicting cardiac events after TAVR. Hypothesis: We hypothesized that the improvement in MIBG parameter with TAVR treatment can be an indicator of better prognosis. Methods: This single-center prospective observational study enrolled patients with AS between July 2017 and May 2019. MIBG scintigraphy was performed before and after TAVR to evaluate the delayed heart-mediastinum ratio (d-H/M). Patients were classified into three pairs of groups based on the baseline and post-TAVR d-H/M (≥2.0 or &lt;2.0) and on the presence of TAVR-related improvement in d-H/M (i.e. Δ d-H/M [post-TAVR – baseline] &gt;0 or ≤0). The study endpoint was the occurrence of major adverse cardiac events (MACE), defined as a composite of all-cause death, non-fatal myocardial infarction, and hospitalization due to heart failure. Results: Among the 187 consecutive patients who underwent TAVR, 107 (27 men; median age: 86 years) were evaluated. Over a median follow-up of 366 days, 15 (14.0%) patients had MACE. The incidence of MACE was significantly low in patients with d-H/M improvement and/or high post-TAVR d-H/M (≥2.0). Baseline d-H/M and frailty were associated with poor response of d-H/M to TAVR treatment. Moreover, post-TAVR d-H/M had significant effects on MACE, with an adjusted hazard ratio of 1.264 (95% confidence interval, 0.034-2.480; p=0.04). Conclusions: Both d-H/M improvement and high post-TAVR d-H/M were associated with better prognosis in patients who underwent TAVR. Cardiac MIBG imaging is useful for predicting cardiac events after TAVR.

Prognostic significance of cardiac 123I-MIBG SPECT imaging in patients with acute decompensated heart failure with preserved left ventricular ejection fraction

Abstract Background Cardiac sympathetic nerve dysfunction, which is assessed by I-123 metaiodobenzylguanidine (MIBG) imaging, is associated with the poor outcomes in patients with heart failure (HF). Most of the literature on the use of 123I-MIBG imaging is based on planar images in patients with chronic HF and reduced left ventricular ejection fraction (HFrEF), because It is technically challenging to conduct precise 123I-MIBG SPECT analysis in globally denervated heart, which is frequently observed in HFrEF patients. There was no information available on cardiac sympathetic nerve dysfunction evaluated by cardiac MIBG SPECT imaging in acute decompensated HF (ADHF) patients with preserved left ventricular ejection fraction (HFpEF). Purpose We aimed to clarify the prognostic significance of 123I-MIBG SPECT myocardial imaging in ADHF patients with HFpEF. Methods We enrolled 183 patients who were admitted for ADHF with HFpEF, discharged with survival. All patients underwent cardiac MIBG imaging at the timing of discharge. The cardiac MIBG heart to mediastinum ratio (H/M) was calculated on the early image and the delayed image (late H/M). We studied 156 patients after excluding 27 patients whose MIBG SPECT reconstruction was difficult due to too low MIBG uptake or extracardiac accumulation interference. SPECT analysis on the delayed image was conducted by using CardioBull, a fully automated software for the quantification of I-123 MIBG SPECT. All of 17 regional tracer uptake were compared with normal control database. A scoring algorithm for the evaluation of low uptake employs a 5-point scoring system as 0–4 for normal, mildly abnormal, moderately abnormal, severe abnormal, and perfusion defect, respectively. The summed severity (SSS) scores were obtained by summing the score for all segments. SSS could range from 0 to 68. The endpoint of this study is cardiac events defined as the composite of unplanned heart failure hospitalization and cardiac death. Results During a mean follow up period of 2.4±1.6 years, 60 patients reached cardiac events. SSS was significantly high in patients with than without cardiac events (20 [10–27] vs 7 [4–16], p&amp;lt;0.0001). SSS (p&amp;lt;0.0001) was significantly associated with cardiac events after multivariable Cox adjustment of age, sex, creatinine and log-transformed BNP level, although late H/M showed the significant association with the endpoint at the univariate Cox analysis. Kaplan-Meier analysis showed that patients with high SSS (&amp;gt;10, defined by median) had significantly greater risk of cardiac event (56% vs 21%, Hazard ratio: 3.56 (2.00–6.33, p&amp;lt;0.0001). ROC curve analysis showed that area under the curve (AUC) of SSS was 0.746 [95% CI:0.670, 0.812], which was significantly higher than that of late H/M (0.618 [95% CI:0.537, 0.695]) (p=0.0159). Conclusion Cardiac MIBG SPECT imaging was useful for risk stratification in ADHF patients with HFpEF. Funding Acknowledgement Type of funding source: None

Long-term serial changes of cardiac sympathetic nerve dysfunction in acute decompensated heart failure patients with reduced, mid-range and preserved left ventricular ejection fraction

Abstract Background Cardiac sympathetic nerve dysfunction, which is assessed by I-123 metaiodobenzylguanidine (MIBG) imaging, is associated with the poor outcomes in patients with chronic heart failure (CHF). Serial evaluation of cardiac MIBG imaging was shown to be useful for predicting adverse outcome in CHF. However, there was no information available on long-term serial changes of cardiac sympathetic nerve dysfunction after discharge of acute decompensated heart failure (ADHF) hospitalization. Purpose We aimed to clarify the serial change of cardiac MIBG imaging parameter in long-term after discharge of heart failure hospitalization, especially relating to HFrEF (LVEF&amp;lt;40%), HFmrEF (40%≤LVEF&amp;lt;50%) and HFpEF (LVEF≥50%). Methods We studied 112 patients (HFrEF; n=44, HFmrEF; n=23 and HFpEF; n=45) who were admitted for ADHF, discharged with survival and without heart failure hospitalization during follow-up period. All patients underwent cardiac MIBG imaging at the timing of discharge, in 6–12 months and in 18–24 months after discharge. The cardiac MIBG heart to mediastinum ratio (H/M) was calculated on the early image and the delayed image (late H/M). The cardiac MIBG washout rate (WR) was calculated from the early and delayed planar images after taking radioactive decay of I-123 into consideration. Results In HFrEF patients, late H/M was significantly improved from discharge to 6–12 months data (1.60±0.24 vs 1.75±0.31, p&amp;lt;0.0001). Late H/M of HFmrEF patients was also significantly improved from discharge to 18–24 months data (1.71±0.27 vs 1.84±0.29 p=0.043). On the other hand, late H/M of HFpEF patients was not significantly changed. As for WR, WR in HFrEF and HFmrEF patients was significantly improved from discharge to 18–24 months data, although WR of HFpEF was not significantly changed. Conclusion The improvement in cardiac sympathetic nerve dysfunction was observed in patients with HFrEF and HFmrEF, not in HFpEF, after the discharge of acute heart failure hospitalization. Funding Acknowledgement Type of funding source: None

Prognostic value of cardiac 123I-metaiodobenzylguanidine imaging for predicting cardiac events after transcatheter aortic valve replacement

Abstract Background In patients with aortic valve stenosis (AS), cardiac sympathetic nervous (CSN) dysfunction and its improvement after TAVR have been reported; however, the prognostic impact of CSN function remains unclear. This study investigated the prognostic value of cardiac 123I-metaiodobenzylguanidine (MIBG) imaging for the prediction of cardiac events after transcatheter aortic valve replacement (TAVR). Methods This study was a single-center prospective observational study that enrolled patients with AS or failed surgical bioprostheses between July 2017 and May 2019. MIBG scintigraphy was performed before and after TAVR to evaluate the delayed heart–mediastinum ratio (d-H/M). Patients were classified into three pairs of groups based on the baseline and post-TAVR d-H/M (≥2.0 or &amp;lt;2.0) and on the presence of TAVR-related improvement of d-H/M. The study endpoints were major adverse cardiac events (MACE), including all-cause death, myocardial infarction, and hospitalization due to heart failure. The association of d-H/M with MACE following TAVR was based on a Cox proportional hazards ratio model adjusted for multiple prognostic variables. Results Of 187 consecutive patients who underwent TAVR, 111 (31 men; median age: 86 years) were evaluated. Over a median follow-up of 366 days, 16 (14.4%) patients had MACE. The incidence of MACE was significantly lower in patients with d-H/M improvement and/or the high post-TAVR d-H/M (≥2.0). Post-TAVR d-H/M had significant impacts on MACE, with an adjusted hazard ratio of 1.326 (95% confidence interval, 0.139–2.515; p=0.027). Conclusions Both d-H/M improvement and high post-TAVR d-H/M were associated with better prognosis in patients who underwent TAVR. Cardiac MIBG imaging was useful for predicting cardiac events after TAVR. Funding Acknowledgement Type of funding source: None

Association Between Heart Rate Variability and Parkinson's Disease: A Meta-analysis.

A systematic review which aims to assess the evidence regarding the function of the autonomic heart rate regulation system among Parkinson's disease (PD) patients. The main objective of the study is to compare heart rate variability (HRV) between those with and without PD from published studies. The subgroup analyses aimed to investigate the impact of treatment and disease duration on heart rate variability (HRV), assessed by measuring sympathetic and parasympathetic activity via low-frequency (LF) and high-frequency (HF) power spectrum scores, in patients with Parkinson's disease (PD). PubMed, Cochrane Library, Embase and Web of Science were searched using the keywords "Parkinson's disease" and "heart rate variability". Studies that reported at least one HRV variable were included. The quality of the included studies was evaluated, and the relevant information was extracted. A meta-analysis was carried out with Stata software. We followed the PRISMA guidelines for all stages of the meta-analysis. PROSPERO registration number: CRD42021242766. Thirteen references (16 studies) were included in our analysis. The LF values (g -0.27; 95% confidence interval (CI) -0.53 to -0.01) of the patients with PD were lower than the controls. No significant differences in HF values (g -0.11; 95% CI -0.28 to 0.06) were observed between groups. Subgroup analyses of HRV outcomes in patients stratified by treatment status and disease duration were performed. For LF, patients with a disease duration of less than 5 years presented lower HF (g -0.25; 95% CI -0.44 to -0.06) values than controls. Regarding HF, patients receiving treatment presented lower HF (g -0.22; 95% CI -0.40 to 0.05) values than controls, and patients with a disease duration greater than 5 years also presented lower HF (g -0.29; 95% CI -0.56 to -0.03) values than controls. We have confirmed and elaborated on the hypothesis of sympathovagal imbalance in PD. Knowledge of the effect of sympathovagal balance on HRV may inform the design of therapeutic regimens for PD. However, between-study heterogeneity and methodological issues limit the generalizability of the evidence; thus, future studies employing strict methodologies are warranted. Our meta-analysis found that PD is associated with reduced HRV values, which indicates that both sympathetic and vagal activities are decreased. Patients in the early stage of PD have sympathetic autonomic nerve dysfunction, with only minor damage to sympathetic activity.

Prognostic significance of cardiac I-123-metaiodobenzylguanidine imaging in patients with reduced, mid-range, and preserved left ventricular ejection fraction admitted for acute decompensated heart failure: a prospective study in Osaka Prefectural Acute Heart Failure Registry (OPAR).

Cardiac 123I-metaiodobenzylguanidine (123I-MIBG) imaging provides prognostic information in patients with chronic heart failure (HF). However, there is little information available on the prognostic role of cardiac 123I-MIBG imaging in patients admitted for acute decompensated heart failure (ADHF), especially relating to reduced ejection fraction [HFrEF; left ventricular ejection fraction (LVEF) < 40%], mid-range ejection fraction (HFmrEF; 40% ≤ LVEF < 50%) and preserved ejection fraction (HFpEF; LVEF ≥ 50%). We studied 349 patients admitted for ADHF and discharged with survival. Cardiac 123I-MIBG imaging, echocardiography, and venous blood sampling were performed just before discharge. The cardiac 123I-MIBG heart-to-mediastinum ratio (late H/M) was measured on the chest anterior view images obtained at 200 min after the isotope injection. The endpoint was cardiac events defined as unplanned HF hospitalization and cardiac death. During a follow-up period of 2.1 ± 1.4 years, 128 patients had cardiac events (45/127 in HFrEF, 28/78 in HFmrEF, and 55/144 in HFpEF). On multivariable Cox analysis, late H/M was significantly associated with cardiac events in overall cohort (P = 0.0038), and in subgroup analysis of each LVEF subgroup (P = 0.0235 in HFrEF, P = 0.0119 in HFmEF and P = 0.0311 in HFpEF). Kaplan-Meier analysis showed that patients with low late H/M (defined by median) had significantly greater risk of cardiac events in overall cohort (49% vs. 25% P < 0.0001) and in each LVEF subgroup (HFrEF: 48% vs. 23% P = 0.0061, HFmrEF: 51% vs. 21% P = 0.0068 and HFpEF: 50% vs. 26% P = 0.0026). Cardiac sympathetic nerve dysfunction was associated with poor outcome in ADHF patients irrespective of HFrEF, HFmrEF, or HFpEF.

The NADPH oxidase inhibitor apocynin improves cardiac sympathetic nerve terminal innervation and function in heart failure.

What is the central question of this study? Does NADPH oxidase activation mediate cardiac sympathetic nerve denervation and dysfunction in heart failure. What is the main findings and its importance? Cardiac sympathetic nerve terminal density and function were reduced in heart failure after myocardial infarction in rabbits. The NADPH oxidase inhibitor apocynin prevented the reduction in cardiac sympathetic nerve terminal density and function in heart failure. This suggest that NADPH oxidase activation mediates cardiac sympathetic nerve terminal abnormalities in heart failure. NADPH oxidase may be a potential therapeutic target for cardiac sympathetic denervation and dysfunction in heart failure. Congestive heart failure (CHF) is characterized by cardiac sympathetic nerve terminal abnormalities, as evidenced by decreased noradrenaline transporter (NAT) density and cardiac catecholaminergic and tyrosine hydroxylase (TH) profiles. These alterations are associated with increased reactive oxygen species (ROS). NADPH oxidase is a major source of ROS in CHF. In this study, we tested the hypothesis that NADPH oxidase activation mediates cardiac sympathetic nerve terminal abnormalities in CHF. CHF was produced by myocardial infarction (MI) in rabbits. Rabbits with MI or a sham operation were randomized to orally receive an NADPH oxidase inhibitor, apocynin (6mgkg-1 day-1 ), or placebo for 30days. MI rabbits exhibited left ventricular dilatation, systolic dysfunction, and increases in NADPH oxidase activity and 4-hydroxynonenal expression in the remote non-infarcted myocardium, all of which were prevented by treatment with apocynin. Cardiac catecholaminergic histofluorescence profiles and immunostained TH and PGP9.5 expression were decreased, and the decreases were ameliorated by apocynin treatment. NAT, TH and PGP9.5 protein and mRNA expression were reduced and the reduction was mitigated by apocynin treatment. The effects of apocynin were confirmed by utilizing the NADPH oxidase inhibitor diphenyleneiodonium in a separate experiment. In conclusion, the NADPH oxidase inhibitor apocynin attenuated increased myocardial oxidative stress and decreased cardiac sympathetic nerve terminals in CHF after MI in rabbits. These findings suggest that the activation of NADPH oxidase mediates cardiac sympathetic nerve terminal abnormalities in CHF, and the inhibition of NADPH oxidase may be beneficial for the treatment of heart failure.

Relationship between the severity of cerebral white matter hyperintensities and sympathetic nervous activity in older adults.

White matter hyperintensities (WMH), visualized on brain magnetic resonance imaging, represent an abnormality related to the development of geriatric syndromes. Recently, it has been found that low sympathetic nervous activity might be associated with physical and cognitive dysfunction in older adults. Therefore, we investigated the relationship between the severity of cerebral WMH and sympathetic nervous activity, measured by the heart rate variability. We carried out a cross-sectional study of 39 older patients. Holter recording was carried out for 30 min. From the RR intervals on the electrocardiogram, the standard deviation of the normal-to-normal intervals, the standard deviation of all normal-to-normal intervals in all the five segments of the entire recording, low frequency (LF), high frequency (HF) and LF/HF were calculated. In regard to the WMH, periventricular hyperintensities and deep white matter hyperintensities (DWMH) were rated according to the Fazekas classification. The WMH were also rated semiquantitatively according to the methods developed by Junque (periventricular hyperintensities) and de Groot (DWMH). The LF/HF showed significant negative correlations with the total and regional periventricular hyperintensities, as well as DWMH. Multiple regression analysis showed that the negative associations remained significant between the LF/HF and DWMH (total, temporal, occipital). Furthermore, fall risk index significantly correlated with the LF/HF, total and the occipital DWMH. The severity of the DWMH was associated with the LF/HF and the fall risk, one of the important geriatric syndromes, suggesting that WMH, sympathetic nervous dysfunction and geriatric syndrome are interrelated to each other. Geriatr Gerontol Int 2018; 18: 569-575.

Clinical and radiological diversity in genetically confirmed primary familial brain calcification

Primary familial brain calcification (PFBC) is a rare neuropsychiatric disorder with characteristic symmetrical brain calcifications. Patients with PFBC may have a variety of symptoms, although they also may be clinically asymptomatic. Parkinsonism is one of the most common movement disorders; however, the underlying mechanism remains unclear. This condition is typically transmitted in an autosomal dominant fashion. To date, mutations in SLC20A2, PDGFRB, PDGFB, and XPR1 have been reported to cause PFBC. The aim of the study was to identify the genetic cause of brain calcification in probands from three PFBC families and in 8 sporadic patients and to perform clinical and radiological assessments focusing on parkinsonism in mutation carriers. Three familial PFBC probands and their relatives and eight sporadic patients affected with brain calcifications were enrolled in this study. Whole-exome sequencing identified three novel mutations: c.269G > T, p.(Gly90Val) and c.516+1G > A in SLC20A2 in familial cases, and c.602-1G > T in PDGFB in a sporadic patient. The c.516+1G > A mutation resulted in exon 4 skipping in SLC20A2 (p.Val144Glyfs*85). Dopamine transporter single photon emission computed tomography using 123I-ioflupane and 123I-metaiodobenzylguanidine cardiac scintigraphy revealed pre-synaptic dopaminergic deficit and cardiac sympathetic nerve dysfunction in two SLC20A2-related PFBC patients with parkinsonism.

Cardio-oncology: the Nuclear Option.

Cardio-oncology focuses increased effort to decrease cancer treatment-related cardiotoxicity while continuing to improve outcomes. We sought to synthesize the latest in nuclear cardiology as it pertains to the assessment of left ventricular function in preventative guidelines and comparison to other modalities, novel molecular markers of pre-clinical cardiotoxicity, and its role in cardiac amyloid diagnosis. Planar ERNA (equilibrium radionuclide angiocardiography) provides a reliable and proven means of monitoring and preventing anthracycline cardiotoxicity, and SPECT ERNA using solid-state gamma cameras may provide reproducible assessments of left ventricular function with reduced radiation exposure. While certain chemotherapeutics have vascular side effects, the use of stress perfusion imaging has still not been adequately studied for routine use. Similarly, markers of apoptosis, inflammation, and sympathetic nerve dysfunction are promising, but are still not ready for uniform usage. SPECT tracers can assist in nonbiopsy diagnosis of cardiac amyloid. Nuclear cardiology is a significant contributor to the multimodality approach to cardio-oncology.