Identifying treatment heterogeneity in atrial fibrillation using a novel causal machine learning method.

BACKGROUND: Lifelong oral anticoagulation is recommended in patients with atrial fibrillation (AF) to prevent stroke. Over the last decade, multiple new oral anticoagulants (OACs) have expanded the number of treatment options for these patients. While population-level effectiveness of OACs has been compared, it is unclear if there is variability in benefit and risk across patient subgroups. METHODS: We analyzed claims and medical data for 34,569 patients who initiated a nonvitamin K antagonist oral anticoagulant (non-vitamin K antagonist oral anticoagulant (NOAC); apixaban, dabigatran, and rivaroxaban) or warfarin for nonvalvular AF between 08/01/2010 and 11/29/2017 from the OptumLabs Data Warehouse. A machine learning (ML) method was applied to match different OAC groups on several baseline variables including, age, sex, race, renal function, and CHA2DS2 -VASC score. A causal ML method was then used to discover patient subgroups characterizing the head-to-head treatment effects of the OACs on a primary composite outcome of ischemic stroke, intracranial hemorrhage, and all-cause mortality. RESULTS: The mean age, number of females and white race in the entire cohort of 34,569 patients were 71.2 (SD, 10.7) years, 14,916 (43.1%), and 25,051 (72.5%) respectively. During a mean follow-up of 8.3 (SD, 9.0) months, 2,110 (6.1%) of patients experienced the composite outcome, of whom 1,675 (4.8%) died. The causal ML method identified 5 subgroups with variables favoring apixaban over dabigatran; 2 subgroups favoring apixaban over rivaroxaban; 1 subgroup favoring dabigatran over rivaroxaban; and 1 subgroup favoring rivaroxaban over dabigatran in terms of risk reduction of the primary endpoint. No subgroup favored warfarin and most dabigatran vs warfarin users favored neither drug. The variables that most influenced favoring one subgroup over another included Age, history of ischemic stroke, thromboembolism, estimated glomerular filtration rate, Race, and myocardial infarction. CONCLUSIONS: Among patients with AF treated with a NOAC or warfarin, a causal ML method identified patient subgroups with differences in outcomes associated with OAC use. The findings suggest that the effects of OACs are heterogeneous across subgroups of AF patients, which could help personalize the choice of OAC. Future prospective studies are needed to better understand the clinical impact of the subgroups with respect to OAC selection.

Advances in Cardiac Electrophysiology.

Despite the global COVID-19 pandemic, during the past 2 years, there have been numerous advances in our understanding of arrhythmia mechanisms and diagnosis and in new therapies. We increased our understanding of risk factors and mechanisms of atrial arrhythmias, the prediction of atrial arrhythmias, response to treatment, and outcomes using machine learning and artificial intelligence. There have been new technologies and techniques for atrial fibrillation ablation, including pulsed field ablation. There have been new randomized trials in atrial fibrillation ablation, giving insight about rhythm control, and long-term outcomes. There have been advances in our understanding of treatment of inherited disorders such as catecholaminergic polymorphic ventricular tachycardia. We have gained new insights into the recurrence of ventricular arrhythmias in the setting of various conditions such as myocarditis and inherited cardiomyopathic disorders. Novel computational approaches may help predict occurrence of ventricular arrhythmias and localize arrhythmias to guide ablation. There are further advances in our understanding of noninvasive radiotherapy. We have increased our understanding of the role of His bundle pacing and left bundle branch area pacing to maintain synchronous ventricular activation. There have also been significant advances in the defibrillators, cardiac resynchronization therapy, remote monitoring, and infection prevention. There have been advances in our understanding of the pathways and mechanisms involved in atrial and ventricular arrhythmogenesis.

Shared Decision Making in Cardiac Electrophysiology Procedures and Arrhythmia Management.

Shared decision making (SDM) has been advocated to improve patient care, patient decision acceptance, patient-provider communication, patient motivation, adherence, and patient reported outcomes. Documentation of SDM is endorsed in several society guidelines and is a condition of reimbursement for selected cardiovascular and cardiac arrhythmia procedures. However, many clinicians argue that SDM already occurs with clinical encounter discussions or the process of obtaining informed consent and note the additional imposed workload of using and documenting decision aids without validated tools or evidence that they improve clinical outcomes. In reality, SDM is a process and can be done without decision tools, although the process may be variable. Also, SDM advocates counter that the low-risk process of SDM need not be held to the high bar of demonstrating clinical benefit and that increasing the quality of decision making should be sufficient. Our review leverages a multidisciplinary group of experts in cardiology, cardiac electrophysiology, epidemiology, and SDM, as well as a patient advocate. Our goal is to examine and assess SDM methodology, tools, and available evidence on outcomes in patients with heart rhythm disorders to help determine the value of SDM, assess its possible impact on electrophysiological procedures and cardiac arrhythmia management, better inform regulatory requirements, and identify gaps in knowledge and future needs.

World Heart Federation Roadmap on Atrial Fibrillation - A 2020 Update.

The World Heart Federation (WHF) commenced a Roadmap initiative in 2015 to reduce the global burden of cardiovascular disease and resultant burgeoning of healthcare costs. Roadmaps provide a blueprint for implementation of priority solutions for the principal cardiovascular diseases leading to death and disability. Atrial fibrillation (AF) is one of these conditions and is an increasing problem due to ageing of the world's population and an increase in cardiovascular risk factors that predispose to AF. The goal of the AF roadmap was to provide guidance on priority interventions that are feasible in multiple countries, and to identify roadblocks and potential strategies to overcome them. Since publication of the AF Roadmap in 2017, there have been many technological advances including devices and artificial intelligence for identification and prediction of unknown AF, better methods to achieve rhythm control, and widespread uptake of smartphones and apps that could facilitate new approaches to healthcare delivery and increasing community AF awareness. In addition, the World Health Organisation added the non-vitamin K antagonist oral anticoagulants (NOACs) to the Essential Medicines List, making it possible to increase advocacy for their widespread adoption as therapy to prevent stroke. These advances motivated the WHF to commission a 2020 AF Roadmap update. Three years after the original Roadmap publication, the identified barriers and solutions were judged still relevant, and progress has been slow. This 2020 Roadmap update reviews the significant changes since 2017 and identifies priority areas for achieving the goals of reducing death and disability related to AF, particularly targeted at low-middle income countries. These include advocacy to increase appreciation of the scope of the problem; plugging gaps in guideline management and prevention through physician education, increasing patient health literacy, and novel ways to increase access to integrated healthcare including mHealth and digital transformations; and greater emphasis on achieving practical solutions to national and regional entrenched barriers. Despite the advances reviewed in this update, the task will not be easy, but the health rewards of implementing solutions that are both innovative and practical will be great.

Artificial Intelligence and Machine Learning in Arrhythmias and Cardiac Electrophysiology.

Artificial intelligence (AI) and machine learning (ML) in medicine are currently areas of intense exploration, showing potential to automate human tasks and even perform tasks beyond human capabilities. Literacy and understanding of AI/ML methods are becoming increasingly important to researchers and clinicians. The first objective of this review is to provide the novice reader with literacy of AI/ML methods and provide a foundation for how one might conduct an ML study. We provide a technical overview of some of the most commonly used terms, techniques, and challenges in AI/ML studies, with reference to recent studies in cardiac electrophysiology to illustrate key points. The second objective of this review is to use examples from recent literature to discuss how AI and ML are changing clinical practice and research in cardiac electrophysiology, with emphasis on disease detection and diagnosis, prediction of patient outcomes, and novel characterization of disease. The final objective is to highlight important considerations and challenges for appropriate validation, adoption, and deployment of AI technologies into clinical practice.

Wide Complex Tachycardia Differentiation: A Reappraisal of the State-of-the-Art.

The primary goal of the initial ECG evaluation of every wide complex tachycardia is to determine whether the tachyarrhythmia has a ventricular or supraventricular origin. The answer to this question drives immediate patient care decisions, ensuing clinical workup, and long-term management strategies. Thus, the importance of arriving at the correct diagnosis cannot be understated and has naturally spurred rigorous research, which has brought forth an ever-expanding abundance of manually applied and automated methods to differentiate wide complex tachycardias. In this review, we provide an in-depth analysis of traditional and more contemporary methods to differentiate ventricular tachycardia and supraventricular wide complex tachycardia. In doing so, we: (1) review hallmark wide complex tachycardia differentiation criteria, (2) examine the conceptual and structural design of standard wide complex tachycardia differentiation methods, (3) discuss practical limitations of manually applied ECG interpretation approaches, and (4) highlight recently formulated methods designed to differentiate ventricular tachycardia and supraventricular wide complex tachycardia automatically.

Year in Review in Cardiac Electrophysiology.

In the past year, there have been numerous advances in our understanding of arrhythmia mechanisms, diagnosis, and new therapies. We have seen advances in basic cardiac electrophysiology with data suggesting that secretoneurin may be a biomarker for patients at risk of ventricular arrhythmias, and we have learned of the potential role of an NPR-C (natriuretic peptide receptor-C) in atrial fibrosis and the role of an atrial specific 2-pore potassium channel TASK-1 as a therapeutic target for atrial fibrillation. We have seen studies demonstrating the role of sensory neurons in sleep apnea-related atrial fibrillation and the association between bariatric surgery and atrial fibrillation ablation outcomes. Artificial intelligence applied to electrocardiography has yielded estimates of age, sex, and overall health. We have seen new tools for collection of patient-centered outcomes following catheter ablation. There have been significant advances in the ability to identify ventricular tachycardia termination sites through high-density mapping of deceleration zones. We have learned that right ventricular dysfunction may be a predictor of survival benefit after implantable cardioverter-defibrillator implantation in patients with nonischemic cardiomyopathy. We have seen further insights into the role of His bundle pacing on improving outcomes. As our understanding of cardiac laminopathies advances, we may have new tools to predict arrhythmic event rates in gene carriers. Finally, we have seen numerous advances in the treatment of arrhythmias in patients with congenital heart disease.

Guidance for cardiac electrophysiology during the COVID-19 pandemic from the Heart Rhythm Society COVID-19 Task Force; Electrophysiology Section of the American College of Cardiology; and the Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology, American Heart Association.

Coronavirus disease 2019 (COVID-19) is a global pandemic that is wreaking havoc on the health and economy of much of human civilization. Electrophysiologists have been impacted personally and professionally by this global catastrophe. In this joint article from representatives of the Heart Rhythm Society, the American College of Cardiology, and the American Heart Association, we identify the potential risks of exposure to patients, allied healthcare staff, industry representatives, and hospital administrators. We also describe the impact of COVID-19 on cardiac arrhythmias and methods of triage based on acuity and patient comorbidities. We provide guidance for managing invasive and noninvasive electrophysiology procedures, clinic visits, and cardiac device interrogations. In addition, we discuss resource conservation and the role of telemedicine in remote patient care along with management strategies for affected patients.

Stellate ganglion block and cardiac sympathetic denervation in patients with inappropriate sinus tachycardia.

BACKGROUND: Inappropriate sinus tachycardia (IST) remains a clinical challenge because patients often are highly symptomatic and not responsive to medical therapy. OBJECTIVE: To study the safety and efficacy of stellate ganglion (SG) block and cardiac sympathetic denervation (CSD) in patients with IST. METHODS: Twelve consecutive patients who had drug-refractory IST (10 women) were studied. According to a prospectively initiated protocol, five patients underwent an electrophysiologic study before and after SG block (electrophysiology study group). The subsequent seven patients had ambulatory Holter monitoring before and after SG block (ambulatory group). All patients underwent SG block on the right side first, and then on the left side. Selected patients who had heart rate reduction ≥15 beats per minute (bpm) were recommended to consider CSD. RESULTS: The mean (SD) baseline heart rate (HR) was 106 (21) bpm. The HR significantly decreased to 93 (20) bpm (P = .02) at 10 minutes after right SG block and remained significantly slower at 97(19) bpm at 60 minutes. Left SG block reduced HR from 99 (21) to 87(16) bpm (P = .02) at 60 minutes. SG block had no significant effect on blood pressure or HR response to isoproterenol or exercise (all P > .05). Five patients underwent right (n = 4) or bilateral (n = 1) CSD. The clinical outcomes were heterogeneous: one patient had complete and two had partial symptomatic relief, and two did not have improvement. CONCLUSION: SG blockade modestly reduces resting HR but has no significant effect on HR during exercise. Permanent CSD may have a modest role in alleviating symptoms in selected patients with IST.

Feasibility of Performing Radiofrequency Catheter Ablation and Endomyocardial Biopsy in the Same Setting.

In patients with unexplained cardiomyopathy, electroanatomical mapping can identify abnormal tissue to target during electrophysiology-guided endomyocardial biopsy (EP-guided EMB). The objective of this study is to determine whether catheter ablation performed in the same setting as EP-guided EMB increases procedural risk. Sixty-seven patients (mean age 54.4 ± 13.8, 57% male) undergoing EP-guided EMB were included. Radiofrequency catheter ablation was performed in 17 patients (25%) for ventricular arrhythmias and in 2 (3%) for typical atrial flutter. Femoral arterial access was obtained in 90% ablation patients and 40% biopsy-only patients; vascular access complications were more common in the ablation group than in the EMB-only group (p = 0.02). There were no significant differences in rate of tricuspid regurgitation, thromboembolism, or pericardial effusion, whether procedural anticoagulation was used. In conclusion, catheter ablation and procedural anticoagulation can be combined with EP-guided EMB with an increased risk of vascular access complications, but no significant increase in intracardiac complications.

Mortality and Cerebrovascular Events After Heart Rhythm Disorder Management Procedures.

BACKGROUND: Recognition of rates and causes of hard, patient-centered outcomes of death and cerebrovascular events (CVEs) after heart rhythm disorder management (HRDM) procedures is an essential step for the development of quality improvement programs in electrophysiology laboratories. Our primary aim was to assess and characterize death and CVEs (stroke or transient ischemic attack) after HRDM procedures over a 17-year period. METHODS: We performed a retrospective cohort study of all patients undergoing HRDM procedures between January 2000 and November 2016 at the Mayo Clinic. Patients from all 3 tertiary academic centers (Rochester, Phoenix, and Jacksonville) were included in the study. All in-hospital deaths and CVEs after HRDM procedures were identified and were further characterized as directly or indirectly related to the HRDM procedure. Subgroup analysis of death and CVE rates was performed for ablation, device implantation, electrophysiology study, lead extraction, and defibrillation threshold testing procedures. RESULTS: A total of 48 913 patients (age, 65.7±6.6 years; 64% male) who underwent a total of 62 065 HRDM procedures were included in the study. The overall mortality and CVE rates in the cohort were 0.36% (95% confidence interval [CI], 0.31-0.42) and 0.12% (95% CI, 0.09-0.16), respectively. Patients undergoing lead extraction had the highest overall mortality rate at 1.9% (95% CI, 1.34-2.61) and CVE rate at 0.62% (95% CI, 0.32-1.07). Among patients undergoing HRDM procedures, 48% of deaths directly related to the HDRM procedure were among patients undergoing device implantation procedures. Overall, cardiac tamponade was the most frequent direct cause of death (40%), and infection was the most common indirect cause of death (29%). The overall 30-day mortality rate was 0.76%, with the highest being in lead extraction procedures (3.08%), followed by device implantation procedures (0.94%). CONCLUSIONS: Half of the deaths directly related to an HRDM procedure were among the patients undergoing device implantation procedures, with cardiac tamponade being the most common cause of death. This highlights the importance of the development of protocols for the quick identification and management of cardiac tamponade even in procedures typically believed to be lower risk such as device implantation.

Renal Outcomes in Anticoagulated Patients With Atrial Fibrillation.

BACKGROUND: Lifelong oral anticoagulation, either with warfarin or a non-vitamin K antagonist oral anticoagulant (NOAC), is indicated for stroke prevention in most patients with atrial fibrillation (AF). Emerging evidence suggests that NOACs may be associated with better renal outcomes than warfarin. OBJECTIVES: This study aimed to compare 4 oral anticoagulant agents (apixaban, dabigatran, rivaroxaban, and warfarin) for their effects on 4 renal outcomes: ≥30% decline in estimated glomerular filtration rate (eGFR), doubling of the serum creatinine level, acute kidney injury (AKI), and kidney failure. METHODS: Using a large U.S. administrative database linked to laboratory results, the authors identified 9,769 patients with nonvalvular AF who started taking an oral anticoagulant agent between October 1, 2010 and April 30, 2016. Inverse probability of treatment weighting was used to balance more than 60 baseline characteristics among patients in the 4 drug cohorts. Cox proportional hazards regression was performed in the weighted population to compare oral anticoagulant agents. RESULTS: The cumulative risk at the end of 2 years for each outcome was 24.4%, 4.0%, 14.8%, and 1.7% for ≥30% decline in eGFR, doubling of serum creatinine, AKI, and kidney failure, respectively. When the 3 NOACs were pooled, they were associated with reduced risks of ≥30% decline in eGFR (hazard ratio [HR]: 0.77; 95% confidence interval [CI]: 0.66 to 0.89; p < 0.001), doubling of serum creatinine (HR: 0.62; 95% CI: 0.40 to 0.95; p = 0.03), and AKI (HR: 0.68; 95% CI: 0.58 to 0.81; p < 0.001) compared with warfarin. When comparing each NOAC with warfarin, dabigatran was associated with lower risks of ≥30% decline in eGFR and AKI; rivaroxaban was associated with lower risks of ≥30% decline in eGFR, doubling of serum creatinine, and AKI; however, apixaban did not have a statistically significant relationship with any of the renal outcomes. CONCLUSIONS: Renal function decline is common among patients with AF treated with oral anticoagulant agents. NOACs, particularly dabigatran and rivaroxaban, may be associated with lower risks of adverse renal outcomes than warfarin.

Effect of Ventricular Arrhythmia Ablation in Patients With Heart Mate II Left Ventricular Assist Devices: An Evaluation of Ablation Therapy.

BACKGROUND: Patients with advanced heart failure (HF) are predisposed to ventricular arrhythmias (VAs), particularly following implantation of a left ventricular assist device (LVAD). There is minimal evidence for appropriate management strategies. OBJECTIVES: This study aimed to compare the burden of VA and response to ablation performed either before or following LVAD implantation. METHODS: We created a retrospective cohort of patients who underwent both VA ablation and Heart Mate II (Thoratec, Pleasanton, CA, USA) LVAD implantation at Mayo Clinic (Rochester, MN, USA). Patients were stratified based on whether they underwent VA ablation before (pre-LVAD) or after LVAD (post-LVAD) implantation. Descriptive analyses assessed 6-month arrhythmia burden in relation to LVAD implantation and VA ablation. RESULTS: A total of 9 patients underwent both LVAD implantation and VA ablation. There were 3 and 6 patients, respectively, in the pre-LVAD and post-LVAD cohorts. Among patients in the pre-LVAD cohort, the median number of VAs tended to increase after ablation (9 vs. 72) and decreased after LVAD implantation (72 vs. 63). Similarly among patients in the post-LVAD cohort, the median burden of VAs increased after LVAD implantation (1 vs. 22) and the median burden decreased after ablation (22 vs. 13). Two of 6 patients had substrate related to the LVAD inflow cannula site, while other substrate was not related directly to the cannula. CONCLUSIONS: In patients with progressive HF and LVAD implantation, ablation is associated with reduced VA rates. In LVAD patients, most VAs arise from substrate unrelated to the inflow cannula site.

Direct Comparison of Dabigatran, Rivaroxaban, and Apixaban for Effectiveness and Safety in Nonvalvular Atrial Fibrillation.

BACKGROUND: The introduction of non-vitamin K antagonist oral anticoagulants (NOACs) has been a major advance for stroke prevention in atrial fibrillation (AF). Patients and clinicians now have a choice between different NOACs, but there is no direct comparative effectiveness evidence to guide decision-making. We aimed to compare the effectiveness and safety of dabigatran, rivaroxaban, and apixaban in clinical practice. METHODS: Using a large US administrative claims database, we created three one-to-one propensity-score-matched cohorts of patients with nonvalvular AF who were users of dabigatran, rivaroxaban, or apixaban between October 1, 2010 and February 28, 2015 (rivaroxaban vs dabigatran, n = 31,574; apixaban vs dabigatran, n = 13,084; and apixaban vs rivaroxaban, n = 13,130). The primary outcomes were stroke and systemic embolism (effectiveness) and major bleeding (safety) that occurred during treatment. Cox proportional hazards models were used to compare outcomes in propensity-score-matched cohorts. RESULTS: We found no differences between the three NOACs in the risk of stroke or systemic embolism (hazard ratio [HR], 1.00; 95% CI, 0.75-1.32 for rivaroxaban vs dabigatran; HR, 0.82; 95% CI, 0.51-1.31 for apixaban vs dabigatran; and HR, 1.05; 95% CI, 0.64-1.72 for apixaban vs rivaroxaban). Apixaban was associated with a lower risk of major bleeding (HR, 0.50; 95% CI, 0.36-0.70; P < .001 vs dabigatran and HR, 0.39; 95% CI, 0.28-0.54; P < .001 vs rivaroxaban). Rivaroxaban was associated with an increased risk of major bleeding (HR, 1.30; 95% CI, 1.10-1.53; P < .01) and intracranial bleeding (HR, 1.79; 95% CI, 1.12-2.86; P < .05) compared with dabigatran. CONCLUSIONS: Dabigatran, rivaroxaban, and apixaban appear to have similar effectiveness, although apixaban may be associated with a lower bleeding risk and rivaroxaban may be associated with an elevated bleeding risk.

Endomyocardial biopsy-integrating electrode at the bioptome tip.

BACKGROUND: The addition of electroanatomic mapping to a standard echo-guided endomyocardial biopsy could identify areas of abnormal pathology and increase the diagnostic yield of the procedure. METHODS AND RESULTS: In this demonstration of a novel technique, a 45-year-old woman with clinical suspicion for cardiac sarcoidosis underwent right ventricular bipolar electroanatomical mapping with identification of areas of signal fractionation and low voltage. A bioptome, configured to record an electrogram from the tip, was then visualized on the three-dimensional electroanatomic mapping (3DEAM) system, and directed to these areas. The biopsy was assisted by the use of a steerable introducer sheath, and by recording unipolar and extended bipolar signals from the bioptome tip. A prominent change in the signal was detected by the electrode at the bioptome tip when the jaws closed on the endomyocardial tissue. Patient tolerated the procedure without complications, and the biopsied samples were appropriate for pathological analysis. CONCLUSIONS: Using existing technology, the 3DEAM, which integrates unipolar and bipolar signal from the bioptome tip, is feasible, and can be safely added to a standard echocardiographically guided endomyocardial biopsy. Future studies should investigate whether such a technique could increase the safety and diagnostic yield of endomyocardial biopsies in patients with suspected cardiomyopathies.

A common variant near the KCNJ2 gene is associated with T-peak to T-end interval.

BACKGROUND: T-peak to T-end (TPE) interval on the electrocardiogram is a measure of myocardial dispersion of repolarization and is associated with an increased risk of ventricular arrhythmias. The genetic factors affecting the TPE interval are largely unknown. OBJECTIVE: To identify common genetic variants that affect the duration of the TPE interval in the general population. METHODS: We performed a genome-wide association study on 1870 individuals of Finnish origin participating in the Health 2000 Study. The TPE interval was measured from T-peak to T-wave end in leads II, V(2), and V(5) on resting electrocardiograms, and the mean of these TPE intervals was adjusted for age, sex, and Cornell voltage-duration product. We sought replication for a genome-wide significant result in the 3745 subjects from the Framingham Heart Study. RESULTS: We identified a locus on 17q24 that was associated with the TPE interval. The minor allele of the common variant rs7219669 was associated with a 1.8-ms shortening of the TPE interval (P = 1.1 × 10(-10)). The association was replicated in the Framingham Heart Study (-1.5 ms; P = 1.3 × 10(-4)). The overall effect estimate of rs7219669 in the 2 studies was -1.7 ms (P = 5.7 × 10(-14)). The common variant rs7219669 maps downstream of the KCNJ2 gene, in which rare mutations cause congenital long and short QT syndromes. CONCLUSION: The common variant rs7219669 is associated with the TPE interval and is thus a candidate to modify repolarization-related arrhythmia susceptibility in individuals carrying the major allele of this polymorphism.

Thermal preconditioning and heat-shock protein 72 preserve synaptic transmission during thermal stress.

As with other tissues, exposing the mammalian CNS to nonlethal heat stress (i.e., thermal preconditioning) increases levels of heat-shock proteins (Hsps) such as Hsp70 and enhances the viability of neurons under subsequent stress. Using a medullary slice preparation from a neonatal mouse, including the site of the neural network that generates respiratory rhythm (the pre-Bötzinger complex), we show that thermal preconditioning has an additional fundamental effect, protection of synaptic function. Relative to 30 degrees C baseline, initial thermal stress (40 degrees C) greatly increased the frequency of synaptic currents recorded without pharmacological manipulation by approximately 17-fold (p < 0.01) and of miniature postsynaptic currents (mPSCs) elicited by GABA (20-fold) glutamate (10-fold), and glycine (36-fold). Thermal preconditioning (15 min at 40 degrees C) eliminated the increase in frequency of overall synaptic transmission during acute thermal stress and greatly attenuated the frequency increases of GABAergic, glutamatergic, and glycinergic mPSCs (for each, p < 0.05). Moreover, without thermal preconditioning, incubation of slices in solution containing inducible Hsp70 (Hsp72) mimicked the effect of thermal preconditioning on the stress-induced release of neurotransmitter. That preconditioning and exogenous Hsp72 can affect and preserve normal physiological function has important therapeutic implications.