Wireless bioresorbable systems for electrical stimulation can deliver electrotherapy over clinically relevant timeframes, and then subsequently dissolve away in a harmless fashion. Such systems have previously been used in neuroregeneration and cardiac pacing, delivering monophasic pulses to a targeted site. Here we report a wirelessly powered system with programmable control of the stimulation waveforms using tissue-penetrating near-infrared light. The approach relies on a bioresorbable silicon phototransistor that is designed to optically modulate current flows at critical nodes in electrical circuits. We show that the approach can offer precise control over stimulation pulses-allowing monophasic, biphasic and polyphasic waveforms to be delivered to single or multiple sites-and all with power wirelessly delivered to a single receiver unit. Using small and large animal models, we further show that the technology enables single- and dual-chamber cardiac pacing, as well as phrenic neuromuscular stimulation for inducing and blocking diaphragmatic excursion.

Aims Pulmonary veins in the left atrium (LA) are well-established as a critical site for the initiation of atrial fibrillation (AF). Emerging evidence suggests that in persistent AF (persAF), AF triggers may extend beyond LA. However, the extent to which AF-associated remodelling involves the right atrium (RA) in persAF remains a subject of debate. To address this, we employed a proteomic approach aiming at investigating AF-associated remodelling in the RA relative to the LA in persAF.Methods and results RA and LA samples were obtained from sinus rhythm (SR) patients, patients with persAF undergoing open-heart surgery, and non-failing donor hearts rejected for transplantation. A reference spectral library representing the human cardiac proteome was employed to assess the RA and LA proteomes by data-independent acquisition mass spectrometry. Protein levels were quantified by immunoblotting of human atrial tissue. Plasma levels of NT-proANP and NT-proBNP were measured in SR and persAF patients. Fibrosis levels were quantified in paraffin-embedded sections using Masson-Goldner trichrome staining. A spectral library representing 13 539 human proteins was generated from five anatomical regions of five independent donor hearts. In persAF RA, we observed marked myolysis, excessive extracellular matrix deposition and a prominent similarity to the failing ventricular proteome, all comparable to persAF LA. Although significant proteomic differences were observed between the RA and LA from SR patients, a comparison of RA and LA proteomes in persAF patients revealed proteome homogenization between the two atrial chambers. RA contributes to this homogenization by losing RA-specific markers, while gaining LA-specific markers.Conclusion Our findings suggest that RA undergoes comparable AF-associated remodelling to LA, contributing to atrial proteome unification which represents a hallmark of persAF.

Multiparametric investigation of cardiac physiology is crucial for the diagnosis and therapy of heart disease. However, no method exists to simultaneously map multiple parameters that govern cardiac (patho)physiology from beating hearts in vivo. Here, we present a cardiac sensing platform that addresses this challenge, functioning with a wireless interface. Advanced fabrication and assembling strategies enable the heterogeneous integration of transparent microelectrodes, light-emitting diodes, photodiodes, and optical filters into a multilayer array structure on soft substrates. The microelectrodes exhibit superior electrochemical performance for measuring electrical potentials and excellent transparency for co-localized fluorescence measurement. The device shows excellent biocompatibility and records the fluorescence of calcium reporter with performance comparable to imaging cameras. Multiparametric in vivo mapping of electrical excitation, calcium dynamics, and their combined effects on cardiac excitation-contraction coupling is demonstrated during normal rhythm, arrhythmia, and treatment. This technology offers potential widespread use in cardiac research to support scientific discoveries and advance clinical life-saving diagnostics and therapies.

PURPOSE:This study explores the use of heart rate variability (HRV) analysis, a noninvasive technique for assessing the autonomic nervous system, by applying nonlinear dynamics and chaos theory to detect chaotic behavior in RR intervals and assess cardiovascular health. METHODS:Employing the "System Analysis of Heart Rate Dynamics" (SADR) program, this research combines chaos analysis with the short-time Fourier transform to assess nonlinear dynamic parameters in HRV. It includes constructing phase portraits in Takens space and calculating measures of chaos to identify deterministic chaos indicators. RESULTS:The analysis identifies distinct chaos indicators in the cardiac rhythm of healthy volunteers compared to tachyarrhythmia patients, both before and after catheter treatment. Post-radiofrequency ablation (RFA) analysis shows promise as a predictive tool for arrhythmia recurrence. CONCLUSIONS:The findings suggest that HRV analysis, through nonlinear dynamics, can be an effective noninvasive method for predicting arrhythmia recurrence following treatments like catheter ablation. This approach has the potential for early and precise detection of arrhythmia, pending further validation.

Atrial arrhythmias, including atrial fibrillation (AF), are a major contributor to cardiovascular morbidity and mortality. Early detection and effective management are critical to mitigating adverse outcomes such as stroke, heart failure, and overall mortality. Wearable devices have emerged as promising tools for monitoring, detecting, and managing atrial arrhythmias near-continuously. This comprehensive analysis explores these wearable technologies’ current role and capabilities for clinicians’ daily practice. Despite challenges related to data accuracy, privacy, patient compliance, and integration with healthcare systems, ongoing advancements hold significant promise for the future. Continued research and development are essential to fully realize the potential of wearables in improving clinical outcomes for patients with atrial arrhythmias.

Autonomic nerves are crucial in cardiac function and pathology. However, data on the distribution of cholinergic and noradrenergic nerves in normal and pathologic human hearts is lacking. Nonfailing donor hearts were pressure-perfusion fixed, imaged, and dissected. Left ventricular cardiomyopathy samples were also obtained. Fixed frozen sections were immunostained for nerves, and adjacent tissue underwent clearing for 3D visualization. Cholinergic and noradrenergic nerves were evenly abundant in both atria, except the sinoatrial node, where vesicular acetylcholine transporter (VAChT) nerves were dominant. Noradrenergic consistently outnumbered cholinergic nerves in right (RV) and left ventricular (LV) regions. Noradrenergic innervation of LV regions varied between donors. Cholinergic innervation was higher in RV compared to LV samples, which generally had reduced VAChT nerves. Marked neural remodeling occurred in three cardiomyopathy cases. Tyrosine hydroxylase (TH) nerve density was increased in the right atrial appendage, and all nerves showed a trend to decrease in the left atrial appendage. Cholinergic innervation was reduced in the LV, and TH innervation was heterogeneous. Noradrenergic nerves were present in granulation tissue but absent in regions of dense scar. Some border zone regions had reduced TH innervation but no hyperinnervation. Dual innervation of most atrial regions supports balanced regulation of atrial function. Higher cholinergic input to the sinoatrial node favors vagal dominance in heart rate regulation. Innervation patterns support a significant role of noradrenergic input to the ventricle, especially on the left. Both atrial and ventricular nerves remodel in cardiomyopathy, providing a foundation for asymmetric neural input and dysregulation of cardiac electromechanical function.

BACKGROUND:Atrial fibrillation (AF) is a progressive disease involving both structural and functional remodeling. Although over the past decade, digital twin-guided therapy has been proposed and applied, accounting for cardiomyocyte functional remodeling remains challenging. We aimed to investigate the contribution of functional remodeling at the cellular level to AF pathogenesis in patients with fibrotic remodeling and to develop novel techniques to predict the location of reentrant drivers. METHODS:To investigate the contribution of cell-scale functional remodeling to AF pathogenesis under the conditions of fibrotic remodeling, we combined 3-dimensional atrial digital twins with pathology-specific single-cell models. The latter were developed using recordings in myocytes isolated from patients in sinus rhythm, paroxysmal, postoperative, and persistent AF. To quantify AF dynamics in the digital twins, we developed a novel algorithm for locating reentrant drivers by backtracking the conduction velocity field from the wavebreak regions. RESULTS:We demonstrate that our novel algorithm is at least 700× faster than the traditional phase singularity analysis. The inducibility of simulated AF was not pathology-dependent, but pathological models demonstrate a more extensive arrhythmogenic substrate than the sinus rhythm. We observed a correlation between wavebreak probability and fibrosis density, with the highest regression slope for the persistent AF model and the lowest for the sinus rhythm model. CONCLUSIONS:AF driver locations in atrial fibrotic substrates depend on electrophysiological remodeling; differences between pathology-specific models are explained by differences in wavebreak patterns. Specifically, reentrant drivers tend to dwell in the regions with the highest wavebreak probability.

The widespread prevalence and significant consequences of cardiac arrhythmias have been addressed by adopting cardiac stimulation and neuromodulation implantable devices. The oldest, most commonly employed, and most well-known technology is the permanent transvenous cardiac pacemaker. However, in select emergent clinical scenarios and transient pathologies, temporary pacing is preferred. More recently, neuromodulatory vagal nerve stimulation has emerged to address neurologic, psychiatric, and nociceptive pathologies, generating significant clinical and scientific interest in the invention of temporary corollary devices for a subset of indications of nociceptive origin. The dominance of particular implant approaches and anatomic targets in both temporary pacing and neuromodulation in the clinic is owed to capabilities and limitations present in the current technological landscape. However, recent innovations in industry and academia may lead to a fundamental shift in how temporary pacing and neuromodulation are delivered in terms of procedural approach and patient outcomes. In this review, we present an overview of contemporary temporary pacemakers, neuromodulatory therapies, and devices, highlighting novel temporary pacing technologies from the clinic, industry, and academia, such as temporary permanent pacemakers, innovations in non-blood-contacting devices, bioresorbable pacemakers, and advances in neuromodulatory approaches.

The cardiac conduction system (CCS) orchestrates the electrical impulses that enable coordinated contraction of the cardiac chambers. The T-box transcription factors TBX3 and TBX5 are required for CCS development and associated with overlapping and distinct human CCS diseases. We evaluated the coordinated role of Tbx3 and Tbx5 in the murine ventricular conduction system (VCS). We engineered a compound Tbx3:Tbx5 conditional knockout allele for both genes located in cis on mouse chromosome 5. Conditional deletion of both T-box transcriptional factors in the VCS, using the VCS-specific MinK CreERT2 , caused loss of VCS function and molecular identity. Combined Tbx3 and Tbx5 deficiency in the adult VCS led to conduction defects, including prolonged PR and QRS intervals and elevated susceptibility to ventricular tachycardia. These electrophysiological defects occurred prior to detectable alterations in cardiac contractility or histologic morphology, indicative of a primary conduction system defect. Tbx3:Tbx5 double-knockout VCS cardiomyocytes revealed a transcriptional shift toward non-CCS-specialized working myocardium, indicating a change to their cellular identity. Furthermore, optical mapping revealed a loss of VCS-specific conduction system propagation. Collectively, these findings indicate that Tbx3 and Tbx5 coordinate to control VCS molecular fate and function, with implications for understanding cardiac conduction disorders in humans.

AbstractThe cardiac conduction system (CCS) orchestrates the electrical impulses that enable coordinated contraction of the cardiac chambers. The T-box transcription factorsTBX3andTBX5are required for cardiac conduction system development and associated with overlapping and distinct human cardiac conduction system diseases. We evaluated the coordinated role ofTbx3andTbx5in the murine ventricular conduction system (VCS). We engineered a compoundTbx3:Tbx5conditional knockout allele for both genes located incison mouse chromosome 5. Conditional deletion of both T-box transcriptional factors in the ventricular conduction system, using the VCS-specificMinK:Cre,caused loss of VCS function and molecular identity. CombinedTbx3andTbx5deficiency in the adult VCS led to conduction defects, including prolonged PR and QRS intervals and elevated susceptibility to ventricular tachycardia. These electrophysiological defects occurred prior to detectable alterations in cardiac contractility or histologic morphology, indicative of a primary conduction system defect.Tbx3:Tbx5double knockout VCS cardiomyocytes revealed a transcriptional shift towards non-CCS-specialized working myocardium, indicating a change to their cellular identity. Furthermore, optical mapping revealed a loss of VCS-specific conduction system propagation. Collectively, these findings indicate thatTbx3andTbx5coordinate to control VCS molecular fate and function, with implications for understanding cardiac conduction disorders in humans.

Below is a case report of treatment of a patient with persistent tachysystolic atrial fibrillation (AF), chronic heart failure (CHF) with a moderately reduced left ventricular ejection fraction (EF) and patent foramen ovale (PFO) with an atrial septal aneurysm. A 58-year-old man (with body mass index of 27.8 kg/m2) with tachysystolic persistent AF (duration 3 months) was hospitalized due to an increase in CHF symptoms (CHF functional class according to NYHA is II-III). The patient had been constantly receiving therapy in accordance with current recommendations (angiotensin receptor blockers, diuretics, beta-blockers, amiodorone and rivaroxaban). Transthoracic echocardiography showed a moderate decrease in ejection fraction (EF) (41%), an increase in the left (47 mm) and right (51x74 mm) atria. The patient underwent AF radiofrequency catheter ablation (RFA) in the left atrium, which identified PFO. The final stage of RFA was performed by external electrical cardioversion with successful restoration of sinus rhythm. Four months after RFA, despite a stable sinus rhythm, the patient maintained a moderately reduced LV EF (44%) and dilatation of the left (44 mm) and right (43x65 mm) atria. Transesophageal echocardiography revealed an aneurysmally altered atrial septum and a positive bubble test with a large number of bubbles. In accordance with current recommendations, the patient had indications for primary prevention of stroke - endovascular occlusion of the PFO, which was performed. Three months after PFO closure, the patient discontinued diuretics, amiodarone, and rivaroxaban. Combined therapy in a patient with persistent AF, with a moderately reduced EF and verified PFO, which included pathogenetic therapy for CHF, prescription of antiarrhythmic drugs, RFA of the AF substrate, and interventional closure of the PFO, made it possible to effectively control sinus rhythm, significantly reduce the manifestations of CHF and provide primary prevention of embolic disorders.

PURPOSE:Remodeling of sympathetic nerves and ACE2 has been implicated in cardiac pathology, and ACE2 also serves as a receptor for SARS-CoV-2. However, there is limited histological knowledge about the transmural distribution of sympathetic nerves and the cellular localization and distribution of ACE2 in human left ventricles from normal or diseased hearts. Goals of this study were to establish the normal pattern for these parameters and determine changes that occurred in decedents with cardiovascular disease alone compared to those with cardiac pathology and severe COVID-19. METHODS:We performed immunohistochemical analysis on sections of left ventricular wall from twenty autopsied human hearts consisting of a control group, a cardiovascular disease group, and COVID-19 ARDS, and COVID-19 non-ARDS groups. RESULTS:Using tyrosine hydroxylase as a noradrenergic marker, we found substantial sympathetic nerve loss in cardiovascular disease samples compared to controls. Additionally, we found heterogeneous nerve loss in both COVID-19 groups. Using an ACE2 antibody, we observed robust transmural staining localized to pericytes in the control group. The cardiovascular disease hearts displayed regional loss of ACE2 in pericytes and regional increases in staining of cardiomyocytes for ACE2. Similar changes were observed in both COVID-19 groups. CONCLUSIONS:Heterogeneity of sympathetic innervation, which occurs in cardiac disease and is not increased by severe COVID-19, could contribute to arrhythmogenesis. The dominant localization of ACE2 to pericytes suggests that these cells would be the primary target for potential cardiac infection by SARS-CoV-2. Regional changes in ACE2 staining by myocytes and pericytes could have complex effects on cardiac pathophysiology.

Limited comparative data exist regarding the risk of cardiogenic emboli in patients with isolated atrial flutter (AFL). Some studies suggest a lower complication risk in AFL compared to atrial fibrillation (AFib), but methodological limitations and conflicting reports necessitate a comprehensive investigation. Our analysis proposes that isolated AFL carries a lower risk of ischemic events and left atrial thrombus formation than AFib. Importantly, we caution against applying stroke risk assessment approaches designed for AFib to AFL patients, as it may lead to harmful overestimations and unnecessary anticoagulant prescriptions. Furthermore, we highlight the current lack of sufficient data to determine the overall clinical benefit of prolonged anticoagulant therapy in patients with isolated AFL, especially when CHA2DS2-VASc index values are below 4. This review challenges existing perceptions, offering insights into the nuanced risk profiles of the transitional nature of isolated AFL due to the high incidence of AFib development within a year of AFL diagnosis. In conclusion, tailored risk assessments and further research are essential for precise clinical decision-making in this dynamic landscape.

Atrial fibrillation (AF) is a progressive disease involving both structural and functional remodeling. To investigate the contribution of cell-scale functional remodeling to AF pathogenesis, we combined personalized 3D anatomical models with pathology-specific ionic models. The latter were developed using recordings in myocytes isolated from patients in sinus rhythm, paroxysmal, postoperative, and persistent AF. To quantify AF dynamics, we developed a novel algorithm for locating RDs by backtracking the conduction velocity field from the wavebreak regions. We demonstrate that our novel algorithm is at least 700 times faster than the traditional phase singularity analysis. The inducibility of simulated AF was not pathology-dependent, but pathological models demonstrate a more extensive arrhythmogenic substrate compared to the sinus rhythm. AF driver locations depend on electrophysiological remodeling; differences between pathology-specific models are explained by differences in wavebreak patterns. Specifically, RDs tend to dwell in the regions with the highest wavebreak probability.

Transparent microelectrode arrays (MEAs) that allow multimodal investigation of the spatiotemporal cardiac characteristics are important in studying and treating heart disease. Existing implantable devices, however, are designed to support chronic operational lifetimes and require surgical extraction when they malfunction or are no longer needed. Meanwhile, bioresorbable systems that can self-eliminate after performing temporary functions are increasingly attractive because they avoid the costs/risks of surgical extraction. We report the design, fabrication, characterization, and validation of a soft, fully bioresorbable, and transparent MEA platform for bidirectional cardiac interfacing over a clinically relevant period. The MEA provides multiparametric electrical/optical mapping of cardiac dynamics and on-demand site-specific pacing to investigate and treat cardiac dysfunctions in rat and human heart models. The bioresorption dynamics and biocompatibility are investigated. The device designs serve as the basis for bioresorbable cardiac technologies for potential postsurgical monitoring and treating temporary patient pathological conditions in certain clinical scenarios, such as myocardial infarction, ischemia, and transcatheter aortic valve replacement.

EDITORIAL article Front. Pharmacol., 13 June 2023Sec. Pharmacogenetics and Pharmacogenomics Volume 14 - 2023 | https://doi.org/10.3389/fphar.2023.1234219

Eco/bioresorbable electronics represent an emerging class of technology defined by an ability to dissolve or otherwise harmlessly disappear in environmental or biological surroundings after a period of stable operation. The resulting devices provide unique capabilities as temporary biomedical implants, environmental sensors, and related systems. Recent publications report schemes to overcome challenges in fabrication that follow from the low thermostability and/or high chemical reactivity of the eco/bioresorbable constituent materials. Here, this work reports the use of high-speed sewing machines, as the basis for a high-throughput manufacturing technique that addresses many requirements for these applications, without the need for high temperatures or reactive solvents. Results demonstrate that a range of eco/bioresorbable metal wires and polymer threads can be embroidered into complex, user-defined conductive patterns on eco/bioresorbable substrates. Functional electronic components, such as stretchable interconnects and antennas are possible, along with fully integrated systems. Examples of the latter include wirelessly powered light-emitting diodes, radiofrequency identification tags, and temporary cardiac pacemakers. These advances add to a growing range of options in high-throughput, automated fabrication of eco/bioresorbable electronics.