COVID-19-associated Brugada pattern electrocardiogram: Systematic review of case reports.

AIMS: To summarize published case reports of patients diagnosed with coronavirus disease 2019 (COVID-19) and Brugada pattern electrocardiogram (ECG). METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist were followed. A literature search was conducted using PubMed, EMBASE, and Scopus up until September 2021. The incidence, clinical characteristics, and management outcomes of COVID-19 patients with a Brugada pattern ECG were identified. RESULTS: A total of 18 cases were collected. The mean age was 47.1 years and 11.1% were women. No patients had prior confirmed diagnosis of Brugada syndrome. The most common presenting clinical symptoms were fever (83.3%), chest pain (38.8%), shortness of breath (38.8%), and syncope (16.6%). All 18 patients presented with type 1 Brugada pattern ECG. Four patients (22.2%) underwent left heart catheterization, and none demonstrated the presence of obstructive coronary disease. The most common reported therapies included antipyretics (55.5%), hydroxychloroquine (27.7%), and antibiotics (16.6%). One patient (5.5%) died during hospitalization. Three patients (16.6%) who presented with syncope received either an implantable cardioverter defibrillator or wearable cardioverter defibrillator at discharge. At follow-up, 13 patients (72.2%) had resolution of type 1 Brugada pattern ECG. CONCLUSION: COVID-19-associated Brugada pattern ECG seems relatively rare. Most patients had resolution of the ECG pattern once their symptoms have improved. Increased awareness and timely use of antipyretics is warranted in this population.

Esophageal injury associated with catheter ablation for atrial fibrillation: Determinants of risk and protective strategies.

Catheter ablation has become an important element in the management of atrial fibrillation. Several technical advances allowed for better safety profiles and lower recurrence rates, leading to an increasing number of ablations worldwide. Despite that, major complications are still reported, and esophageal thermal injury remains a significant concern as atrioesophageal fistula (AEF) is often fatal. Recognition of the mechanisms involved in the process of esophageal lesion formation and the identification of the main determinants of risk have set the grounds for the development and improvement of different esophageal protective strategies. More sensitive esophageal temperature monitoring, safer ablation parameters and catheters, and different energy sources appear to collectively reduce the risk of esophageal thermal injury. Adjunctive measures such as the prophylactic use of proton-pump inhibitors, as well as esophageal cooling or deviation devices, have emerged as complementary methods with variable but promising results. Nevertheless, as a multifactorial problem, no single esophageal protective measure has proven to be sufficiently effective to eliminate the risk, and further investigation is still warranted. Early screening in the patients at risk and prompt intervention in the cases of AEF are important risk modifiers and yield better outcomes.

Preclinical evaluation of efficacy and pharmacokinetics of gentamicin containing extracellular-matrix envelope.

BACKGROUND: Using synthetic antibiotic-eluting envelope (ABE) is an effective intervention for prevention of cardiovascular implantable electronic device (CIED) infection. The biologic extracellular-matrix envelope (ECME), may offer potential advantages over the synthetic ABE. To further minimize the risk of infection, the ECME can be hydrated in gentamicin prior to CIED implantation. We aimed to evaluate the efficacy and pharmacokinetics (PK) of gentamicin containing ECME in an animal model. METHODS: For all experiments, the ECME was hydrated in gentamicin (40 mg/Ml) (treatment) for 2 min. In vitro antimicrobial efficacy against six different bacterial species was assessed. In vivo experiments were conducted using a rabbit model of CIED pocket infection. Serum and ECM gentamicin concentrations were measured. Five different organisms were inoculated into the device pocket of control (ECME hydrated in 0.9% saline) and treatment groups. Macroscopic appearance and colony forming units from CIED, ECME, and tissue were determined. RESULTS: No bacteria were recovered from any culture after 12 h of exposure to the gentamicin containing ECME. Serum gentamicin levels dropped below the limit of quantification at 15 h after implant. Gentamicin concentration in the ECME remained relatively stable for up to 7 days. Signs of clinical infection were observed in the control but not in the treatment group. In the presence of gentamicin, statistically significant reduction was demonstrated across all tested bacterial species. CONCLUSIONS: In this preclinical animal infection model, gentamicin containing ECME was highly effective in reducing bacterial burden in the implant pocket, while systemic exposure after implantation remained low.

Failed Maximal Defibrillation Threshold Testing in the Subcutaneous Implantable Cardioverter Defibrillator.

The subcutaneous implantable cardioverter defibrillator (S-ICD) registry included very few patients with a body mass index (BMI) greater than 40. We present a case of a 40-year-old male with a BMI of 44 and ejection fraction of 25% who underwent S-ICD implantation for primary prevention of sudden cardiac death in the setting of a nonischemic cardiomyopathy. Defibrillation threshold (DFT) testing failed at high output. A posterior to anterior radiograph demonstrated migration of the components despite positioning under fluoroscopy. After repositioning, repeat DFT testing showed an inconsistent efficacy. We discuss the probabilistic nature of DFT testing, clinical factors affecting the S-ICD implant in the obese population and offer a novel insight from this specific experience.

MRI Evaluation of Radiofrequency, Cryothermal, and Laser Left Atrial Lesion Formation in Patients with Atrial Fibrillation.

BACKGROUND:  Catheter ablation utilizing radiofrequency (RF), Cryothermal (Cryo), or Laser energy is effective for treatment of atrial fibrillation (AF). Late gadolinium enhancement magnetic resonance imaging (LGE-MRI) has been used to estimate the burden of left atrial (LA) fibrosis, but no data exist regarding structural changes following each modality. We sought to compare the baseline to postprocedure change in LA scar burden following RF, Cryo, or Laser ablation for treatment of AF. METHODS: Seventeen patients with AF underwent initial pulmonary vein (PV) isolation (PVI) using RF (n = 7), Cryo (n = 5), and Laser (n = 5). LGE-MRI was performed prior to and at 24 hours and 3 months after PVI. RESULTS: In a linear mixed-effects model, accounting for intrapatient clustering of data and interpatient differences in baseline scar, LGE extent was significantly increased at 24 hours postablation (+14.6 ± 1.9% of LA myocardium, P < 0.001), and remained stable from 24 hours to 3 months (+0.12 ± 1.9%, P = 0.951). There was no statistically significant difference between the postablation scar extent among ablation modalities when compared to RF (Cryo +4.5 ± 3.0%, P = 0.123; Laser -3.2 ± 3.0%, P = 0.291). The PV antral LGE intensity was increased by 25.1 ± 3.8% (P<0.001) 24 hours after ablation and additionally increased by 8.1 ± 3.8 at 3 months (P = 0.033). CONCLUSIONS: Radiofrequency, Cryo, and laser ablation result in increased LGE extent and intensity at 24 hours and 3 months postablation. No statistically significant difference was noted in the extent of fibrosis induced by any modality.

Hormonal changes as a potential cause for monthly fluid status variation as indicated by intrathoracic impedance.

Early detection of decompensated heart failure enables clinicians to tailor medical therapy to individual patient needs. The utility of transthoracic impedance assessment in the early diagnosis of volume overload has been documented in the literature. We describe the case of a young woman without congestive heart failure who was noted to have cyclical variations of transthoracic impedances that correlated with her menstrual cycle and discuss other factors that may confound proper diagnosis of volume overload in patients with implantable cardioverter-defibrillators.

Comparing the Efficacy of Targeted and Blast Portal Messaging in Message Opening Rate and Anticoagulation Initiation in Patients With Atrial Fibrillation in the Preventing Preventable Strokes Study II: Prospective Cohort Study.

BACKGROUND: The gap in anticoagulation use among patients with atrial fibrillation (AF) is a major public health threat. Inadequate patient education contributes to this gap. Patient portal-based messaging linked to educational materials may help bridge this gap, but the most effective messaging approach is unknown. OBJECTIVE: This study aims to compare the responsiveness of patients with AF to an AF or anticoagulation educational message between 2 portal messaging approaches: sending messages targeted at patients with upcoming outpatient appointments 1 week before their scheduled appointment (targeted) versus sending messages to all eligible patients in 1 blast, regardless of appointment scheduling status (blast), at 2 different health systems: the University of Massachusetts Chan Medical School (UMass) and the University of Florida College of Medicine-Jacksonville (UFL). METHODS: Using the 2 approaches, we sent patient portal messages to patients with AF and grouped patients by high-risk patients on anticoagulation (group 1), high-risk patients off anticoagulation (group 2), and low-risk patients who may become eligible for anticoagulation in the future (group 3). Risk was classified based on the congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke, vascular disease, age between 65 and 74 years, and sex category (CHA2DS2-VASc) score. The messages contained a link to the Upbeat website of the Heart Rhythm Society, which displays print and video materials about AF and anticoagulation. We then tracked message opening, review of the website, anticoagulation use, and administered patient surveys across messaging approaches and sites using Epic Systems (Epic Systems Corporation) electronic health record data and Google website traffic analytics. We then conducted chi-square tests to compare potential differences in the proportion of patients opening messages and other evaluation metrics, adjusting for potential confounders. All statistical analyses were performed in SAS (version 9.4; SAS Institute). RESULTS: We sent 1686 targeted messages and 1450 blast messages. Message opening was significantly higher with the targeted approach for patients on anticoagulation (723/1156, 62.5% vs 382/668, 57.2%; P=.005) and trended the same in patients off anticoagulation; subsequent website reviews did not differ by messaging approach. More patients off anticoagulation at baseline started anticoagulation with the targeted approach than the blast approach (adjusted percentage 9.3% vs 2.1%; P<.001). CONCLUSIONS: Patients were more responsive in terms of message opening and subsequent anticoagulation initiation with the targeted approach.

Phrenic nerve injury: An underrecognized and potentially preventable complication of pulmonary vein isolation using a wide-area circumferential ablation approach.

INTRODUCTION: Phrenic nerve injury (PNI) is a well-known, although uncommon, complication of pulmonary vein isolation (PVI) using radiofrequency energy. Currently, there is no consensus about how to avoid or minimize this injury. The purpose of this study was to determine how often the phrenic nerve, as identified using a high-output pacing, lies along the ablation trajectory of a wide-area circumferential lesion set. We also sought to determine if PVI can be achieved without phrenic nerve injury by modifying the ablation lesion set so as to avoid those areas where phrenic nerve capture (PNC) is observed. METHODS AND RESULTS: We prospectively enrolled 100 consecutive patients (age 61.7 ± 9.2 years old, 75 men) who underwent RF PVI using a wide-area circumferential ablation approach. A high-output (20 mA at 2 milliseconds) endocardial pacing protocol was performed around the right pulmonary veins and the carina where a usual ablation lesion set would be made. A total of 30% of patients had PNC and required modification of ablation lines. In the group of patients with PNC, the carina was the most common site of capture (85%) followed by anterior right superior pulmonary vein (RSPV) (70%) and anterior right inferior pulmonary vein (RIPV) (30%). A total of 25% of PNC group had capture in all 3 (RSPV, RIPV, and carina) regions. There was no difference in the clinical characteristics between the groups with and without PNC. RF PVI caused no PNI in either group. CONCLUSION: High output pacing around the right pulmonary veins and the carina reveals that the phrenic nerve lies along a wide-area circumferential ablation trajectory in 30% of patients. Modification of ablation lines to avoid these sites may prevent phrenic nerve injury during RF PVI.

High-Risk Apical Hypertrophic Cardiomyopathy Requiring an Implantable Cardioverter-Defibrillator: A Case Report of an Overlooked Etiology.

Apical hypertrophic cardiomyopathy is a rare variant of hypertrophic cardiomyopathy characterized by abnormal heart muscle thickening, specifically affecting the left ventricle's apex. Classically revealing both giant T-wave inversions in the precordial leads of an electrocardiogram and a spade-like configuration of the left ventricular cavity on ventriculograms, the diagnosis of the apical variant has evolved with cardiac magnetic resonance imaging. Despite being well known among East Asian populations, the diagnosis of apical hypertrophic cardiomyopathy is often underestimated and overlooked among American patients due to the non-specific nature of echocardiography. In this case report, we present the diagnosis of apical hypertrophic cardiomyopathy in a middle-aged African American male with chronic palpitations. The diagnosis was confirmed using cardiac magnetic resonance imaging, which revealed extensive myocardial fibrosis. Ultimately, the patient was treated with an implantable cardioverter-defibrillator. Our case aims to enhance the understanding and facilitate the recognition and management of apical hypertrophic cardiomyopathy, particularly among non-Asian individuals. Current challenges revolve around robust risk stratification strategies for patients at high risk for sudden cardiac death that require device therapy.

A Case of Sick Sinus Syndrome With Prolonged Asystole Masquerading as a Transient Ischemic Attack.

Sick sinus syndrome (SSS) is a term used to describe dysfunction of the sinoatrial (SA) node that can lead to various cardiac arrhythmias that predominately manifest in the elderly. Commonly implicated arrhythmias vary from inappropriate bradycardia, tachycardia, sinus pauses, and rarely sinus arrest. Despite being a common reason for permanent pacemaker implantation, little is known regarding the incidence of SSS and there is even less reporting on SSS complicated by prolonged asystole. We present a case highlighting an infrequently observed manifestation of SSS with recurrent, prolonged ventricular asystolic episodes that were causing previously unexplained episodes of confusion and agonal breathing. Our patient was a 75-year-old male with a past medical history of hypertension, dyslipidemia, and prior transient ischemic attacks (TIAs) that presented after an acute mental status change. The initial leading differential diagnosis was believed to be a TIA and he was admitted to neurology service for further evaluation. The patient had recurring episodes of confusion associated with agonal breathing that upon closer review of the cardiac telemetry revealed sinus bradycardia to the 40s interrupted by several prolonged episodes of asystole, the longest lasting 20 seconds. Due to his symptoms and to avoid potential deterioration resulting in hemodynamic instability, the electrophysiology service urgently placed a temporary transvenous pacemaker and then later implanted a leadless pacemaker. On outpatient follow-up, he no longer had episodes of confusion, and no further asystolic episodes were noted on his device check.

Recovery of Transient High-Grade Atrioventricular Block Managed With Corticosteroid Therapy Without Device Implantation in Newly Diagnosed Cardiac Sarcoidosis: A Case Report.

Atrioventricular blocks (AVBs) presenting in cardiac sarcoidosis (CS) remain an ongoing challenge for clinicians. While most initiate immunosuppressive therapy with the goal of pursuing device implantation, there is some ambiguity as to which patient cohorts actually benefit from device therapy. We present a case of a 39-year-old African American male with a past medical history of hypertension and no prior cardiac history who presented with substernal chest pain in the setting of a hypertensive emergency. He was later diagnosed with cardiac sarcoidosis by cardiac magnetic resonance imaging. His hospital course was complicated by transient Mobitz II atrioventricular block. He was started on prednisone, and while initially scheduled for an implantable cardioverter-defibrillator (ICD), his conduction block recovered. Through a multidisciplinary approach, the patient was discharged on medical management with outpatient follow-up. Since his initial hospitalization, the patient has not had any concerning cardiovascular events over the past year and has not been treated with device therapy. Our case illustrates the feasibility of effectively managing patients with cardiac sarcoidosis presenting with transient atrioventricular blocks only with corticosteroid therapy without needing device implantation.

SOLVx therapeutics vaccine - Activate T-cell immunity using broad surveillance epitope strategy against mutant strains SARS-COV2.

Highly mutable Coronavirus-19 continuously reconstructs its genome and renders prophylactic vaccines ineffective. The objective of the present study was to demonstrate the anti-viral efficacy and safety of the SOLVx therapeutics vaccine. The peptides were designed with Neo7Logix R&D and synthesized with Genescript GLP laboratory with 95 % purity. BALB/C mice were used to develop the HCoV-229E mutant coronavirus model and viral mRNA confirmation in the lung tissue was assessed with qPCR. Mice were euthanized and effects of treatment on various parameters (Viral mRNA in lungs, cytokine levels, PBMC differentiation, hematological and biochemical) were assessed with respective biological samples. Immuno-typing analysis of PBMCs by flowcytometry showed marked increase in T cell subsets, % of B cells and NK cell population in mice treated with SOLVx (Series 1) in a dose dependent manner. Serum immunoglobulin G, and M levels were increased significantly (P < 0.001). In the peptide treatment groups, there was a dose dependent statistically significant decrease in IL-6, IL-10 and TNF-α levels (P < 0.001). IFN-γ was elevated in treatment group significantly (P < 0.001). In conclusion, the qPCR results suggested that the SOLVx vaccine (Series 1) reduced the SARS-COV2 virus infectivity in a dose dependent manner. The humoral, cellular and functional activity of the SOLVx showed that it worked through multi-mechanistic targeting the virus evolution, offering immune response, defense and eradication of the SARS-COV2 virus.

Physician antibiotic hydration preferences for biologic antibacterial envelopes during cardiac implantable device procedures.

Background: Cardiac implantable electronic device (CIED) infection is a potentially serious complication of CIED procedures. Infection risk mitigation includes using guideline-recommended pre-operative intravenous antibacterial prophylaxis (IV ABX). The use of antibiotic-eluting CIED envelopes has also been shown to reduce infection risk. The relationship between and potential benefits associated with guideline-recommended IV ABX in combination with antibacterial envelopes have not been characterized. Methods: Biologic envelopes made from non-crosslinked extracellular matrix (ECM) were implanted into 1,102 patients receiving CIEDs. The implanting physician decided patient selection for using a biologic envelope and envelope hydration solution. Observational data was analyzed on IV ABX utilization rates, antibacterial envelope usage, and infection outcomes. Results: Overall compliance with IV ABX was 96.6%, and most patients received a biologic envelope hydrated in antibiotics (77.1%). After a mean follow-up of 223 days, infection rates were higher for sites using IV ABX <80% of the time vs. sites using ≥80% (5.6% vs. 0.8%, p = 0.008). Physicians demonstrated preference for hydration solutions containing gentamicin in higher-risk patients, which was found by multivariate analysis to be associated with a threefold reduction in infection risk (OR 3.0, 95% CI, 1.0-10.0). Conclusion: These findings suggest that use of antibiotics, particularly gentamicin, in biologic envelope hydration solution may reduce infection risk, and use of antibacterial envelopes without adjunct IV ABX may not be sufficient to reduce CIED infections. Clinical trial registration: [https://clinicaltrials.gov/], identifier [NCT02530970].

Effects of opioid receptor agonist and antagonist medications on electrocardiogram changes and presentation of cardiac arrhythmia: review article.

BACKGROUND/PURPOSE: Mortality associated with prescription opioids has significantly increased over the past few decades and is considered a global pandemic. Prescribed opioids can cause cardiac arrhythmias, leading to fatal outcomes and unexpected death, even in the absence of structural cardiac disease. Despite the extent of cardiac toxicity and death associated with these medications, there is limited data to suggest their influences on cardiac electrophysiology and arrhythmias, with the exception of methadone. The goal of our review is to describe the possible mechanisms and to review the different ECG changes and arrhythmias that have been reported. METHODS: A literature search was performed using Google Scholar, PubMed, Springer, Ovid, and Science Direct to identify studies that demonstrated the use of prescription opioids leading to electrocardiogram (ECG) changes and cardiac arrhythmias. RESULTS: Many of the commonly prescribed opioid medications can uniquely effect the ECG, and can lead to the development of various cardiac arrhythmias. One of the most significant side effects of these drugs is QTc interval prolongation, especially when administered to patients with a baseline risk for QTc prolongation. A prolonged QTc interval can cause lethal torsades de pointes and ventricular fibrillation. Obtaining an ECG at baseline, following a dosage increase, or after switching an opioid medication, is appropriate in patients taking certain prescribed opioids. Opioids are often used first line for the treatment of acute and chronic pain, procedural sedation, medication opioid use disorders, and maintenance therapy. CONCLUSIONS: To reduce the risk of cardiac arrhythmias and to improve patient outcomes, consideration of accurate patient selection, concomitant medications, electrolyte monitoring, and vigilant ECG monitoring should be considered.

Preventing preventable strokes: A study protocol to push guideline-driven atrial fibrillation patient education via patient portal.

Background: The main approach to preventing stroke in patients with atrial fibrillation (AF) is anticoagulation (AC), but only about 60% of at-risk individuals are on AC. Patient-facing electronic health record-based interventions have produced mixed results. Little is known about the impact of health portal-based messaging on AC use. Objective: The purpose of this study was describe a protocol we will use to measure the association between AC use and patient portal message opening. We also will measure patient attitudes toward education materials housed on a professional society Web site. Methods: We will send portal messages to patients aged ≥18 years with AF 1 week before an office/teleconference visit with a primary care or cardiology provider. The message will be customized for 3 groups of patients: those on AC; those at elevated risk but off AC; and those not currently at risk but may be at risk in the future. Within the message, we will embed a link to UpBeat.org, a Web site of the Heart Rhythm Society containing patient educational materials. We also will embed a link to a survey. Among other things, the survey will request patients to rate their attitude toward the Heart Rhythm Society Web pages. To measure the effectiveness of the intervention, we will track AC use and its association with message opening, adjusting for potential confounders. Conclusion: If we detect an increase in AC use correlates with message opening, we will be well positioned to conduct a future comparative effectiveness trial. If patients rate the UpBeat.org materials highly, patients from other institutions also may benefit from receiving these materials.

Novel oscillatory mechanisms in the cholinergic control of Guinea pig sino-atrial node discharge.

UNLABELLED: Oscillatory Mechanisms in Sinus Node Cholinergic Control. INTRODUCTION: The role of the oscillatory after-potential V(os) and pre-potential ThV(os) in cholinergic control of discharge was studied in sino-atrial node (SAN). METHODS AND RESULTS: A microelectrode technique was used in isolated guinea-pig SAN superfused in vitro in high [K(+) ](o) to visualize V(os) and ThV(os) . The cholinergic agonist carbachol (CCh) decreased the amplitude and slope of V(os) and ThV(os) at a time when there was no increase in maximum diastolic potential. The slowing in SAN rate was due to slower and smaller ThV(os) that missed intermittently the threshold and occurred gradually later in diastole, but not to a decrease in the intrinsic rate of ThV(os) . Eventually, quiescence followed. Larger CCh concentrations quickly induced a hyperpolarization that altogether prevented the occurrence of oscillatory potentials. During CCh washout, ThV(os) reappeared and consistently reinitiated discharge. Lower [Ca(2+) ](o) also decreased slopes and amplitude of V(os) and ThV(os) , thereby slowing and stopping SAN discharge, as CCh did. Overdrive temporarily offset the negative chronotropic effects of CCh and of low [Ca(2+) ](o.) Cesium (a blocker of hyperpolarization-activated current I(f) ) did not abolish CCh inhibitory effects on oscillatory potentials. CONCLUSIONS: The cholinergic agonist CCh: (1) slows SAN discharge by decreasing the amplitude of V(os) and ThV(os) , but not the rate of ThV(os) ; (2) can cause hyperpolarization that altogether suppresses the oscillatory potentials; (3) is mimicked in its effects by low [Ca(2+) ](o) ; (4) is antagonized by procedures that increase cellular calcium; and (5) modifies the oscillatory potentials independently of I(f) .

Late massive radial artery pseudoaneurysm following cardiac catheterization: A case report.

INTRODUCTION: Transradial artery approach for cardiac catheterization was first introduced in the late 1980s and has now become the approach of choice due to its anatomical advantage, reduction in complications, and overall improved patient experience. CASE PRESENTATION: We present a case of a 77 year-old female who presented with an extremely rare and late complication of radial artery pseudoaneurysm after transradial coronary intervention. The patient presented at a post-procedural follow-up with severe pain at the radial access site and was found to have a partially thrombosed pseudoaneurysm. Given the anatomical variance of the pseudoaneurysm, the patient underwent successful open surgical repair. CLINICAL DISCUSSION: Although radial artery access is a relatively safe approach in comparison to the transfemoral approach, the risk of adverse events still exists. Among the complications of the transradial approach, pseudoaneurysms are relatively rare, occurring in less than 0.1% of cases. Regardless, early identification of this complication is essential to timely intervention. CONCLUSION: Our case highlights the importance of post procedural monitoring and early identification and diagnosis of the complication to facilitate appropriate therapy.

Proarrhythmic Manifestations of Neuromuscular Dystrophinopathies.

Muscular dystrophy has been an elusive term ever since it was first described in the 19th century. Introduced in 1891 by Wilhelm Heinrich Erb, muscular dystrophy has been classified as part of a larger group of genetically determined, progressive degenerative neuromuscular disorders termed "dystrophinopathies." Cardiac arrhythmias may occur during the neurologic course of the disease. Although descriptions of the dystrophinopathies have been reported in the literature, few articles address the use of antiarrhythmic pharmacotherapy in patients with muscular dystrophy. We discuss the pathophysiology of the most common dystrophinopathies, their proarrhythmic sequelae, and the therapeutic use of antiarrhythmic agents in the clinical setting.