Biology subjects

Ajijola, O. A.

Publications and source records attributed to Ajijola, O. A..

6 recordsLinked to original sources

bioRxiv2026

TRPV1-cardiac afferent ablation after completed myocardial infarction prevents arrhythmogenic remodeling

Background Therapies to prevent ventricular arrhythmias after completed myocardial infarction (MI) remain limited. Although TRPV1 afferent ablation at acute MI improves cardiac remodeling, the effect of delayed subacute targeting remains unknown. Objective We investigated whether ablating cardiac TRPV1 afferents during the subacute post-MI window mitigates structural, electrophysiological, and neuro-cardiac axis remodeling to suppress ventricular arrhythmias. Methods Yorkshire pigs underwent sham surgery or anterior MI creation. Two weeks post-MI, animals were randomized to percutaneous epicardial resiniferatoxin (RTX, for cardiac-selective TRPV1 afferent depletion) or vehicle administration. Four weeks later, terminal studies assessed the effects of RTX on cardiac structure and function, ventricular arrhythmogenesis, and neuro-cardiac axis remodeling using in vivo electrophysiologic mapping, real-time neurotransmitter sensing, immunohistochemistry, and transcriptomic profiling. Results Cardiac TRPV1 afferent depletion was confirmed by blunted responses to TRPV1 agonists. RTX-treated animals exhibited improved left ventricular function, reduced end-diastolic diameter, and suppressed ventricular tachycardia/fibrillation (VT/VF) inducibility. Endocardial electroanatomic mapping revealed improved VT/VF electrophysiologic correlates in RTX-treated animals, including fewer deceleration zones and late potentials. Epicardial multielectrode mapping demonstrated reduced electrophysiologic heterogeneity in the scar border zone. Real-time release of adrenergic neurotransmitters (noradrenaline and neuropeptide Y) was normalized during sympathoexcitation in RTX-treated animals. Histologically, RTX treatment attenuated scar border zone myocardial fibrosis and sympathetic nerve sprouting, while suppressing T cell infiltration in cardiac sensory ganglia. Bulk RNA-sequencing of stellate ganglia revealed downregulation of adrenergic genes. Conclusion Cardiac TRPV1 afferent ablation post-completed MI alters disease trajectory by mitigating structural, functional, and neuro-cardiac axis remodeling. Targeting cardiac TRPV1 afferents represents a promising subacute post-MI therapeutic strategy.

physiology↗

bioRxiv2024

Comparative specialization of intrinsic cardiac neurons in humans, mice, and pigs

Intrinsic cardiac neurons (ICNs) play a crucial role in the proper functioning of the heart; yet a paucity of data pertaining to human ICNs exists. We took a multidisciplinary approach to complete a detailed cellular comparison of the structure and function of ICNs from mice, pigs, and humans. Immunohistochemistry of whole and sectioned ganglia, transmission electron microscopy, intracellular microelectrode recording and dye filling for quantitative morphometry were used to define the neurophysiology, histochemistry, and ultrastructure of these cells across species. The densely packed, smaller ICNs of mouse lacked dendrites, formed axosomatic connections, and had high synaptic efficacy constituting an obligatory synapse. At Pig ICNs, a convergence of subthreshold cholinergic inputs onto extensive dendritic arbors supported greater summation and integration of synaptic input. Human ICNs were tonically firing, with synaptic stimulation evoking large suprathreshold excitatory postsynaptic potentials like mouse, and subthreshold potentials like pig. Ultrastructural examination of synaptic terminals revealed conserved architecture, yet small clear vesicles (SCVs) were larger in pigs and humans. The presence and localization of ganglionic neuropeptides was distinct, with abundant VIP observed in human but not pig or mouse ganglia, and little SP or CGRP in pig ganglia. Action potential waveforms were similar, but human ICNs had larger after-hyperpolarizations. Intrinsic excitability differed; 93% of human cells were tonic, all pig neurons were phasic, and both phasic and tonic phenotypes were observed in mouse. In combination, this publicly accessible, multimodal atlas of ICNs from mice, pigs, and humans identifies similarities and differences in the evolution of ICNs.

neuroscience↗

bioRxiv2024

Anatomical and functional organization of cardiac fibers in the porcine cervical vagus nerve allows spatially selective efferent neuromodulation

Cardiac disease progression reflects the dynamic interaction between adversely remodeled neurohumoral control systems and an abnormal cardiac substrate. Vagal nerve stimulation (VNS) is an attractive neuromodulatory option to dampen this dynamic interaction; however, it is limited by off-target effects. Spatially-selective VNS (sVNS) offers a promising solution to induce cardioprotection while mitigating off-target effects by specifically targeting pre-ganglionic parasympathetic efferent cardiac fibers. This approach also has the potential to enhance therapeutic outcomes by eliminating time-consuming titration required for optimal VNS. Recent studies have demonstrated the independent modulation of breathing rate, heart rate, and laryngeal contraction through sVNS. However, the spatial organization of afferent and efferent cardiac-related fibers within the vagus nerve remains unexplored. By using trial-and-error sVNS in vivo in combination with ex vivo micro-computed tomography fascicle tracing, we show the significant spatial separation of cardiac afferent and efferent fibers (179{+/-}55{degrees} SD microCT, p<0.05 and 200{+/-}137{degrees} SD, p<0.05 sVNS - degrees of separation across a cross-section of nerve) at the mid-cervical level. We also show that cardiac afferent fibers are located in proximity to pulmonary fibers consistent with recent findings of cardiopulmonary convergent neurons and circuits. We demonstrate the ability of sVNS to selectively elicit desired scalable heart rate decrease without stimulating afferent-related reflexes. By elucidating the spatial organization of cardiac-related fibers within the vagus nerve, our findings pave the way for more targeted neuromodulation, thereby reducing off-target effects and eliminating the need for titration. This, in turn, will enhance the precision and efficacy of VNS therapy in treating cardiac pathology, allowing for improved therapeutic efficacy. Condensed AbstractSpatially-selective vagus nerve stimulation (sVNS) presents a promising approach for addressing chronic heart disease with enhanced precision. Our study reveals significant spatial separation between cardiac afferent and efferent fibers in the vagus nerve, particularly at the mid-cervical level. Utilizing trial-and-error sVNS in vivo and micro-computed tomography fascicle tracing, we demonstrate the potential for targeted neuromodulation, achieving therapeutic effects like scalable heart rate decrease without stimulating afferent-related reflexes. This spatial understanding opens avenues for more effective VNS therapy, minimizing off-target effects and eliminating the need for titration, thereby expediting therapeutic outcomes in myocardial infarction and related conditions. TweetWith functional and structural imaging, we found organization of vagal efferent & afferent cardiac regions. We can selectively activate only cardiac efferents to achieve bradycardia; desired to reduce the effects of sympathetic overactivation associated with heart disease #VNS #Cardiac #VagusNerve Key PointsO_LISpatially-selective vagus nerve stimulation (sVNS) presents a promising approach for addressing chronic heart disease with enhanced precision. C_LIO_LIOur study reveals significant spatial separation between cardiac afferent and efferent fibers in the vagus nerve, particularly at the mid-cervical level. C_LIO_LIUtilizing trial-and-error sVNS in vivo and micro-computed tomography fascicle tracing, we demonstrate the potential for targeted neuromodulation, achieving therapeutic effects like scalable heart rate decrease without stimulating afferent-related reflexes. C_LIO_LIThis spatial understanding opens avenues for more effective VNS therapy, minimizing off-target effects and eliminating the need for titration, thereby expediting therapeutic outcomes in myocardial infarction and related conditions. C_LI

neuroscience↗

bioRxiv2023

Tiered Sympathetic Control of Cardiac Function Revealed by Viral Tracing and Single Cell Transcriptome Profiling

The cell bodies of postganglionic sympathetic neurons innervating the heart primarily reside in the stellate ganglion (SG), alongside neurons innervating other organs and tissues. Whether cardiac-innervating stellate ganglionic neurons (SGNs) exhibit diversity and distinction from those innervating other tissues is not known. To identify and resolve the transcriptomic profiles of SGNs innervating the heart we leveraged retrograde tracing techniques using adeno-associated virus (AAV) expressing fluorescent proteins (GFP or Td-tomato) with single cell RNA sequencing. We investigated electrophysiologic, morphologic, and physiologic roles for subsets of cardiac-specific neurons and found that three of five adrenergic SGN subtypes innervate the heart. These three subtypes stratify into two subpopulations; high (NA1a) and low (NA1b and NA1c) Npy-expressing cells, exhibit distinct morphological, neurochemical, and electrophysiologic characteristics. In physiologic studies in transgenic mouse models modulating NPY signaling, we identified differential control of cardiac responses by these two subpopulations to high and low stress states. These findings provide novel insights into the unique properties of neurons responsible for cardiac sympathetic regulation, with implications for novel strategies to target specific neuronal subtypes for sympathetic blockade in cardiac disease.

neuroscience↗

bioRxiv2021

Metrics of High Cofluctuation and Entropy to Describe Control of Cardiac Function in the Stellate Ganglion

Stellate ganglia within the intrathoracic cardiac control system receive and integrate central, peripheral, and cardiopulmonary information to produce postganglionic cardiac sympathetic inputs. Pathological anatomical and structural remodeling occurs within the neurons of the stellate ganglion (SG) in the setting of heart failure. A large proportion of SG neurons function as interneurons whose networking capabilities are largely unknown. Current therapies are limited to targeting sympathetic activity at the cardiac level or surgical interventions such as stellectomy, to treat heart failure. Future therapies that target the stellate ganglion will require understanding of their networking capabilities to modify any pathological remodeling. We observe SG networking by examining cofluctuation and specificity of SG networked activity to cardiac cycle phases. We investigate network processing of cardiopulmonary transduction by SG neuronal populations in porcine with chronic pacing-induced heart failure and control subjects during extended in-vivo extracellular microelectrode recordings. We find that information processing and cardiac control in chronic heart failure by the SG, relative to controls, exhibits: i) more frequent, short-lived, high magnitude cofluctuations, ii) greater variation in neural specificity to cardiac cycles, and iii) neural network activity and cardiac control linkage that depends on disease state and cofluctuation magnitude.

bioengineering↗

bioRxiv2021

ATRIOVENTRICULAR NODAL FUNCTION, ATRIAL FIBRILLATION AND VENTRICULAR TACHYCARDIA IN GIRAFFES

Unique cardiovascular adaptations in giraffes (Giraffa Camelopardalis reticulata) have been the focus of numerous investigations for almost a century. The vertical distance between the heart and brain impose high pressure on the giraffe left ventricle leading to thickening that exceeds heart in other mammals. Yet, cardiovascular function appears to be unimpacted by these morphologic differences. Physiologically adapted atrioventricular conduction may contribute to these unique cardiovascular characteristics. Atrioventricular (AV) function was assessed to determine whether physiologically adapted AV intervals might optimize the delay between atrial and ventricular contractions. Using ambulatory and intracardiac recordings, we report a longer PR interval in giraffes than predicted by allometric scaling. Slow ventricular response during atrial fibrillation further supports species-specific atrioventricular adaptations.

zoology↗