Spinal neuromodulation mitigates myocardial ischemia-induced sympathoexcitation by suppressing the intermediolateral nucleus hyperactivity and spinal neural synchrony

IntroductionMyocardial ischemia disrupts the cardio-spinal neural network that controls the cardiac sympathetic preganglionic neurons, leading to sympathoexcitation and ventricular tachyarrhythmias (VTs). Spinal cord stimulation (SCS) is capable of suppressing the sympathoexcitation caused by myocardial ischemia. However, how SCS modulates the spinal neural network is not fully known.MethodsIn this pre-clinical study, we investigated the impact of SCS on the spinal neural network in mitigating myocardial ischemia-induced sympathoexcitation and arrhythmogenicity. Ten Yorkshire pigs with left circumflex coronary artery (LCX) occlusion-induced chronic myocardial infarction (MI) were anesthetized and underwent laminectomy and a sternotomy at 4−5 weeks post-MI. The activation recovery interval (ARI) and dispersion of repolarization (DOR) were analyzed to evaluate the extent of sympathoexcitation and arrhythmogenicity during the left anterior descending coronary artery (LAD) ischemia. Extracellular in vivo and in situ spinal dorsal horn (DH) and intermediolateral column (IML) neural recordings were performed using a multichannel microelectrode array inserted at the T2-T3 segment of the spinal cord. SCS was performed for 30 min at 1 kHz, 0.03 ms, 90% motor threshold. LAD ischemia was induced pre- and 1 min post-SCS to investigate how SCS modulates spinal neural network processing of myocardial ischemia. DH and IML neural interactions, including neuronal synchrony as well as cardiac sympathoexcitation and arrhythmogenicity markers were evaluated during myocardial ischemia pre- vs. post-SCS.ResultsARI shortening in the ischemic region and global DOR augmentation due to LAD ischemia was mitigated by SCS. Neural firing response of ischemia-sensitive neurons during LAD ischemia and reperfusion was blunted by SCS. Further, SCS showed a similar effect in suppressing the firing response of IML and DH neurons during LAD ischemia. SCS exhibited a similar suppressive impact on the mechanical, nociceptive and multimodal ischemia sensitive neurons. The LAD ischemia and reperfusion-induced augmentation in neuronal synchrony between DH-DH and DH-IML pairs of neurons were mitigated by the SCS.DiscussionThese results suggest that SCS is decreasing the sympathoexcitation and arrhythmogenicity by suppressing the interactions between the spinal DH and IML neurons and activity of IML preganglionic sympathetic neurons

Spinal Anesthesia Reduces Myocardial Ischemia-triggered Ventricular Arrhythmias by Suppressing Spinal Cord Neuronal Network Interactions in Pigs

Background: Cardiac sympathoexcitation leads to ventricular arrhythmias. Spinal anesthesia modulates sympathetic output and can be cardioprotective. However, its effect on the cardio-spinal reflexes and network interactions in the dorsal horn cardiac afferent neurons and the intermediolateral nucleus sympathetic neurons that regulate sympathetic output is not known. The authors hypothesize that spinal bupivacaine reduces cardiac neuronal firing and network interactions in the dorsal horn–dorsal horn and dorsal horn–intermediolateral nucleus that produce sympathoexcitation during myocardial ischemia, attenuating ventricular arrhythmogenesis. Methods: Extracellular neuronal signals from the dorsal horn and intermediolateral nucleus neurons were simultaneously recorded in Yorkshire pigs (n = 9) using a 64-channel high-density penetrating microarray electrode inserted at the T2 spinal cord. Dorsal horn and intermediolateral nucleus neural interactions and known markers of cardiac arrhythmogenesis were evaluated during myocardial ischemia and cardiac load–dependent perturbations with intrathecal bupivacaine. Results: Cardiac spinal neurons were identified based on their response to myocardial ischemia and cardiac load–dependent perturbations. Spinal bupivacaine did not change the basal activity of cardiac neurons in the dorsal horn or intermediolateral nucleus. After bupivacaine administration, the percentage of cardiac neurons that increased their activity in response to myocardial ischemia was decreased. Myocardial ischemia and cardiac load–dependent stress increased the short-term interactions between the dorsal horn and dorsal horn (324 to 931 correlated pairs out of 1,189 pairs, P \u3c 0.0001), and dorsal horn and intermediolateral nucleus neurons (11 to 69 correlated pairs out of 1,135 pairs, P \u3c 0.0001). Bupivacaine reduced this network response and augmentation in the interactions between dorsal horn–dorsal horn (931 to 38 correlated pairs out of 1,189 pairs, P \u3c 0.0001) and intermediolateral nucleus–dorsal horn neurons (69 to 1 correlated pairs out of 1,135 pairs, P \u3c 0.0001). Spinal bupivacaine reduced shortening of ventricular activation recovery interval and dispersion of repolarization, with decreased ventricular arrhythmogenesis during acute ischemia. Conclusions: Spinal anesthesia reduces network interactions between dorsal horn–dorsal horn and dorsal horn–intermediolateral nucleus cardiac neurons in the spinal cord during myocardial ischemia. Blocking short-term coordination between local afferent–efferent cardiac neurons in the spinal cord contributes to a decrease in cardiac sympathoexcitation and reduction of ventricular arrhythmogenesis

Examination of psychological risk factors for chronic pain following cardiac surgery: protocol for a prospective observational study

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. INTRODUCTION: Approximately 400 000 Americans and 36 000 Canadians undergo cardiac surgery annually, and up to 56% will develop chronic postsurgical pain (CPSP). The primary aim of this study is to explore the association of pain-related beliefs and gender-based pain expectations on the development of CPSP. Secondary goals are to: (A) explore risk factors for poor functional status and patient-level cost of illness from a societal perspective up to 12 months following cardiac surgery; and (B) determine the impact of CPSP on quality-adjusted life years (QALYs) borne by cardiac surgery, in addition to the incremental cost for one additional QALY gained, among those who develop CPSP compared with those who do not. METHODS AND ANALYSES: In this prospective cohort study, 1250 adults undergoing cardiac surgery, including coronary artery bypass grafting and open-heart procedures, will be recruited over a 3-year period. Putative risk factors for CPSP will be captured prior to surgery, at postoperative day 3 (in hospital) and day 30 (at home). Outcome data will be collected via telephone interview at 6-month and 12-month follow-up. We will employ generalised estimating equations to model the primary (CPSP) and secondary outcomes (function and cost) while adjusting for prespecified model covariates. QALYs will be estimated by converting data from the Short Form-12 (version 2) to a utility score. ETHICS AND DISSEMINATION: This protocol has been approved by the responsible bodies at each of the hospital sites, and study enrolment began May 2015. We will disseminate our results through CardiacPain.Net, a web-based knowledge dissemination platform, presentation at international conferences and publications in scientific journals. TRIAL REGISTRATION NUMBER: NCT01842568

Three Dimensional Speckle Tracking Based Strain Imaging Identifies Alterations in Dynamic Left Ventricular Function after Cardiac Surgery

Three-dimensional (3D) echocardiography based strain imaging is an emerging modality to assess dynamic left ventricular function in patients undergoing cardiac surgery. Adult patients undergoing cardiac surgery (n=182) were prospectively imaged with 3D transthoracic echocardiograms (TTE) pre- and post-operatively and analyzed for left ventricular 3D; ejection fraction (EF), global peak systolic area (GAS), longitudinal (GLS), circumferential (GCS), and radial (GRS) strain. 3D strain correlated well with 3D EF. Receiver operating curves identified 3D GAS as the best indicator for ventricular function, with a normal cutoff of -25%. Pre-operative 3D strain was an independent predictor of ICU stay and inotrope score, increasing predictive value of known pre-operative risk factor models, especially in patients with reduced ventricular function. Demonstrating that after cardiac surgery, there is an acute reduction in post-operative left ventricular function that can be accurately measured with 3D speckle tracking strain imaging and strain measures may be predictive of post-operative outcomes

Augmentation of cardiac sympathetic tone by percutaneous low-level stellate ganglion stimulation in humans: a feasibility study.

Modulation of human cardiac mechanical and electrophysiologic function by direct stellate ganglion stimulation has not been performed. Our aim was to assess the effect of low-level left stellate ganglion (LSG) stimulation (SGS) on arrhythmias, hemodynamic, and cardiac electrophysiological indices. Patients undergoing ablation procedures for arrhythmias were recruited for SGS. A stimulating electrode was placed next to the LSG under fluoroscopy and ultrasound imaging; and SGS (5-10 Hz, 10-20 mA) was performed. We measured hemodynamic, intracardiac and ECG parameters, and activation recovery intervals (ARIs) (surrogate for action potential duration) from a duodecapolar catheter in the right ventricular outflow tract. Five patients underwent SGS (3 males, 45 ± 20 years). Stimulating catheter placement was successful, and without complication in all patients. SGS did not change heart rate, but increased mean arterial blood pressure (78 ± 3 mmHg to 98 ± 5 mmHg, P < 0.001) and dP/dt max (1148 ± 244 mmHg/sec to 1645 ± 493 mmHg/sec, P = 0.03). SGS shortened mean ARI from 304 ± 23 msec to 283 ± 17 msec (P < 0.001), although one patient required parasympathetic blockade. Dispersion of repolarization (DOR) increased in four patients and decreased in one, consistent with animal models. QT interval, T-wave duration and amplitude at baseline and with SGS were 415 ± 15 msec versus 399 ± 15 msec (P < 0.001); 201 ± 12 msec versus 230 ± 28 msec; and 0.2 ± 0.09 mV versus 0.22 ± 0.08 mV, respectively. At the level of SGS performed, no increase in arrhythmias was seen. Percutaneous low-level SGS shortens ARI in the RVOT, and increases blood pressure and LV contractility. These observations demonstrate feasibility of percutaneous SGS in humans

Diagnostic and predictive values of circulating tetrahydrobiopterin levels as a novel biomarker in patients with thoracic and abdominal aortic aneurysms.

We have previously shown that circulating levels of tetrahydrobiopterin (H4B) function as a robust biomarker for aortic aneurysms in several independent animal models. In the present study, we examined diagnostic and predictive values of circulating H4B levels in human patients of thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) for the first time, while clinically applicable biomarkers for aortic aneurysms have never been previously available. Ninety-five patients scheduled for TAA repair surgeries and 53 control subjects were recruited at University of California Los Angeles (UCLA) Ronald Regan Medical Center, while 44 control subjects and 29 AAA patients were recruited through National Institute of Health (NIH) National Disease Research Interchange (NDRI) program. We had intriguing observations that circulating H4B levels were substantially lower in TAA and AAA patients, linearly correlated with aortic H4B levels (blood: R = 0.8071, p < 0.0001, n = 75; plasma: R = 0.7983, p < 0.0001, n = 75), and associated with incidence of TAA (blood: adjusted OR 0.495; 95% CI 0.379-0.647; p < 0.001; plasma: adjusted OR 0.501; 95% CI 0.385-0.652; p < 0.001) or AAA (blood: adjusted OR 0.329; 95% CI 0.125-0.868; p = 0.025) after adjustment for other factors. Blood or plasma H4B levels below 0.2 pmol/μg serve as an important threshold for prediction of aortic aneurysms independent of age and gender (for TAA risk - blood: adjusted OR 419.67; 95% CI 59.191-2975.540; p < 0.001; plasma: adjusted OR 206.11; 95% CI 40.956-1037.279; p < 0.001). This threshold was also significantly associated with incidence of AAA (p < 0.001 by Chi-square analysis). In addition, we observed previously unrecognized inverse association of Statin use with TAA, and an association of AAA with arrhythmia. Taken together, our data strongly demonstrate for the first time that circulating H4B levels can serve as a first-in-class, sensitive, robust and independent biomarker for clinical diagnosis and prediction of TAA and AAA in human patients, which can be rapidly translated to bedside to fundamentally improve clinical management of the devastating human disease of aortic aneurysms

Inflammatory and apoptotic remodeling in autonomic nervous system following myocardial infarction.

BackgroundChronic myocardial infarction (MI) triggers pathological remodeling in the heart and cardiac nervous system. Abnormal function of the autonomic nervous system (ANS), including stellate ganglia (SG) and dorsal root ganglia (DRG) contribute to increased sympathoexcitation, cardiac dysfunction and arrythmogenesis. ANS modulation is a therapeutic target for arrhythmia associated with cardiac injury. However, the molecular mechanism involved in the pathological remodeling in ANS following cardiac injury remains to be established.Methods and resultsIn this study, we performed transcriptome analysis by RNA-sequencing in thoracic SG and (T1-T4) DRG obtained from Yorkshire pigs following either acute (3 to 5 hours) or chronic (8 weeks) myocardial infarction. By differential expression and weighted gene co-expression network analysis (WGCNA), we identified significant transcriptome changes and specific gene modules in the ANS tissues in response to myocardial infarction at either acute or chronic phases. Both differential expressed genes and the member genes of the WGCNA gene module associated with post-infarct condition were significantly enriched for inflammatory signaling and apoptotic cell death. Targeted validation analysis supported a significant induction of inflammatory and apoptotic signal in both SG and DRG following myocardial infarction, along with cellular evidence of apoptosis induction based on TUNEL analysis. Importantly, these molecular changes were observed specifically in the thoracic segments but not in their counterparts obtained from lumbar sections.ConclusionMyocardial injury leads to time-dependent global changes in gene expression in the innervating ANS. Induction of inflammatory gene expression and loss of neuron cell viability in SG and DRG are potential novel mechanisms contributing to abnormal ANS function which can promote cardiac arrhythmia and pathological remodeling in myocardium

Progression of Myocardial Ischemia Leads to Unique Changes in Immediate-Early Gene Expression in the Spinal Cord Dorsal Horn

The pathological conse-quences of ischemic heart disease involve signaling through the autonomic nervous system. Although early activation may serve to maintain hemodynamic stability, persistent aberrant sympathoexcitation contributes to the development of lethal arrhythmias and heart failure. We hypothesized that as the myocardium reacts and remodels to ischemic injury over time, there is an analogous sequence of gene expression changes in the thoracic spinal cord dorsal horn, the processing center for incoming afferent fibers from the heart to the central nervous system. Acute and chronic myocardial ischemia (MI) was induced in a large animal model of Yorkshire pigs, and the thoracic dorsal horn of treated pigs, along with control nonischemic pigs, was harvested for transcriptome analysis. We identified 32 differentially expressed genes between healthy and acute ischemia cohorts and 46 differentially expressed genes between healthy and chronic ischemia cohorts. The canonical immediate-early gene c-fos was upregulated after acute MI, along with fosB, dual specificity phosphatase 1 and 2 (dusp1 and dusp2), and early growth response 2 (egr2). After chronic MI, there was a persistent yet unique activation of immediate-early genes, including fosB, nuclear receptor subfamily 4 group A members 1±3 (nr4a1, nr4a2, and nr4a3), egr3, and TNF-β-induced protein 3 (tnfaip3). In addition, differentially expressed genes from the chronic MI signature were enriched in pathways linked to apoptosis, immune regulation, and the stress response. These findings support a dynamic progression of gene expression changes in the dorsal horn with maturation of myocardial injury, and they may explain how early adaptive autonomic nervous system responses can maintain hemodynamic stability, whereas prolonged maladaptive signals can predispose patients to arrhythmias and heart failure. NEW & NOTEWORTHY Activation of the autonomic nervous system after myocardial injury can provide early cardiovascular support or prolonged aberrant sympathoexcitation. The later response can lead to lethal arrhythmias and heart failure. This study provides evidence of ongoing changes in the gene expression signature of the spinal cord dorsal horn as myocardial injury progresses over time. These changes could help explain how an adaptive nervous system response can become maladaptive over time