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ABSTRACT: Our present understanding of electrocution followed a long path of detours and speculation. It is now hard to appreciate how mysterious was an unexpected sudden death-without visible trauma-and we should be sympathetic to the surprising theories that came from well-intentioned attempts to find something in the autopsy of an electrocution victim.The early hypotheses (1880s) tended to favor effects on the central nervous system, but the emphasis switched to arterial and hematological mechanisms as well as respiratory arrest (ie, asphyxia) along with a widespread publication debate. While careful animal experimentation slowly established that electrocution was due to the induction of VF (ventricular fibrillation), the older hypotheses held sway for many decades. Even today, the neurogenic and asphyxial explanations reappear occasionally.Despite 170 years of research, the phenomenon of electrocution continues to generate new hypotheses for its mechanism.
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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. Tailored risk assessments and further research are essential for precise clinical decision-making in this dynamic landscape.
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This commentary documents how federal funding agencies are changing the criteria by which they distribute taxpayer money intended for scientific research. Increasingly, STEMM (Science, Technology, Engineering, Mathematics, and Medicine) funding agencies are requiring applicants for funding to include a plan to advance DEI ("Diversity, Equity, and Inclusion") in their proposals and to dedicate a part of the research budget to its implementation. These mandates undermine the academic freedom of researchers and the unbiased generation of knowledge needed for a well-functioning democracy. Maintaining excellence in science is fundamental to the continuation of the U.S. as a global economic leader. Science provides a basis for solving important global challenges such as security, energy, climate, and health. Diverting funding from science into activities unrelated to the production of knowledge undermines science's ability to serve humankind. When funding agencies politicize science by using their power to further a particular ideological agenda, they contribute to public mistrust in science. Hijacking science funding to promote DEI is thus a threat to our society.
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This paper reports the real time monitoring of siderite deposition, on both Au- and Fe-coated surfaces, using the changes in frequency and dissipation of quartz crystal microbalance with dissipation (QCMD). In an iron chloride solution saturated with carbon dioxide, buffered with sodium bicarbonate to pH 6.8, roughly spherical particles of siderite formed within 15 min, which subsequently deposited on the QCMD crystal surface. Imaging of the surface showed a layer formed from particles ca. < 0.5 µm in diameter. Larger particles are clearly deposited on top of the lower layer; these larger particles are >1 µm in diameter. Monitoring of the frequency clearly differentiates the formation of the lower layer from the larger crystals deposited on top at later times. The elastic moduli calculated from QCMD data showed a progressive dissipation increase; the modeling of the solid-liquid interface using a flat approximation resulted in a poor estimation of elastic and storage moduli. Rather, the impedance modeled as a viscoelastic layer in contact with a semi-infinite liquid, where a random bumpy surface with a Gaussian correlator is used, is much more accurate in determining the elastic and storage moduli as losses from the uneven interface are considered. A further step considers that the film is in fact a composite consisting of hard spherical particles of siderite with water in the vacant spaces. This is treated by considering the individual contributions of the phases to the losses measured, thereby further improving the accuracy of the description of the film and the QCMD data. Collectively, this work presents a new framework for the use of QCMD, paired with traditional approaches, to enhance the understanding of crystal deposition and film formation as well as quantify the often evolving mechanical properties.
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Myocarditis is clinically characterized by chest pain, arrhythmias, and heart failure, and treatment is often supportive. Mutations in DSP, a gene encoding the desmosomal protein desmoplakin, have been increasingly implicated in myocarditis. To model DSP-associated myocarditis and assess the role of innate immunity, we generated engineered heart tissues (EHTs) using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with heterozygous DSP truncating variants (DSPtvs) and a gene-edited homozygous deletion cell line (DSP-/-). At baseline, DSP-/- EHTs displayed a transcriptomic signature of innate immune activation, which was mirrored by cytokine release. Importantly, DSP-/- EHTs were hypersensitive to Toll-like receptor (TLR) stimulation, demonstrating more contractile dysfunction compared with isogenic controls. Relative to DSP-/- EHTs, heterozygous DSPtv EHTs had less functional impairment. DSPtv EHTs displayed heightened sensitivity to TLR stimulation, and when subjected to strain, DSPtv EHTs developed functional deficits, indicating reduced contractile reserve compared with healthy controls. Colchicine or NF-κB inhibitors improved strain-induced force deficits in DSPtv EHTs. Genomic correction of DSP p.R1951X using adenine base editing reduced inflammatory biomarker release from EHTs. Thus, EHTs replicate electrical and contractile phenotypes seen in human myocarditis, implicating cytokine release as a key part of the myogenic susceptibility to inflammation. The heightened innate immune activation and sensitivity are targets for clinical intervention.
Subject(s)
Immunity, Innate , Induced Pluripotent Stem Cells , Myocarditis , Myocytes, Cardiac , Humans , Myocarditis/genetics , Myocarditis/immunology , Myocarditis/pathology , Immunity, Innate/genetics , Induced Pluripotent Stem Cells/metabolism , Induced Pluripotent Stem Cells/immunology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/immunology , Myocytes, Cardiac/pathology , Male , Genetic Predisposition to Disease , FemaleABSTRACT
BACKGROUND: Although moderate endurance exercise has been reported to improve cardiovascular health, its effects on cardiac structure and function are not fully characterized, especially with respect to sexual dimorphism. We aimed to assess the effects of moderate endurance exercise on cardiac physiology in male versus female mice. METHODS AND RESULTS: C57BL/6J mice of both sexes were run on a treadmill for 6 weeks. ECG and echocardiography were performed every 2 weeks. After 6 weeks of exercise, mice were euthanized, and triple parametric optical mapping was performed on Langendorff perfused hearts to assess cardiac electrophysiology. Arrhythmia inducibility was tested by programmed electrical stimulation. Left ventricular tissue was fixed, and RNA sequencing was performed to determine exercise-induced transcriptional changes. Exercise-induced left ventricular dilatation was observed in female mice alone, as evidenced by increased left ventricular diameter and reduced left ventricular wall thickness. Increased cardiac output was also observed in female exercised mice but not males. Optical mapping revealed further sexual dimorphism in exercise-induced modulation of cardiac electrophysiology. In female mice, exercise prolonged action potential duration and reduced voltage-calcium influx delay. In male mice, exercise reduced the calcium decay constant, suggesting faster calcium reuptake. Exercise increased arrhythmia inducibility in both male and female mice; however, arrhythmia duration was increased only in females. Lastly, exercise-induced transcriptional changes were sex dependent: females and males exhibited the most significant changes in contractile versus metabolism-related genes, respectively. CONCLUSIONS: Our data suggest that moderate endurance exercise can significantly alter multiple aspects of cardiac physiology in a sex-dependent manner. Although some of these effects are beneficial, like improved cardiac mechanical function, others are potentially proarrhythmic.
Subject(s)
Arrhythmias, Cardiac , Mice, Inbred C57BL , Physical Conditioning, Animal , Animals , Female , Male , Arrhythmias, Cardiac/physiopathology , Arrhythmias, Cardiac/etiology , Physical Conditioning, Animal/physiology , Mice , Sex Factors , Ventricular Function, Left/physiology , Action Potentials , Physical Endurance/physiology , Ventricular Remodeling/physiology , Heart Rate/physiology , Isolated Heart Preparation , Sex CharacteristicsABSTRACT
State-of-the-art innovations in optical cardiac electrophysiology are significantly enhancing cardiac research. A potential leap into patient care is now on the horizon. Optical mapping, using fluorescent probes and high-speed cameras, offers detailed insights into cardiac activity and arrhythmias by analysing electrical signals, calcium dynamics, and metabolism. Optogenetics utilizes light-sensitive ion channels and pumps to realize contactless, cell-selective cardiac actuation for modelling arrhythmia, restoring sinus rhythm, and probing complex cell-cell interactions. The merging of optogenetics and optical mapping techniques for 'all-optical' electrophysiology marks a significant step forward. This combination allows for the contactless actuation and sensing of cardiac electrophysiology, offering unprecedented spatial-temporal resolution and control. Recent studies have performed all-optical imaging ex vivo and achieved reliable optogenetic pacing in vivo, narrowing the gap for clinical use. Progress in optical electrophysiology continues at pace. Advances in motion tracking methods are removing the necessity of motion uncoupling, a key limitation of optical mapping. Innovations in optoelectronics, including miniaturized, biocompatible illumination and circuitry, are enabling the creation of implantable cardiac pacemakers and defibrillators with optoelectrical closed-loop systems. Computational modelling and machine learning are emerging as pivotal tools in enhancing optical techniques, offering new avenues for analysing complex data and optimizing therapeutic strategies. However, key challenges remain including opsin delivery, real-time data processing, longevity, and chronic effects of optoelectronic devices. This review provides a comprehensive overview of recent advances in optical mapping and optogenetics and outlines the promising future of optics in reshaping cardiac electrophysiology and therapeutic strategies.
Subject(s)
Electrophysiologic Techniques, Cardiac , Optogenetics , Humans , Electrophysiologic Techniques, Cardiac/methods , Optogenetics/methods , Cardiac Electrophysiology/methods , Heart , Arrhythmias, Cardiac/therapyABSTRACT
BACKGROUND: The relationship between heart failure (HF) and atrial fibrillation (AF) is clear, with up to half of patients with HF progressing to AF. The pathophysiological basis of AF in the context of HF is presumed to result from atrial remodeling. Upregulation of the transcription factor FOG2 (friend of GATA2; encoded by ZFPM2) is observed in human ventricles during HF and causes HF in mice. METHODS: FOG2 expression was assessed in human atria. The effect of adult-specific FOG2 overexpression in the mouse heart was evaluated by whole animal electrophysiology, in vivo organ electrophysiology, cellular electrophysiology, calcium flux, mouse genetic interactions, gene expression, and genomic function, including a novel approach for defining functional transcription factor interactions based on overlapping effects on enhancer noncoding transcription. RESULTS: FOG2 is significantly upregulated in the human atria during HF. Adult cardiomyocyte-specific FOG2 overexpression in mice caused primary spontaneous AF before the development of HF or atrial remodeling. FOG2 overexpression generated arrhythmia substrate and trigger in cardiomyocytes, including calcium cycling defects. We found that FOG2 repressed atrial gene expression promoted by TBX5. FOG2 bound a subset of GATA4 and TBX5 co-bound genomic locations, defining a shared atrial gene regulatory network. FOG2 repressed TBX5-dependent transcription from a subset of co-bound enhancers, including a conserved enhancer at the Atp2a2 locus. Atrial rhythm abnormalities in mice caused by Tbx5 haploinsufficiency were rescued by Zfpm2 haploinsufficiency. CONCLUSIONS: Transcriptional changes in the atria observed in human HF directly antagonize the atrial rhythm gene regulatory network, providing a genomic link between HF and AF risk independent of atrial remodeling.
Subject(s)
Atrial Fibrillation , Atrial Remodeling , Heart Failure , Humans , Mice , Animals , Atrial Fibrillation/genetics , Gene Regulatory Networks , Calcium/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Heart Atria , Heart Failure/genetics , Genomics , GATA4 Transcription Factor/geneticsABSTRACT
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.
Subject(s)
COVID-19 , Cardiovascular Diseases , Heart Diseases , Humans , SARS-CoV-2 , Angiotensin-Converting Enzyme 2 , Peptidyl-Dipeptidase AABSTRACT
Severe cardiotoxic effects limit the efficacy of doxorubicin (DOX) as a chemotherapeutic agent. Activation of intracellular stress signaling networks, including p38 mitogen-activated protein kinase (MAPK), has been implicated in DOX-induced cardiotoxicity (DIC). However, the roles of the individual p38 isoforms in DIC remain incompletely elucidated. We recently reported that global p38δ deletion protected female but not male mice from DIC, whereas global p38γ deletion did not significantly modulate it. Here we studied the in vivo roles of p38α and p38ß in acute DIC. Male and female mice with cardiomyocyte-specific deletion of p38α or global deletion of p38ß and their wild-type counterparts were injected with DOX. Survival and health were tracked for 10 days postinjection. Cardiac function was assessed by echocardiography and electrocardiography and fibrosis by Picrosirius red staining. Expression and activation of signaling proteins and inflammatory markers were measured by Western blot, phosphorylation array, and chemokine/cytokine array. Global p38ß deletion significantly aggravated DIC and worsened cardiac electrical and mechanical function deterioration in female mice. Mechanistically, DIC in p38ß-null female mice correlated with increased autophagy, sustained hyperactivation of proapoptotic JNK signaling, as well as remodeling of a myocardial inflammatory environment. In contrast, cardiomyocyte-specific deletion of p38α improved survival of DOX30-treated male mice 5 days posttreatment but did not influence cardiac function in DOX-treated male or female mice. Our data highlight the sex- and isoform-specific roles of p38α and p38ß MAPKs in DOX-induced cardiac injury and suggest a novel in vivo function of p38ß in protecting female mice from DIC.NEW & NOTEWORTHY We show that p38α and p38ß have distinct in vivo functions in a murine model of acute DIC. Specifically, although conditional cardiomyocyte-specific p38α deletion exhibited mild cardioprotective effects in male mice, p38ß deletion exacerbated the DOX cardiotoxicity in female mice. Our findings caution against employing pyridinyl imidazole inhibitors that target both p38α and p38ß isoforms as a cardioprotective strategy against DIC. Such an approach could have undesirable sex-dependent effects, including attenuating p38ß-dependent cardioprotection in females.
Subject(s)
Cardiotoxicity , Myocytes, Cardiac , Male , Female , Mice , Animals , Myocytes, Cardiac/metabolism , Cardiotoxicity/metabolism , Anthracyclines , Antibiotics, Antineoplastic , Signal Transduction , Doxorubicin/toxicity , Mice, Knockout , Apoptosis , Oxidative StressABSTRACT
Ryanodine receptor 2 (RyR2) hyperactivity is observed in structural heart diseases that are a result of ischemia or heart failure. It causes abnormal calcium handling and calcium leaks that cause metabolic, electrical, and mechanical dysfunction, which can trigger arrhythmias. Here, we tested the antiarrhythmic potential of dantrolene (RyR inhibitor) in human hearts. Human hearts not used in transplantation were obtained, and right ventricular outflow tract (RVOT) wedges and left ventricular (LV) slices were prepared. Pseudo-ECGs were recorded to determine premature ventricular contraction (PVC) incidences. Optical mapping was performed to determine arrhythmogenic substrates. After baseline optical recordings, tissues were treated with 1) isoproterenol (250 nM), 2) caffeine (200 mM), and 3) dantrolene (2 or 10 mM). Optical recordings were obtained after each treatment. Isoproterenol and caffeine treatment increased PVC incidence, whereas dantrolene reduced the PVC burden. Isoproterenol shortened action potential duration (APD) in the RV, RVOT, and LV regions and shortened calcium transient duration (CaTD) in the LV. Caffeine further shortened APD in the RV, did not modulate APD in the RVOT, and prolonged APD in the LV. In addition, in the LV, CaTD prolongation was also observed. More importantly, adding dantrolene did not alter APD in the RV or RVOT regions but produced a trend toward APD prolongation and significant CaTD prolongation in the LV, restoring these parameters to baseline values. In conclusions, dantrolene treatment suppresses triggers and reverses arrhythmogenic substrates in the human heart and could be a novel antiarrhythmic therapy in patients with structural heart disease.NEW & NOTEWORTHY Ryanodine receptor 2 hyperactivity is observed in structural heart diseases caused by ischemia or heart failure. It causes abnormal calcium leaks, which can trigger arrhythmias. To prevent arrhythmias, we applied dantrolene in human hearts ex vivo. Isoproterenol and caffeine treatment increased PVC incidence, whereas dantrolene reduced the PVC burden. Dantrolene treatment suppresses triggers and reverses arrhythmogenic substrates and could be a novel antiarrhythmic therapy in patients with structural heart disease.
Subject(s)
Heart Failure , Ryanodine Receptor Calcium Release Channel , Humans , Ryanodine Receptor Calcium Release Channel/metabolism , Dantrolene/pharmacology , Isoproterenol/pharmacology , Ryanodine/pharmacology , Calcium/metabolism , Caffeine/pharmacology , Arrhythmias, Cardiac/drug therapy , Anti-Arrhythmia Agents/pharmacology , Action PotentialsABSTRACT
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.
Subject(s)
Absorbable Implants , Electronics , Metals , Polymers , SolventsABSTRACT
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.
Subject(s)
Absorbable Implants , Heart Diseases , Humans , Rats , Animals , Microelectrodes , HeartABSTRACT
Myocardial infarction (MI) is one of the leading causes of death and disability. Recently developed cardiac patches provide mechanical support and additional conductive paths to promote electrical signal propagation in the MI area to synchronize cardiac excitation and contraction. Cardiac patches based on conductive polymers offer attractive features; however, the modest levels of elasticity and high impedance interfaces limit their mechanical and electrical performance. These structures also operate as permanent implants, even in cases where their utility is limited to the healing period of tissue damaged by the MI. The work presented here introduces a highly conductive cardiac patch that combines bioresorbable metals and polymers together in a hybrid material structure configured in a thin serpentine geometry that yields elastic mechanical properties. Finite element analysis guides optimized choices of layouts in these systems. Regular and synchronous contraction of human induced pluripotent stem cell-derived cardiomyocytes on the cardiac patch and ex vivo studies offer insights into the essential properties and the bio-interface. These results provide additional options in the design of cardiac patches to treat MI and other cardiac disorders.
Subject(s)
Induced Pluripotent Stem Cells , Myocardial Infarction , Humans , Absorbable Implants , Myocytes, Cardiac , Polymers/chemistry , TechnologyABSTRACT
Electrocution is a death caused by an application of electrical current to the human body. Our present understanding of electrocution-as the induction of ventricular fibrillation (VF)-followed a nearly century-long path of misunderstandings and speculation primarily focused on hypotheses of asphyxia as well as central nervous system trauma. It is hard for us today to appreciate the past mystery of an unexpected sudden death usually bereft of visible trauma. Even today, a false dogma exists that direct-current shocks can cause asystole instead of VF. A lightning discharge (up to 500 megavolts) is differentiated because it can cause substantial acute and chronic neural effects leading to other cardiac arrest rhythms. The human heart is exquisitely sensitive to alternating currents, and VF can be induced with currents of one-eighth that required for mere pacing. Because of these low currents, this effect obtains only in the TQ interval, and low-power electrocution does not involve the vulnerable period. If a current is strong enough to electrocute, generally it will do so in 1-2 seconds; longer shocks do not tend to be more dangerous. Regardless of concomitant drug dosing, the electrocution cardiac arrest rhythm is still VF, suggesting that electrocution is a stand-alone cause of death; the electrical current does not potentiate the effects of the drug. The experimental and clinical data supporting VF as the mechanism for electrocution are provided.
ABSTRACT
At the core of the aluminum (Al) ion battery is the liquid electrolyte, which governs the underlying chemistry. Optimizing the rheological properties of the electrolyte is critical to advance the state of the art. In the present work, the chloroaluminate electrolyte is made by reacting AlCl3 with a recently reported acetamidinium chloride (Acet-Cl) salt in an effort to make a more performant liquid electrolyte. Using AlCl3:Acet-Cl as a model electrolyte, we build on our previous work, which established a new method for extracting the ionic conductivity from fitting voltammetric data, and in this contribution, we validate the method across a range of measurement parameters in addition to highlighting the model electrolytes' conductivity relative to current chloroaluminate liquids. Specifically, our method allows the extraction of both the ionic conductivity and voltammetric data from a single, simple, and routine measurement. To bring these results in the context of current methods, we compare our results to two independent standard conductivity measurement techniques. Several different measurement parameters (potential scan rate, potential excursion, temperature, and composition) are examined. We find that our novel method can resolve similar trends in conductivity to conventional methods, but typically, the values are a factor of two higher. The values from our method, on the other hand, agree closely with literature values reported elsewhere. Importantly, having now established the approach for our new method, we discuss the conductivity of AlCl3:Acet-Cl-based formulations. These electrolytes provide a significant improvement (5-10× higher) over electrolytes made from similar Lewis base salts (e.g., urea or acetamide). The Lewis base salt precursors have a low economic cost compared to state-of-the-art imidazolium-based salts and are non-toxic, which is advantageous for scale-up. Overall, this is a noteworthy step at designing cost-effective and performant liquid electrolytes for Al-ion battery applications.