Multidisciplinary approaches to gliosarcoma: A case report and review of the literature.

A 58-year-old right-handed man presented to our tertiary care center with gliosarcoma (GS) infiltration through the dura, skull, and soft tissue. Patient had a previous history of right temporal GS, with four intracranial surgeries prior to presentation. A multidisciplinary approach was used to treat the lesion and perform reconstruction.

Sex, HIV Status, and Measures of Cardiac Stress and Fibrosis in Uganda.

Background Biomarkers of myocardial stress and fibrosis are elevated in people living with HIV and are associated with cardiac dysfunction. It is unknown whether sex influences these markers of heart failure risk in sub-Saharan Africa, where HIV burden is high and where the vast majority of women with HIV live. Methods and Results Echocardiograms and 6 plasma biomarkers (suppression of tumorigenicity-2, growth differentiation factor 15, galectin 3, soluble fms-like tyrosine kinase-1, NT-proBNP [N-terminal pro-B-type natriuretic peptide], and cystatin C) were obtained from 100 people living with HIV on antiretroviral therapy and 100 HIV-negative controls in Uganda. All participants were ≥45 years old with ≥1 major cardiovascular risk factor. Multivariable linear and logistic regression models were used to assess associations between biomarkers, echocardiographic variables, HIV status, and sex, and to assess whether sex modified these associations. Overall, mean age was 56 years and 62% were women. Suppression of tumorigenicity-2 was higher in men versus women (P<0.001), and growth differentiation factor 15 was higher in people living with HIV versus controls (P<0.001). Sex modified the HIV effect on cystatin C and NT-proBNP (both P for interaction <0.025). Women had more diastolic dysfunction than men (P=0.02), but there was no evidence of sex-modifying HIV effects on cardiac structure and function. Cardiac biomarkers were more strongly associated with left ventricular mass index in men compared with women. Conclusions There are prominent differences in biomarkers of cardiac fibrosis and stress by sex and HIV status in Uganda. The predictive value of cardiac biomarkers for heart failure in people living with HIV in sub-Saharan Africa should be examined, and novel risk markers for women should be further explored.

A systematic review of pharmacologic therapies for the cardiomyopathy of Duchenne muscular dystrophy.

OBJECTIVE: To perform a systematic review of studies evaluating pharmacologic therapies for the cardiomyopathy of Duchenne muscular dystrophy (DMD). METHODS: PubMed, Google Scholar, and Embase were searched through October 8, 2020. Articles were selected using pre-determined criteria; 26 underwent detailed review by two co-authors. Study quality was assessed with the Newcastle-Ottawa scoring system (NOS); GRADE assessment evaluated their overall clinical importance. RESULTS: There were few randomized controlled trials. Two of four trials of angiotensin converting enzyme inhibitors (ACEI) or ACEI plus beta-blockers (BB) found improved LV function. Two of two randomized trials of aldosterone antagonists (AA), when added to ACEI and BB therapy, demonstrated less decline of LV circumferential strain over 1 year of treatment. Observational studies of ACEI and BB had differing patient ages, symptomatology, cohort size, study duration and baseline heart function. LV function, assessed via unblinded imaging, was the most frequent outcome measure. LV dysfunction improved in some trials but was unconfirmed in others. Class IV heart failure patients had transient improvement of symptoms and LVEF. Most NOS scores reflected a low level of study quality. The Grade certainty rating, used for the summation of studies, was between "low" and "moderate." CONCLUSION: Randomized trial evidence was inconsistent that either ACEI or BB or their combination improve LV function and/or alter progressive LV dysfunction. When ACEI and BB therapy are initiated for symptomatic Class IV heart failure, symptoms and LVEF improve transiently. AAs retard the rate of decline of LV function when initiated in younger DMD patients.

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 < 0.0001), and dorsal horn and intermediolateral nucleus neurons (11 to 69 correlated pairs out of 1,135 pairs, P < 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 < 0.0001) and intermediolateral nucleus-dorsal horn neurons (69 to 1 correlated pairs out of 1,135 pairs, P < 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.

Spinal cord neural network interactions: implications for sympathetic control of the porcine heart.

Inherent and acquired factors determine the integrated autonomic response to cardiovascular stressors. Excessive sympathoexcitation to ischemic stress is a major contributor to the potential for sudden cardiac death. To define fundamental aspects of cardiac-related autonomic neural network interactions within the thoracic cord, specifically as related to modulating sympathetic preganglionic (SPN) neural activity. Adult, anesthetized Yorkshire pigs (n = 10) were implanted with penetrating high-density microarrays (64 electrodes) at the T2 level of the thoracic spinal cord to record extracellular potentials concurrently from left-sided dorsal horn (DH) and SPN neurons. Electrical stimulation of the T2 paravertebral chain allowed for antidromic identification of SPNs located in the intermediolateral cell column (57 of total 1,760 recorded neurons). Cardiac stressors included epicardial touch, occlusion of great vessels to transiently alter preload/afterload, and transient occlusion of the left anterior descending coronary artery (LAD). Spatial/temporal assessment of network interactions was characterized by cross-correlation analysis. While some DH neurons responded solely to changes in preload/afterload (8.5 ± 1.9%) or ischemic stress (10.5 ± 3.9%), the majority of cardiovascular-related DH neurons were multimodal (30.2 ± 4.7%) with ischemia sensitivity being one of the modalities (26.1 ± 4.7%). The sympathoexcitation associated with transient LAD occlusion was associated with increased correlations from baseline within DH neurons (2.43 ± 0.61 to 7.30 ± 1.84%, P = 0.04) and between SPN to DH neurons (1.32 ± 0.78 to 7.24 ± 1.84%, P = 0.02). DH to SPN network correlations were reduced during great vessel occlusion. In conclusion, increased intrasegmental network coherence within the thoracic spinal cord contributes to myocardial ischemia-induced sympathoexcitation.NEW & NOTEWORTHY In an in vivo pig model, we demonstrate using novel high-resolution neural electrode arrays that increased intrasegmental network coherence within the thoracic spinal cord contributes to myocardial ischemia-induced sympathoexcitation.

Progression of myocardial ischemia leads to unique changes in immediate-early gene expression in the spinal cord dorsal horn.

The pathological consequences 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-α-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.

Spinal cord stimulation reduces ventricular arrhythmias during acute ischemia by attenuation of regional myocardial excitability.

Myocardial ischemia creates autonomic nervous system imbalance and can trigger cardiac arrhythmias. We hypothesized that neuromodulation by spinal cord stimulation (SCS) will attenuate local cardiac sympathoexcitation from ischemia-induced increases in afferent signaling, reduce ventricular arrhythmias, and improve myocardial function during acute ischemia. Yorkshire pigs (n = 20) were randomized to SCS (50 Hz at 200-µs duration, current 90% motor threshold) or sham operation (sham) for 30 min before ischemia. A four-pole SCS lead was placed percutaneously in the epidural space (T1-T4), and a 56-electrode mesh was placed over the heart for high-resolution electrophysiological recordings, including activation recovery intervals (ARIs), activation time, repolarization time, and dispersion of repolarization. Electrophysiological and hemodynamic measures were recorded at baseline, after SCS/sham, during acute ischemia (300-s coronary artery ligation), and throughout reperfusion. SCS 1) reduced sympathoexcitation-induced ARI and repolarization time shortening in the ischemic myocardium; 2) attenuated increases in the dispersion of repolarization; 3) reduced ventricular tachyarrythmias [nonsustained ventricular tachycardias: 24 events (3 sham animals) vs. 1 event (1 SCS animal), P < 0.001]; and 4) improved myocardial function (dP/dt from baseline to ischemia: 1,814 ± 213 to 1,596 ± 282 mmHg/s in sham vs. 1,422 ± 299 to 1,380 ± 299 mmHg/s in SCS, P < 0.01). There was no change in ventricular electrophysiology during baseline conditions without myocardial stress or in the nonischemic myocardium. In conclusion, in a porcine model of acute ventricular ischemia, SCS reduced regional myocardial sympathoexcitation, decreased ventricular arrhythmias, and improved myocardial function. SCS decreased sympathetic nerve activation locally in the ischemic myocardium with no effect observed in the normal myocardium, thus providing mechanistic insights into the antiarrhythmic and myocardial protective effects of SCS.NEW & NOTEWORTHY In a porcine model of ventricular ischemia, spinal cord stimulation decreased sympathetic nerve activation regionally in ischemic myocardium with no effect on normal myocardium, demonstrating that the antiarrhythmic effects of spinal cord stimulation are likely due to attenuation of local sympathoexcitation in the ischemic myocardium and not changes in global myocardial electrophysiology.